Chapter 55. Treatment of Schizophrenia

Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

1 of 51

10/05/2009 16:35

Print Close Window

Tsung-Ung W. Woo, Carla M. Canuso, Joanne D. Wojcik, Mary F. Brunette, Alan I. Green: Chapter 55. Treatment of

Schizophrenia, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F.

Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI:

10.1176/appi.books.9781585623860.423569. Printed 5/10/2009 from www.psychiatryonline.com

Textbook of Psychopharmacology >

Chapter 55. Treatment of Schizophrenia

TREATMENT OF SCHIZOPHRENIA: INTRODUCTION

Schizophrenia is a debilitating brain disorder characterized by a chronic relapsing and remitting

course of psychosis that is superimposed on persistent “deficit” features such as cognitive

dysfunction and negative symptoms. It appears to be equally prevalent across geographical and

cultural boundaries (see Jablensky et al. 1992), afflicting approximately 1% of the population

(Perala et al. 2007).

The etiology and pathophysiology of schizophrenia remain poorly understood, but the importance of

genetic factors is consistently supported by twin (Gottesman 1991; Kendler 1983), family

(Gottesman 1991; Kendler 1983; Tsuang et al. 1980), and adoption (Kety et al. 1964, 1994)

studies. In the past few years, a number of genes have been identified as being associated with

schizophrenia. Furthermore, intensive research has focused on trying to understand how these

candidate genes may play a role in the pathophysiology of schizophrenia (G. Harrison 2004; P. J.

Harrison and Owen 2003; Porteous et al. 2006; Stefansson et al. 2004). Although the heritability of

schizophrenia is high, it appears that environmental events, such as stress (Moghaddam and

Jackson 2004), or epigenetic factors (E. Costa et al. 2003, 2006; Tsankova et al. 2007) also play an

important role in modulating the expression of the disease genes and, therefore, in the

development of particular schizophrenia phenotypes. This notion is highlighted by the observation

that the concordance rate for schizophrenia in monozygotic twins is far less than 100%; it usually

lies between 46% and 53% (Gottesman 1991). The environmental factors that have been

suggested to contribute to the pathophysiology of schizophrenia include in utero virus (Browne et

1. 2000; Buka et al. 2001; Mednick et al. 1988), toxoplasmosis (Dickerson et al. 2007; Hinze-Selch

et al. 2007; Mortensen et al. 2007), malnutrition (A. S. Brown et al. 1996), cannabis use (Macleod

et al. 2006), and obstetric or perinatal complications (Cannon 1997; Cannon et al. 2000; Geddes

and Lawrie 1995). Although significant progress has been made in recent years toward

understanding the neural basis of schizophrenia, the exact cascade of events—for example, how

interactions between genes and environmental factors lead to the emergence of the illness—has yet

to be elucidated (Ross et al. 2006; Tsankova et al. 2007; Weinberger 1996).

Considerable progress has been made in the pharmacological treatment of schizophrenia since the

serendipitous discovery in the early 1950s of chlorpromazine as the first effective antipsychotic

medication (Lehmann and Hanrahan 1954). Many other antipsychotic agents, all sharing

chlorpromazine’s dopamine D2 receptor–blocking ability, were subsequently developed. These

“conventional,” or first-generation, antipsychotics are all effective in the treatment of positive

symptoms of psychosis, but they all have limited beneficial effects on negative symptoms and

cognitive deficits. Furthermore, these first-generation agents commonly produce extrapyramidal

side effects (EPS), including parkinsonism, akathisia, and tardive dyskinesia.

Since 1990, a second generation of antipsychotic drugs has become available in the United States.

These second-generation agents are also commonly referred to as “atypical” or “novel”

antipsychotics, largely because of their reduced propensity, compared with the conventional

agents, to cause EPS. It has been postulated that this unique property (i.e., the low risk of EPS)

may reflect the potent serotonin2A (5-HT2A) receptor antagonistic effects or, more specifically, the

high ratio of 5-HT2A to D2 receptor occupancy of these drugs (Meltzer 1989). More recently, it has

been proposed that the rapid dissociation (high dissociation constant) of these drugs from D2Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

2 of 51

10/05/2009 16:35

receptors may be another very important pharmacological property that determines “atypicality”

(Kapur and Remington 2001; Seeman 2002).

With the introduction and widespread use of the second-generation antipsychotics, the focus of

treatment has been gradually expanding beyond targeting psychotic or positive symptoms of the

illness alone. Second-generation agents have been reported to improve some aspects of negative

symptoms and cognitive impairment—elements of the disorder not typically responsive to

first-generation antipsychotics, at least the high-potency ones (see below). An ability to ameliorate

cognitive deficits, in particular, would be important, because such deficits have been found to be

strong predictors of long-term functional outcome of the illness (M. F. Green 1996; M. F. Green and

Nuechterlein 1999). In fact, development of compounds that can improve cognition has rapidly

become one of the main foci in schizophrenia research in just the past few years (Fenton et al.

2003; Hyman and Fenton 2003; Marder 2006).

It should be stressed, however, as will be elaborated in this chapter, that although some of the data

on the efficacy of second-generation antipsychotics in the treatment of negative symptoms and

cognitive impairment are encouraging, they are by no means conclusive. It may be that rational

development of yet newer drugs with novel mechanisms may be necessary before negative

symptoms and cognitive deficits can be treated in a clinically meaningful manner (Carpenter and

Gold 2002; M. F. Green 2002). This drug discovery and development process is likely to rely

critically on an improved understanding of the neurobiological basis of both negative symptoms and

cognitive deficits.

In recent years, the field has developed a focused interest in early diagnosis and early intervention

in patients who are just becoming psychotic. Studies are under way to determine whether it is

possible to delay or even prevent the emergence of psychosis. In the years to come, it is likely that

this emphasis on early intervention will expand with further research on the treatment of

prodromal states, in an attempt to improve the overall course or perhaps even prevent the actual

onset of overt illness in individuals who appear likely to develop schizophrenia.

[The authors would like to acknowledge the contribution of Holly L.L. Pierce in the preparation of

this chapter.]

CLINICAL MANIFESTATIONS OF SCHIZOPHRENIA

There is a growing consensus, following the seminal work of several investigators (e.g., Andreasen

1985; Crow 1985), that schizophrenia can be conceptualized as a disorder with at least two more or

less orthogonal dimensions of symptomatology: positive and negative symptoms. Positive, or

psychotic, symptoms usually are the symptoms that first trigger psychiatric attention, and

traditionally, the onset of schizophrenia is clinically synonymous with the emergence of overt

psychosis. This concept, however, is gradually changing, because accumulating evidence indicates

that the schizophrenia disease process probably begins long before the onset of psychosis. For

example, existing evidence from animal studies suggests that brain insults occurring during the

first trimester of pregnancy and/or during the perinatal period could have late-occurring

detrimental effects on the normal functioning of the brain (Bertolino et al. 2002; D. A. Lewis and

Levitt 2002; O’Donnell et al. 2002; Waddington et al. 1998; Weinberger 1987). Interestingly, subtle

neurological abnormalities, as well as intellectual and cognitive difficulties, have been observed in

children who later show symptoms of schizophrenia (Walker et al. 1999). Finally, research suggests

that patients begin to experience a gradual decline in their level of social and cognitive functioning

for a period of up to 5 years before the onset of overt psychosis. During this time, they

characteristically have symptoms that are similar to the negative symptoms of schizophrenia

(Cannon et al. 2007; Hafner et al. 1994, 1999; Yung and McGorry 1996b). Furthermore, it appears

that during this prodromal stage of the illness, several regions of the cerebral cortex undergo

pronounced volumetric reduction (Borgwardt et al. 2007; Pantelis et al. 2003).

Positive Symptoms

Positive symptoms are perceptual or cognitive features that “normal” individuals usually do notPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

3 of 51

10/05/2009 16:35

experience. They include hallucinations, delusions, and disorganized thinking, although

disorganization also can be conceptualized as an independent symptom dimension (Liddle et al.

1989). As a general rule, positive symptoms tend to respond to treatment with antipsychotic

medications; traditionally, they have been the focus of treatment with these medications. Although

positive symptoms are dramatic, and while in the midst of them, patients’ ability to function is

usually severely disrupted, studies have quite consistently shown that such symptoms do not

appear to bear any significant association with or predict the long-term functional outcome of the

illness (M. F. Green et al. 2000). It also should be emphasized that psychotic symptoms are not

specific to schizophrenia; they can occur in a wide spectrum of other psychiatric, neurological, and

medical disorders. Therefore, it is essential to rule out other possible causes of psychosis before a

diagnosis of schizophrenia is made.

Negative Symptoms

Negative symptoms represent a “loss” of functions or abilities that people without schizophrenia

normally possess. They include anhedonia, affective flattening, alogia, avolition, and asociality.

Negative symptoms are somewhat associated with intellectual and neurocognitive impairment

(Dickerson et al. 1996; Harvey et al. 1998), and they are better predictors of long-term functional

outcome and psychosocial functioning of schizophrenia patients than are positive symptoms

(Buchanan et al. 1994; Dickerson et al. 1996; Harvey and Keefe 1998). However, neurocognitive

deficits, as discussed below, remain the strongest predictors of outcome (M. F. Green 1996). As

mentioned above, negative symptoms may have developed long before the actual “onset” of the

illness (Hafner et al. 1994, 1999; Yung and McGorry 1996b), which is traditionally defined as the

beginning of psychosis. In fact, many prodromal symptoms of schizophrenia may be

phenomenologically indistinguishable from negative symptoms. Importantly, EPS produced by

antipsychotic medications can sometimes resemble negative symptoms of schizophrenia.

To clarify matters, the concepts of primary versus secondary negative symptoms have been

introduced (Carpenter et al. 1988). Thus, primary negative symptoms represent the core negative

symptoms reflecting the schizophrenia disease process. Secondary negative symptoms, on the

other hand, may resemble primary negative symptoms, but they are caused by or are secondary to

positive symptoms of psychosis or the antipsychotic medications themselves. This distinction has

important treatment implications. For example, a reduction in medication dosage may alleviate

some secondary negative symptoms, but this strategy is unlikely to have a beneficial effect on

primary negative symptoms.

DIAGNOSIS OF SCHIZOPHRENIA

According to DSM-IV-TR (American Psychiatric Association 2000), to make the diagnosis of

schizophrenia, there must be evidence of continuous symptomatic disturbance for at least 6 months

accompanied by a decline from the premorbid level of functioning. Thus, in line with the

Kraepelinian concept (Kraepelin 1919/1971), DSM-IV-TR emphasizes the longitudinal course of

deterioration of the illness. This 6-month period can include functional deterioration occurring

during the prodromal phase before the onset of overt psychosis. Within the 6-month period, the

patient must have two or more of the following symptoms for at least 1 month: delusions,

hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative

symptoms. If the duration of psychotic symptoms is less than 1 month because of successful

treatment with antipsychotic medication, a diagnosis of schizophrenia still may be made. Of course,

before the diagnosis of schizophrenia is made, other medical or psychiatric conditions need to be

considered and ruled out.

NEUROCOGNITIVE DEFICITS IN SCHIZOPHRENIA

In the early Kraepelinian formulation of schizophrenia (or dementia praecox), cognitive

impairments represented core deficits (Kraepelin 1919/1971). This Kraepelinian concept was

somewhat displaced by an emphasis on psychotic symptoms in the diagnosis and treatment of

schizophrenia until recently, when the field of schizophrenia research witnessed substantial

resurgence of interest in neurocognitive dysfunction in schizophrenia. Research on cognition mayPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

4 of 51

10/05/2009 16:35

facilitate the identification of endophenotypes (i.e., genetic traits) of schizophrenia and also may

have significant treatment implications: cognitive deficits are strong predictors of long-term

functional outcome of patients with schizophrenia, and unfortunately, they are also among the

features that are most resistant to treatment (M. F. Green 1996; M. F. Green et al. 2000). Further

research on cognitive deficits may result in the development of more effective pharmacological,

cognitive, and psychosocial interventions in the management and perhaps treatment of these

deficits.

Schizophrenia appears to be associated with a decline in general cognitive function at some point

during the course of the illness. Various studies have shown that this decline may either predate

the onset of psychosis (Aylward et al. 1984; David et al. 1997; Nelson et al. 1990; Russell et al.

1997; Simon et al. 2007) or occur concurrently with or subsequent to the first psychotic episode

(Nelson et al. 1990). It appears that after this initial decline, the level of cognitive impairment

follows a relatively stable course for several decades without evidence of further significant

deterioration (Elvevag and Goldberg 2000; Goldberg et al. 1993). Several aspects of cognitive

impairment that are well documented in schizophrenia are briefly discussed below.

Verbal Declarative Memory

Among the cognitive functions that are known to be disturbed in schizophrenia, verbal declarative

memory impairment, which can be manifested as disturbances in the encoding, storage, and

retrieval of mnemonic items, is one of the most consistent findings. It also represents one of the

most severe deficits (Saykin et al. 1991, 1994) that is independent of other cognitive impairment,

such as attentional deficits. Memory impairment may represent a core feature of the illness (Saykin

et al. 1991), one that is stable over time and relatively independent of clinical course (Censits et al.

1997; Gur et al. 1998). It does not appear to be an artifact of antipsychotic medications because

memory impairment occurs in drug-naive first-episode patients (Saykin et al. 1994). In addition, it

also occurs in otherwise psychiatrically healthy close relatives of schizophrenia patients (Toomey et

1. 1998), suggesting that verbal memory impairment may be an endophenotype of schizophrenia.

Interestingly, an association between the degree of memory impairment and the severity of

negative symptoms has been found (Harvey et al. 1998; Zakzanis 1998). Like memory deficits,

negative symptoms also appear to be quite resistant to treatment and are relatively stable during

the course of the illness. Thus, memory impairment and negative symptoms in schizophrenia may

involve a shared neuroanatomical substrate. Because memory function is largely mediated by

medial temporal structures and negative symptoms are generally associated with prefrontal

deficits, information-processing disturbances between the prefrontal and the temporal cortices may

represent a prominent feature of schizophrenia (Gur et al. 1998; Heckers et al. 1998).

Working Memory

Working memory is the ability to hold information on-line when other perceptual, cognitive, or

mnemonic information is not immediately present in order to guide future behavior and action

(Baddeley 1986). This function is mediated by a neural system of which the prefrontal cortex is a

key component (Goldman-Rakic 1996). There have been robust findings of impaired performance of

schizophrenic patients on tasks that tap working memory (Park and Holzman 1992), impairments

that do not appear to be caused by antipsychotic medications (Goldberg and Weinberger 1996). The

fact that working memory impairment is also observed in many first-degree relatives of patients

with schizophrenia (Park et al. 1995) suggests that this feature, like verbal declarative memory

deficits, may conceivably represent an endophenotype of the illness. Finally, working memory has

been extensively studied in nonhuman primates, and the neural elements that support working

memory are relatively well understood (Fuster 2000; Goldman-Rakic 1996). Interestingly,

postmortem studies have found that many of these neural elements appear to be disturbed in

schizophrenia (D. A. Lewis and Lieberman 2000; D. A. Lewis et al. 2005).

Executive Function

Traditionally, the term executive function has been used to describe the specific role of thePrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

5 of 51

10/05/2009 16:35

prefrontal cortex in the temporal organization, planning, and sequential execution of goal-directed

behavior based on representational information that is constantly being generated and updated

(Stuss and Benson 1986). Executive function deficits in schizophrenia, such as those tapped by the

Wisconsin Card Sorting Test (WCST), have been frequently described. In a series of well-controlled

experiments, Weinberger et al. (1986) showed that during the performance of the WCST, normal

control subjects differed from schizophrenic subjects by the selective activation of the dorsolateral

prefrontal cortex, as shown by a differential increase in the regional cerebral blood flow (rCBF) to

this part of the prefrontal cortex. The lack of action of the prefrontal cortex has been referred to as

“hypofrontality” (Ingvar and Franzen 1974). This observation was replicated in subsequent studies

when the prefrontal cortex was functionally challenged with the performance of cognitive tasks (K.

1. Berman and Weinberger 1999; Carter et al. 1998), although negative findings also have been

reported (e.g., Frith et al. 1995; Manoach et al. 1999; Spence et al. 1998).

Attention

Attention plays a key role in mediating many cognitive processes. Attention deficits are well

documented in schizophrenia and may in part contribute to the many cognitive disturbances seen in

this illness (Braff 1993, 1999; Nuechterlein and Dawson 1984). For example, schizophrenic subjects

tend to perform poorly on the Continuous Performance Test, a commonly used task to tap sustained

attention. Attention deficit in schizophrenia may reflect an underlying “gating” deficit in which

patients have difficulties “filtering out” information that is context-irrelevant or distracting (Braff

1993). One of the most consistent findings in patients with schizophrenia is a deficit in the

phenomenon of prepulse inhibition (PPI). For example, a sound (prepulse) that occurs 30–500

msec before a sudden loud tone (i.e., a stimulus that normally triggers a startle response) will

prevent or reduce the amplitude of the startle response (Braff et al. 1992). However, in patients

with schizophrenia, this PPI of the response to the stimulus is diminished (Braff et al. 1992).

Interestingly, PPI deficits are also observed in unaffected relatives of patients with schizophrenia

(Cadenhead et al. 2000), a finding that is consistent with the notion that such deficits may serve as

a trait marker or an endophenotype of schizophrenia.

COURSE OF SCHIZOPHRENIA

Schizophrenia is a chronic illness with the onset of psychotic symptoms usually occurring around

late adolescence and early adulthood (D. A. Lewis and Lieberman 2000). The age at onset is

approximately 5 years later in women than in men (Angermeyer et al. 1990; Faraone et al. 1994;

Hambrecht et al. 1992; Szymanski et al. 1995). The onset of illness also tends to be more acute in

women, as compared with the typically more insidious onset in men, and women tend to have had a

higher level of premorbid functioning. Although there may be no clear sex differences in

cross-sectional symptomatology of the illness (Hafner et al. 1993; Szymanski et al. 1995), the

differences in the age at onset, tempo of onset, and level of premorbid functioning, all of which are

prognostic factors, are consistent with the fact that women in general tend to have a more

favorable outcome.

Accumulating evidence suggests that schizophrenia is a neurodevelopmental disorder (D. A. Lewis

and Levitt 2002; Murray 1994; Pilowsky et al. 1993; Waddington 1993; Weinberger 1987, 1996). It

has been postulated that disturbances in brain development during the first and second trimesters

may contribute to the pathophysiology of the illness (Waddington 1993). Other factors such as

obstetric complications may further alter the course of brain development (Cannon 1997; Cannon et

1. 2000; Geddes and Lawrie 1995). Minor physical anomalies (Lane et al. 1997), neurological soft

signs (Browne et al. 2000; Lawrie et al. 2001; Rosso et al. 2000), and neuromotor abnormalities

(Walker et al. 1999) have been observed in children who later develop schizophrenia, consistent

with the notion that the pathophysiological process leading to schizophrenia appears to have begun

much earlier than the onset of psychosis.

For a period of 2–5 years before the onset of the first overt psychotic episode, up to three-quarters

of the patients who eventually develop schizophrenia show a wide spectrum of “prodromal”

symptoms (Docherty et al. 1978; Freedman and Chapman 1973; Hafner et al. 1992, 1993, 1994; G.Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

6 of 51

10/05/2009 16:35

Huber et al. 1980; Lieberman 2006; Simon et al. 2007; Varsamis and Adamson 1971; Yung and

McGorry 1996a, 1996b). During the prodromal period, behavior changes, such as deterioration in

school, work, social, and interpersonal functioning, are often noted. Prodromal symptoms are

usually affective or cognitive in nature (e.g., depressed mood, social withdrawal, decreased

concentration and attention, decreased motivation, agitation, anxiety, and sleep disturbances).

Many of these symptoms are highly reminiscent of and, in fact, perhaps clinically indistinguishable

from the negative symptoms and cognitive deficits seen in schizophrenia itself. Other symptoms

occurring in the prodromal period, such as suspiciousness, magical thinking, and paranoia, may

resemble positive or psychotic symptoms but tend to be transient and not particularly complex;

these quasi-psychotic symptoms eventually coalesce into full-blown psychotic symptoms that

characterize the onset of the illness.

After the onset of the first episode of psychosis, the course of the illness is often characterized by a

gradual and at times continuous deterioration, especially in the first 2–5 years (McGlashan 1998).

Some evidence suggests that functional deterioration may be accompanied by a gradual loss of gray

matter volume of the cerebral cortex (DeLisi et al. 1997; Kasai et al. 2003a, 2003b; Salisbury et al.

2007; van Haren et al. 2007; Zipursky et al. 1992). In addition, there has been speculation that

these observations of functional and structural brain changes after the onset of psychosis may

reflect a neurodegenerative process (DeLisi 1999; DeLisi et al. 1997; Lieberman 1999). However,

the available evidence in support of the neurodegeneration hypothesis of schizophrenia remains

weak (Carpenter 1998; Weinberger and McClure 2002). Conventionally, the hallmark of

neurodegeneration is neuronal death, which is generally not believed to be occurring, at least not in

large scale, in schizophrenia (Selemon and Goldman-Rakic 1999). However, it is possible that, short

of leading to cell death, neuronal injury can be manifested as loss of dendrites and synapses, which

can contribute to the observation of progressive gray matter loss. Furthermore, gray matter volume

reduction can alternatively be explained as reflecting an exaggerated synaptic pruning process that

is normally occurring during the period of late adolescence and early adulthood (Huttenlocher

2002).

After an initial period of functional deterioration, symptoms tend to become more or less stabilized.

Some degree of amelioration of positive symptoms (and, to a lesser extent, of disorganization

symptoms) may not be uncommon in older patients (Davidson et al. 1995; Harding et al. 1987;

Pfohl and Winokur 1982; Schultz et al. 1997). However, findings of amelioration of psychotic

symptoms should be interpreted in light of the fact that these are also the symptoms most

responsive to treatment with antipsychotic medication, making it difficult to distinguish between

the natural course of the disorder and the accumulated response to treatment. Positive symptoms

usually respond to treatment, whereas negative symptoms are believed to be relatively treatment

resistant and may tend to become increasingly prominent during the course of the illness (Breier et

1. 1991).

Many, but not all, studies (Ho et al. 2000) have implied that early intervention during the very first

episode of psychosis could be associated with better overall prognosis, as measured by fewer

relapses, shorter duration between initiation of antipsychotic treatment and response, and fewer

residual symptoms (Birchwood 1992; Haas et al. 1998; Johnstone et al. 1986; Loebel et al. 1992).

However, these same studies also have shown that the time between the onset of symptoms and

the patient’s first presentation to psychiatric care (i.e., the duration of untreated psychosis) is far

from optimal: the average duration of untreated psychosis is about 1–2 years. Thus, a major goal in

the treatment of schizophrenia is early recognition of illness and timely treatment.

MANAGEMENT OF SCHIZOPHRENIA

Acute Psychosis

The acute phase of schizophrenia is characterized by psychotic symptoms and often by agitation.

Affective symptoms such as depression and mania also may occur. The severity of symptoms may

vary widely, requiring careful evaluation to determine the most optimal treatment setting and

management strategy. The decision to hospitalize a patient usually is based on whether the patientPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

7 of 51

10/05/2009 16:35

has the ability to care for him- or herself or whether he or she poses any risks of harm to self or

others. Regardless of whether treatment is provided in a hospital or in an outpatient setting, acute

psychosis requires use of antipsychotic medication.

Management of an acutely agitated and psychotic patient can pose a challenge. It may be necessary

to physically restrain the patient for his or her own safety and also for the safety of others.

Medications given orally or, in the event of severe agitation, parenterally may be indicated.

Although the practice patterns for treatment of acute psychosis are changing following the

introduction of atypical agents, for initial acute management of severe behavioral dyscontrol, many

physicians still use a high-potency first-generation antipsychotic either alone or in conjunction with

a benzodiazepine (such as lorazepam) and/or an anticholinergic drug (such as benztropine). Prior

to medicating a patient, it is important to inquire about a history of allergic or severe adverse

reactions to the medications to be prescribed. For example, the clinician should be particularly

cautious when deciding to prescribe a high-potency first-generation antipsychotic agent to a

patient with a history of acute dystonic reaction and should avoid such agents in a patient with a

history of neuroleptic malignant syndrome.

If the patient has a history of treatment with antipsychotic medications, one needs to ascertain

whether the current psychosis is the result of noncompliance or a “breakthrough” episode because

of loss of therapeutic response to the medications. Noncompliance with antipsychotic medications

is common and is one of the major causes of symptom exacerbation or full-blown relapse (Crow et

1. 1986; Lieberman et al. 1993; Robinson et al. 1999). Causes of noncompliance vary, but the most

common reasons are side effects, lack of insight into the illness, delusional interpretations about

medication, substance abuse, and lack of a supportive environment (Kampman and Lehtinen 1999).

If the psychotic episode appears to result from medication noncompliance, the clinician may decide

to restart the same medications in the patient, but it is imperative to focus on improving adherence

by providing psychoeducation to the patient (and family, if available) and discussing with the

patient the reasons for nonadherence. Depot medications also should be considered if

noncompliance is a persistent or recurring problem. Of course, in the case of apparent

breakthrough psychosis, change in the patient’s medication regimen may be indicated. Other

causes of exacerbation of psychosis may include comorbid substance abuse or dependence and

comorbid depression, as well as psychosocial stressors including difficulties with housing,

employment, benefits, insurance, disability, family, and friends. Therefore, although medications

are undoubtedly the mainstay for initial treatment of psychosis, other treatment such as

psychotherapy, group therapy, family therapy, dual-diagnosis treatment, social skills training, and

case management are important adjuncts to pharmacological management.

First-Episode Psychosis

Emphasis on the early diagnosis and treatment of the first psychotic episode of schizophrenia arises

from the recent evidence from some, but not all (Ho et al. 2000), studies suggesting that the

duration of untreated psychosis may be associated with poorer overall outcome (Birchwood 1992;

Loebel et al. 1992; Wyatt 1991). One hypothesis to account for this observation is that shortening

of duration of untreated psychosis by early treatment with antipsychotics may decrease the

long-term morbidity of the illness. An alternative hypothesis is that prolonged duration of untreated

psychosis represents a different, more severe form of schizophrenia that, by itself, is associated

with poorer outcome (McGlashan 1999). For example, the delay in obtaining treatment may

indicate a more insidious course of onset of psychosis, which is thought to be associated with

increased long-term morbidity; alternatively, patients who seek treatment earlier may experience a

more acute form of psychosis, which has been suggested to be a predictor of better prognosis

(McGlashan 1999). This hypothesis, however, was not supported by a study in which the mode of

onset of psychosis, whether insidious or acute, was not correlated with outcome (Loebel et al.

1992). In summary, although some studies have indicated that duration of untreated psychosis is

correlated with outcome, whether a prolonged duration of untreated psychosis could be a marker or

a determinant of poor outcome remains to be elucidated (McGlashan 1999).Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

8 of 51

10/05/2009 16:35

Because of the more favorable neurological side-effect profile—mainly the reduced risks of adverse

neurological events such as parkinsonism, akathisia, and tardive dyskinesia—the second-generation

antipsychotics are often considered for the initial treatment of first-episode psychosis. However, as

discussed below, many of these medications carry other medically important side effects, including

weight gain. Because patients are likely to require long-term treatment, clinicians should pay close

attention to antipsychotic side effects and to their potential morbidity. In general, a conservative

titration schedule is appropriate for first-episode patients, in part to minimize side effects but also

to take into account that these patients may require only low doses for the control and remission of

symptoms (Remington et al. 1998; Robinson et al. 1999; Schooler et al. 2005; Wyatt 1995).

After remission of an initial episode of psychosis in a patient with a diagnosis of schizophrenia,

potential discontinuation of medication, even if done very gradually, is controversial and often not

attempted. Any decision about this should be made in light of studies showing that the relapse rate

is very high after medication discontinuation in first-episode schizophrenia (Crow et al. 1986;

Johnson 1985; Kane et al. 1982; Robinson et al. 1999). Gitlin et al. (2001), using a low threshold to

define recurrence of symptoms, reported that the relapse rate in the first year after medication

discontinuation was 78% and increased to 98% by the end of the second year. Moreover, Robinson

et al. (1999) found that the relapse rate among self-selected first-episode patients who

discontinued their medication was five times the rate among those who continued taking

medication. Studies suggest that relapse rates may be lower if uninterrupted medication treatment

occurs for at least 1 year after the resolution of psychosis (Kissling et al. 1991).

If a decision is made to initiate a trial of medication discontinuation, the discontinuation should be

done very gradually, and the patient should continue to be monitored closely for an extended

period. Fortunately, in one study of medication discontinuation in recent-onset patients (Gitlin et al.

2001), the combination of close clinical supervision after medication discontinuation and rapid

reinstatement of treatment at the first signs of symptom exacerbation was able to prevent frank

psychosis and rehospitalization in most patients.

Choice of Antipsychotics

Since the early 1990s, second-generation antipsychotics have been used widely with the belief that

these agents were more effective, better tolerated, and ultimately more cost-effective than

first-generation antipsychotics. However, little data comparing first- and second-generation

antipsychotics existed. To address this knowledge gap, the National Institute of Mental Health

(NIMH) sponsored the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study

(Lieberman et al. 2005). The study was designed to compare the effectiveness of four

second-generation antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and a

representative first-generation antipsychotic (perphenazine) in “real world” schizophrenia patients.

The primary outcome parameter was discontinuation of treatment. Of the 1,432 subjects who

received at least one dose, 74% discontinued study medication before 18 months: 64% of subjects

on olanzapine discontinued, compared with 74%–82% on perphenazine, quetiapine, risperidone,

and ziprasidone. More subjects receiving olanzapine discontinued due to weight gain and metabolic

effects, whereas more subjects assigned to perphenazine discontinued due to EPS (Lieberman et al.

2005). Interestingly, individuals assigned to olanzapine and risperidone who were continuing with

their baseline medication had significantly longer times until discontinuation than did those

assigned to switch antipsychotics (Essock et al. 2006). Phase 2 of the CATIE study included two

treatment pathways (efficacy and tolerability) with randomized follow-up medication based on the

reason for discontinuation of the previous antipsychotic drug (McEvoy et al. 2006; Stroup et al.

2006). For subjects who failed to improve with an atypical antipsychotic, clozapine was more

effective than switching to another atypical antipsychotic (McEvoy et al. 2006), and in patients who

failed to respond to perphenazine, olanzapine and quetiapine were more effective than risperidone

(Stroup et al. 2006). Moreover, in subjects who discontinued an atypical agent due to tolerability or

efficacy but who were unwilling to be randomized to clozapine, risperidone and olanzapine were

more effective than quetiapine or ziprasidone (Stroup et al. 2006). Finally, while the CATIE

cost-effectiveness analysis found perphenazine to be less costly and similarly effective (based onPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

9 of 51

10/05/2009 16:35

quality adjusted life-years) than each of the atypical antipsychotics, the authors note that these

results cannot be generalized to all patient populations, and they suggest that these findings do not

warrant policies that would unconditionally restrict access to a particular medication (Rosenheck et

1. 2006).

Similar to the NIMH-sponsored CATIE study, the United Kingdom’s National Health Service funded

the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS). This study of

227 schizophrenia-spectrum patients randomly assigned to first- and second-generation

antipsychotics (other than clozapine) found no difference between the groups in quality of life,

symptoms, or health care costs at 1 year (P. B. Jones et al. 2006). The applicability of these results

to U.S. populations may be difficult as this study included several medications that are not available

in the United States.

Neither the CATIE nor the CUtLASS study addressed the comparative effects of oral and long-acting

injectable antipsychotics. Older mirror-image studies in which patients served as their own controls

provide evidence of substantial benefit for first-generation long-acting injectable (LAI)

antipsychotics over first-generation oral medications (Schooler 2003). Risperidone is the only

second-generation antipsychotic currently available in an LAI formulation. Further research

evaluating the comparative effects of risperidone LAI to oral atypical agents is needed.

Taken together, the CATIE and the CUtLASS studies indicate that antipsychotic medications are

generally effective but have a variety of shortcomings. Moreover, the effectiveness of a given

antipsychotic appears to vary according to clinical circumstances, suggesting the need for

individualized therapy based on differences in efficacy and tolerability and, perhaps, reflecting why

several medication trials may be necessary in the treatment of patients with schizophrenia (Stroup

et al. 2007). Additionally, this variation in effectiveness may underlie the increasing use of

antipsychotic polypharmacy, for which there is no empirical basis.

Physicians must thoroughly inquire about the patient’s past experience with medications and side

effects when selecting an antipsychotic, discuss risks and benefits of each treatment option, and

consider the patient’s preference. Attempts to optimize current medication regimens (e.g., dosage

adjustments or psychosocial interventions) may be useful before deciding to switch medications

(Essock et al. 2006). Clozapine should be considered for patients who have failed to respond to

other second-generation medications. LAI antipsychotics may be considered for patients with poor

adherence. Physicians need to be well informed about the differential tolerability of all

antipsychotics. First-generation agents clearly have the highest risk of EPS and tardive dyskinesia

(Glazer 2000b; Jeste et al. 1998; Tollefson et al. 1997). Risperidone and the newly available

paliperidone tend to elevate serum prolactin levels and may cause EPS at higher doses. Although

weight gain and metabolic disturbances are associated with all of the second-generation agents

(with the possible exception of ziprasidone and aripiprazole), olanzapine and clozapine appear to

have the highest likelihood of causing these side effects (Allison et al. 1999; American Diabetes

Association et al. 2004). Sedation is commonly observed in patients receiving quetiapine,

olanzapine, or clozapine. Both ziprasidone and paliperidone carry product labeling for QTc

prolongation and should be used with caution in patients at risk for QTc prolongation. Finally,

clozapine, because of its side effects of agranulocytosis, seizures, and myocarditis, is generally

reserved for patients with treatment-resistant illness or suicidality.

Maintenance Treatment

The major goals of maintenance treatment are prevention of relapse and improvement in

psychosocial and vocational function. The primary methods used to achieve these goals are, as at

all phases, an integration of optimal psychopharmacological and psychosocial treatments.

Treatment and prevention of other psychiatric comorbidities, such as substance abuse and

dependence, are important aspects of maintenance treatment. Also, with the use of the

second-generation antipsychotics in particular, treatment and prevention of medical comorbidities

that may be associated with these drugs, as well as those that may result from the lifestyle of some

patients with schizophrenia who are given these drugs, have become a very important part ofPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

10 of 51

10/05/2009 16:35

long-term management.

Prevention of relapse improves long-term clinical outcomes (Wyatt et al. 1998) and reduces the

associated economic burden of the illness (Bernardo et al. 2006). With each relapse, the time it

takes to achieve clinical stability lengthens, with the possible consequence of ultimate

unresponsiveness to treatment (Lieberman et al. 1993; Wyatt et al. 1998). Several studies have

demonstrated that higher rates of relapse are associated with medication discontinuation (Beasley

et al. 2003; Carpenter et al. 1990; Herz et al. 1991; Jolley et al. 1990; Kramer et al. 2007; Muller et

1. 1992; Pietzcker et al. 1993; Schooler et al. 1997). All available atypical antipsychotics have been

granted U.S. Food and Drug Administration (FDA) approval for the maintenance treatment of

schizophrenia. Moreover, some evidence suggests that atypical antipsychotics may be more

effective than conventional agents in forestalling relapse (Conley and Kelly 2002; Csernansky et al.

2002; Leucht et al. 2003a; Schooler 2006; Tran et al. 1998). While it is not clear whether this

apparent advantage for atypicals over conventional antipsychotics is related to better tolerability

and adherence (Leucht 2004), nonadherence to medication is a significant predictor of relapse

(Schooler 2006). LAI atypical antipsychotics have the potential to improve medication adherence

and thus improve long-term outcomes, but this requires further research. New research on

long-term clinical outcomes in patients with schizophrenia will be aided by the newly proposed and

validated remission criteria for the disorder (Andreasen et al. 2005; van Os et al. 2006).

An ongoing treatment alliance among the patient, the family, and the treating clinicians is a crucial

factor in maximizing medication and overall treatment adherence. Psychoeducation about illness,

relapse, and side effects, as well as specific strategies to manage or avoid particular side effects in

the context of an ongoing treatment partnership, helps to increase compliance. Medication

adherence is the cornerstone of treatment throughout all phases of schizophrenia.

Treatment-Resistant Schizophrenia

Within this chapter, we have emphasized the pervasive nature of negative symptoms and

neurocognitive deficits and their resistance to treatment. However, even if we focus only on

psychotic symptoms, which tend to respond favorably to antipsychotic medications, at least 30% of

patients still can be classified as having incomplete to poor response to antipsychotics, with

persistent psychotic symptoms (Kane et al. 1988, 2007; Tamminga 1999). Furthermore, patients

may show differential therapeutic response to medications; the fact that a patient fails to respond

to one or two antipsychotic medications does not necessarily imply that he or she will not respond

to a third agent. For research purposes, Kane et al. (1988) operationally defined treatment

resistance as 1) lack of significant response to at least three adequate trials of neuroleptics from at

least two different chemical classes in the past 5 years and 2) persistently poor social and

occupational functioning.

Most of the available data suggest that clozapine is the most effective drug for treatment-resistant

schizophrenia (Kane et al. 2001; S. W. Lewis et al. 2006; McEvoy et al. 2006). However, because of

the serious side effects produced by clozapine and the requirement for frequent white blood cell

count monitoring, some patients and some psychiatrists are reluctant to use it, and some patients

are unable to tolerate it. However, whether the other second-generation agents even approach the

effectiveness of clozapine for the treatment of these chronically ill patients is unclear. In studies

that have compared the efficacy of risperidone and clozapine in treatment-resistant schizophrenia,

risperidone has been shown to be either as effective as (Bondolfi et al. 1998) or less effective than

(Breier et al. 1999; Volavka et al. 2002) clozapine. Moreover, patients with treatment-resistant

illness may require high doses of risperidone, increasing the likelihood of EPS. Some evidence has

indicated that olanzapine at higher dosages (e.g., 30 mg/day) may be as effective as clozapine in

improving both positive and negative symptoms (Tollefson et al. 2001; Volavka et al. 2002),

although not all studies agree (Buchanan et al. 2005). Other preliminary data also suggest the

possible utility of quetiapine, aripiprazole, and ziprasidone in treatment-resistant patients (Emsley

et al. 2000; Kane et al. 2006, 2007).

In summary, clozapine remains the primary medication for treatment-resistant schizophrenia,Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

11 of 51

10/05/2009 16:35

although some studies suggest that other second-generation agents also may have a role in the

management of this disorder. Clinically, judicious combinations of antipsychotics from different

classes are sometimes used for patients who fail to respond to monotherapy (including those who

fail to respond to clozapine), as may the addition of other agents, such as mood stabilizers.

Unfortunately, however, no controlled data suggest that any specific combination is more effective

than others. Some of the more commonly used regimens include the combination of an atypical

agent with a high-potency conventional agent such as haloperidol and the combination of two

atypical agents. Clearly, more research is needed to guide treatment in such patients.

Neurocognitive Deficits

Neurocognitive deficits, especially disturbances in executive functioning, memory, and attention

(M. F. Green 1996; M. F. Green et al. 2000), are closely associated with the long-term functional

outcome of patients with schizophrenia. It appears that second-generation antipsychotics may

improve some aspects of cognition in schizophrenia, as found in a meta-analysis of 15 studies on

the cognitive-enhancing effects of these drugs (Bilder et al. 2002). In contrast, conventional

antipsychotics have usually been believed not to be efficacious in alleviating these deficits (Cassens

et al. 1990; Spohn and Strauss 1989), although findings from the CATIE study suggest that at least

some of them might be (Keefe et al. 2007). The therapeutic effects of the newer antipsychotics are

most notable in measures of verbal fluency and executive functioning, whereas improvement in

memory may be more limited. One recently published study suggested that clozapine, olanzapine,

and risperidone all showed superiority over haloperidol in the improvement in global

neurocognitive measures, including assessments of memory, attention, motor speed, and executive

functions (Bilder et al. 2002). However, it must be noted that the available studies are limited, and

many are methodologically compromised (Harvey and Keefe 2001). Thus, whether such

improvement represents a genuine amelioration of cognitive deficits as a result of correction of the

underlying neural system dysfunctions or rather simply epiphenomenal improvement resulting from

the differential side-effect profiles between the first- and the second-generation drugs remains

debatable (Carpenter and Gold 2002). Moreover, in contrast to the idea that second-generation

drugs are superior to the older drugs in the treatment of neurocognitive deficits, data obtained from

the CATIE trial (Keefe et al. 2007) show that at 18 months of treatment, perphenazine was actually

more effective than any of the second-generation drugs in improving all domains of neurocognitive

deficits (Keefe et al. 2007). The authors postulate that a number of factors could potentially explain

this unexpected finding, including sample size, differences between mid-potency drugs such as

perphenazine and high-potency drugs (e.g., haloperidol) that were commonly used in prior studies,

the “real-world” features of the CATIE sample, and prior drug trials before entering the study

(Keefe et al. 2007). Finally, regardless of the comparable efficacy of first- and second-generation

compounds, a critical question that remains unanswered is whether any of the apparent statistically

significant improvements in neurocognitive deficits measured in the laboratory can actually be

translated into improved functional outcomes, for example, in terms of employment, school

performance, or social role (for a discussion, see M. F. Green 2002).

PSYCHOSOCIAL TREATMENT OF SCHIZOPHRENIA

Despite the proven efficacy of antipsychotics in the treatment of schizophrenia, most patients

continue to have some degree of residual positive symptoms, negative symptoms, and cognitive

deficits, and many (even those who take their medications regularly) have difficulty attaining or

regaining their desired level of social and occupational functioning. Thus, the optimal treatment of

patients with schizophrenia requires the integration of pharmacotherapy with psychosocial

interventions that target functional goals. Treatment is ideally offered by a multidisciplinary team

that includes, at a minimum, a medication prescriber and a clinician who understands psychosocial

rehabilitation but may also include employment and housing specialists. Programs that utilize

clinical case managers to directly assist patients in accessing services and to provide the

psychosocial interventions are ideal (Rapp and Goscha 2004). To date, several different types of

psychosocial interventions have been empirically shown to reduce rates of relapse and

rehospitalization, and a variety of treatments may assist patients in acquiring social and vocationalPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

12 of 51

10/05/2009 16:35

skills and possibly in managing residual psychotic symptoms (Bustillo et al. 2001; Lauriello et al.

1999; Penn and Mueser 1996). Furthermore, the interaction between pharmacological and

psychosocial treatments appears to be more than additive because each can enhance the effects of

the other and affect different domains of outcome (Marder 2000).

Relapse Prevention

It has long been noted that patients with highly critical or overinvolved family members (so-called

high-expressed-emotion [EE] families) have a higher risk of relapse (G. W. Brown and Rutter

1966). In a classic study, M. J. Goldstein et al. (1978) reported that a 6-week therapy focusing on

teaching families more effective communication dispute-resolution skills reduced relapse rates for

up to 6 months. Many other studies have since confirmed the efficacy of family psychoeducation

interventions (involving education, training in problem-solving techniques, and/or in cognitive and

behavioral management strategies) to prevent relapse and to improve other outcomes (Falloon et

1. 1982; Pilling et al. 2002; Pitschel-Walz et al. 2001; Tarrier et al. 1988). In addition, the positive

impact of family interventions seems to persist beyond the time of intervention (Sellwood et al.

2001). Finally, despite the fact that families and patients at different stages of the illness may have

specific needs and preferences (e.g., first-episode patients may need more intensive and

personalized intervention, whereas families of patients with long-term illness may need continuous

long-term support [Montero et al. 2005]), the effectiveness of family psychoeducation in

preventing relapse has been found to be independent of either the specific form or the intensity of

the intervention (Bustillo et al. 2001).

Another psychosocial intervention that has been shown to be effective in preventing relapse or

rehospitalization in schizophrenia is assertive community treatment (ACT). This intervention, which

involves intensive multidisciplinary team management and service delivery in both community and

inpatient settings, is designed for individuals who experience intractable symptoms and high levels

of functional impairment. At least 30 studies of ACT have shown advantages over standard

community treatment in reducing symptoms, family burden, and hospitalization and in improving

independent living, housing stability, and quality of life (Mueser et al. 1998; Phillips et al. 2001;

Stein and Test 1980). However, it appears that the advantages of ACT do not persist after

discontinuation of the program, even after prolonged delivery of services. Finally, ACT also does not

have much effect on social adjustment or competitive employment.

Improvement of Psychosocial Functioning

Most patients with schizophrenia have personal goals that involve social and occupational

functioning in the community. Hence, psychosocial treatment of patients with schizophrenia targets

impairments in these areas. While past research (e.g., the Camarillo State Hospital Study [May et

1. 1978]) showed that dynamic psychotherapy was unsuccessful in the treatment of patients with

schizophrenia, other forms of individual and group psychotherapy may improve social adjustment

and symptom management. In a 3-year study, Hogarty et al. (1997a) found that weekly individual

personal therapy, in which an incremental psychoeducational approach based on the patient’s

phase of recovery was used, had a significant advantage over supportive therapy, family therapy,

and combined treatment in improving social adjustment. Yet personal therapy did not appear to be

more effective than the other treatments in preventing relapse (Hogarty et al. 1997b).

Interestingly, cognitive-behavioral therapy (CBT) may have a role in the management of persistent

psychotic symptoms, particularly delusions, in patients with schizophrenia (Chadwick et al. 1994;

Granholm et al. 2005; Tarrier et al. 2000). CBT involves the use of techniques such as distraction,

cognitive reframing of psychotic beliefs or experiences, and verbal challenge followed by reality

testing (Penn and Mueser 1996). Review and meta-analyses of CBT for psychosis suggest a positive

effect, although not for reducing relapse (Bellack 2004; C. Jones et al. 2004; Pilling et al. 2002).

Further study is needed to demonstrate the efficacy of this treatment paradigm for the

management of psychotic symptoms.

Social skills training (SST) is one treatment strategy to help individuals acquire interpersonal

disease management and independent living skills that can be delivered in the context of aPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

13 of 51

10/05/2009 16:35

comprehensive treatment approach. Reviews of SST (Bellack and Mueser 1993; Kopelowicz et al.

2006) have described three models of SST: basic, social problem solving, and cognitive

remediation. Within the basic model, complex social scenarios are broken down to simpler

components, the therapist models correct behaviors, and the patient learns through repeated

role-play. This model has been shown to be potentially effective in improving specific social skills

for 1 year (Bellack and Mueser 1993). Additionally, the combination of this form of SST with

antipsychotic medication appears to be more effective than medication alone in reducing relapse,

provided weekly SST is maintained (Hogarty et al. 1986). However, despite skill acquisition, this

learning does not appear to generalize to improved social competence within the community (Dilk

and Bond 1996).

The social problem-solving model focuses on impaired information processing, which is thought to

cause social skills deficits, in hopes of achieving a generalized improvement in social adjustment.

This model targets symptom and medication management, recreation, basic conversation, and

self-care in educational modules, and it has been shown to be effective in enhancing skills (Eckman

et al. 1992), although improvements in adaptive functioning within the community are still modest

(Liberman et al. 1998; Marder et al. 1996). To enhance generalization to community functioning,

interventions that utilize cueing and support in everyday community interactions by “indigenous

supporters” such as clinicians, friends, or family seem to improve transfer of newly learned social

skills to everyday community interactions (e.g., Glynn et al. 2002).

Finally, the cognitive remediation model of SST targets more fundamental cognitive deficits, in

areas such as attention, memory, and planning, with the aim of supporting more complex cognitive

processes used in learning social skills. Although initial studies following this model have shown

some benefit on basic cognitive processes (Brenner et al. 1992), small studies of more complex

cognitive and social skills have been mixed (Hodel and Brenner 1994; Spencer et al. 1994; Wykes et

1. 1999). One study of cognitive enhancement therapy, an integrated approach to the concomitant

training of neurocognitive and social cognitive abilities as well as social skills, showed improvement

in social adjustment (Hogarty et al. 2004) that persisted over 3 years (Hogarty et al. 2006).

Recent work to improve social functioning has focused on social cognition, the capacity to perceive

the intentions and dispositions of others (Penn et al. 2006). Interventions targeting social cognition

attempt to improve areas that are problematic in individuals with schizophrenia: 1) theory of mind

(the ability to represent the mental states of others and make inferences about another’s

intentions); 2) attributional style; and 3) the ability to perceive facial affect in others. A preliminary

study of social cognition and interaction training during 18 weekly sessions comprised of emotion

training, figuring out situations, and integration of skills into real life suggests that this may be a

promising approach for improving interpersonal functioning and for directly managing symptoms of

psychosis (Combs et al. 2007).

Illness management and recovery (IMR) is a manualized package of empirically supported

approaches (psychoeducation, cognitive-behavioral approaches for medication adherence, relapse

prevention planning, SST, and coping skills training) delivered in weekly group or individual

sessions that are utilized with a recovery focus that targets each individual’s personal life goals

(Mueser et al. 2006). Preliminary research shows that this combination of approaches results in

improved symptoms and community functioning (Mueser et al. 2006).

Whereas family psychoeducation, CBT, SST, and IMR may improve symptoms and/or social

functioning, they do not appear to affect employment status. In addition, traditional vocational

rehabilitation programs have assisted with transitional and sheltered employment, but they have

not been successful in helping patients with schizophrenia to obtain and maintain competitive

employment (Lehman 1995). However, more than 14 studies suggest that supported employment

programs, which use rapid job searches, on-the-job training, continuous job support, and

integration with mental health treatment, are more effective than traditional methods in helping

patients obtain competitive employment (Bond 2004). Research is currently under way to

investigate modifications of supported employment, the role of cognitive remediation (McGurk et al.Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

14 of 51

10/05/2009 16:35

2007), and other strategies to improve the ability of supported employment to help patients

maintain employment.

In addition to employment, the ability to maintain a residence in the community is an important

marker of community functioning and a frequently voiced personal goal of patients with

schizophrenia. A variety of approaches have been studied to help these patients obtain and

maintain stable community residential tenure. Simple provision of access to affordable housing by

Section 8 certificates improves housing stability (Hurlburt et al. 1996b). Supported housing,

broadly defined as access to independent housing of the patient’s choice (often supported with

housing subsidies) that is coupled with access to community mental health and support services,

improves residential stability and reduces hospitalization (Rog 2004). ACT for homeless individuals

has also been shown to reduce homelessness (Coldwell and Bender 2007).

As multiple effective psychosocial interventions exist and are still being developed, the choice of

which intervention to apply should depend not only on therapeutic efficacy but also on each

individual’s goals and preferences. Patients and their families need to be given information about

treatment options and should be engaged in discussions with their treatment providers about how

treatments can be useful in the context of an individual’s symptoms, comorbidities, and needs and

preferences.

MANAGEMENT OF MEDICAL COMORBIDITY

Obesity, Metabolic Syndrome, and Diabetes Mellitus

Medication side effects, as well as lifestyle and disease factors, place patients with schizophrenia at

increased risk of developing obesity and metabolic side effects, including glucose intolerance, type

2 diabetes, diabetic ketoacidosis, and hyperlipidemia (Dixon et al. 2000; Meyer and Koro 2004;

Wirshing et al. 2002, 2003). While clinically significant weight gain occurs in a substantial

proportion of patients receiving an antipsychotic medication (Baptista 1999), a convincing body of

evidence indicates that certain atypical antipsychotics cause more weight gain than other agents

(Allison et al. 1999; Lieberman et al. 2005; Wirshing et al. 1999). A large meta-analytic study of

atypical and typical antipsychotics (Wirshing et al. 1999) found a mean weight gain of 9.8 lbs with

clozapine, 9.1 lbs with olanzapine, and 4.6 lbs with risperidone, compared with 2.4 lbs with

haloperidol, while the atypical antipsychotic ziprasidone was associated with a less than 1-lb

weight gain. Furthermore, the CATIE study demonstrated a greater than 7% weight gain from

baseline in 30% of patients receiving olanzapine, 16% of those receiving quetiapine, 14% of those

receiving risperidone, 12% of those receiving perphenazine, and 7% of those receiving ziprasidone

(Lieberman et al. 2005).

Weight gain induced by antipsychotic medication is usually most rapid early in treatment and may

plateau after 1–2 years (Allison et al. 1999; Stanton 1995). Young patients and those with a low

baseline body mass index may be at increased risk for weight gain (Kinon 1998). This noticeable

and often unacceptable side effect of antipsychotics may contribute to medication noncompliance

and increase the risk of obesity-related comorbidities, such as diabetes and adverse serum lipid

profile (Allison et al. 1999; A. I. Green et al. 2000).

Diabetes mellitus is estimated to occur two to four times more frequently in patients with

schizophrenia compared to the general population (Dixon et al. 2000; Goff et al. 2005; Henderson

et al. 2000; Mukherjee et al. 1996; Wirshing et al. 1998). While the risk of diabetes in schizophrenia

is likely multifactorial, accrued evidence indicates that atypical antipsychotics are associated with

glucose dysregulation (Jin et al. 2004). Several case reports (Koller and Doraiswamy 2002; Koller

et al. 2001, 2003), retrospective studies (Dixon et al. 2000; Wirshing et al. 2002), epidemiological

investigations (Gianfrancesco et al. 2002), and limited prospective studies (Henderson et al. 2000)

of hyperglycemia, new-onset diabetes mellitus, and diabetic ketoacidosis led to heightened

attention to and concern over the metabolic effects of atypical antipsychotics, resulting in the

issuance of warnings by regulatory authorities and class labeling (Jin et al. 2004). Moreover, in

2004 the American Psychiatric Association, together with the American Diabetes Association,Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

15 of 51

10/05/2009 16:35

published consensus guidelines on monitoring and described the differential risk of metabolic

effects for the atypical antipsychotics (American Diabetes Association et al. 2004). Clozapine and

olanzapine are described as having the greatest effect on weight (with increased risk for diabetes),

whereas risperidone and quetiapine are described as having an effect on weight (but with unclear

risk for diabetes). Aripiprazole and ziprasidone are described as having small or no effect on weight

and without risk for diabetes.

Certain atypical antipsychotics (particularly clozapine, olanzapine, and quetiapine) and low-potency

conventional agents have been shown to be associated with hyperlipidemia (Henderson et al. 2000;

Meyer and Koro 2004; Osser et al. 1999), whereas ziprasidone and aripiprazole do not appear to

carry this adverse effect (Kingsbury et al. 2001; Meyer and Koro 2004). The co-occurrence of

atherogenic dyslipidemia with abdominal adiposity, insulin resistance, impaired fasting glucose or

overt diabetes mellitus, and hypertension constitutes the cluster of clinical features known as the

metabolic syndrome, or syndrome X. Given the well-established and close relationship between

metabolic syndrome and coronary heart disease (Isomaa et al. 2001) and the growing awareness of

a range of metabolic issues in patients with schizophrenia, researchers and clinicians are now

focusing on identifying the metabolic syndrome in patients with schizophrenia. Baseline data from

the CATIE study indicated that more than 40% of subjects had metabolic syndrome. Moreover, the

CATIE males were 138% more likely to have metabolic syndrome than matched controls, and the

CATIE females were 251% more likely to have metabolic syndrome than matched controls (McEvoy

et al. 2005).

To minimize iatrogenic medical problems and to ensure optimal treatment outcome, prevention and

management of weight gain and obesity-related conditions in patients with schizophrenia are

essential. In addition to receiving ongoing education about the potential for weight gain, patients

should be counseled about dietary choices, encouraged to exercise, and weighed frequently. In a

recent review of behavioral interventions for weight management, the authors concluded that such

interventions may prevent further weight gain and in some cases may result in weight loss (Loh et

1. 2006).

Centrally acting weight-loss drugs that have the potential to increase biogenic amine activity could

theoretically exacerbate symptoms of psychosis in this population. However, anecdotal reports

suggesting the utility of nizatidine, citmetadine, metformin, topiramate, sibutramine, and

amantadine in the prevention or treatment of antipsychotic-associated obesity exist (Werneke et al.

2002) but have not been substantiated with well-controlled trials. Orlistat, the non–centrally acting

weight-control drug, may theoretically have a role in helping patients with schizophrenia lose

weight, although no clinical trials have been reported to date (A. I. Green et al. 2000). One case

series (Hamoui et al. 2004) suggested that bariatric surgery was as effective in promoting weight

loss in patients with schizophrenia as it is in other obese patients.

The differential propensity of the various agents to cause weight gain, and glucose and lipid

dysregulation, should be taken into consideration when treating individuals at increased risk.

Clinicians should employ monitoring, such as that recommended by the American Diabetes

Association–American Psychiatric Association consensus panel (American Diabetes Association et

1. 2004). Patients who develop glucose intolerance or diabetes may require treatment with

hypoglycemic agents, and those with hyperlipidemia may require lipid-lowering agents in

collaboration with an internist. Although to the best of our knowledge no studies of the long-term

effects of these simple interventions in minimizing the overall morbidity of this patient population

have been done, such interventions may be important in the lowering of long-term morbidity.

Cigarette Smoking

Reports indicate that up to approximately 90% of patients with schizophrenia smoke cigarettes,

over three times the rate seen in the general population (S. Brown et al. 2000; Dalack et al. 1998;

Meyer and Nasrallah 2003). Heavy cigarette smoking contributes to the risk of coronary heart

disease, which accounts for over 50% of the mortality in patients with schizophrenia (Hennekens et

55. 2005). Beyond health, tobacco use results in financial consequences, with some schizophreniaPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

16 of 51

10/05/2009 16:35

patients spending nearly a third of their disability income on cigarettes (Steinberg et al. 2004). It

has been proposed that the high rates of smoking may relate to abnormalities in brain reward

circuitry (including presynaptic nicotinic acetylcholine receptors within mesolimbic and

mesocortical dopamine pathways) and self-medication of clinical symptoms and cognitive deficits

(George and Vessicchio 2001; Knott et al. 2006; Ripoll et al. 2004; Sacco et al. 2005). Indeed, such

hypotheses and observations may provide insight into the neurobiology of schizophrenia and

targets for treatment of both schizophrenia and nicotine addiction (Meyer and Nasrallah 2003).

Treatment of nicotine addiction in the schizophrenia population has been met with limited success

and appears to be even more difficult for this patient population compared with both the general

and other psychiatric populations (Covey et al. 1994). Nonetheless, evidence suggests that a

multimodality approach, which integrates motivation-based treatment, addiction treatment, and

tobacco dependence treatment into mental health settings, may be beneficial (Ziedonis et al. 2003).

Group therapy, when combined with a nicotine patch, may help reduce smoking (George et al.

2000), and bupropion in combination with psychotherapy may reduce tobacco use in patients with

schizophrenia (Evins et al. 2005; Weiner et al. 2001). Additionally, in a case series of patients

previously unable to quit smoking despite tobacco dependence treatment, use of nicotine nasal

spray was associated with substantial reduction in or abstinence from smoking in 9 of 12 patients

(J. M. Williams et al. 2004). Interestingly, whereas typical antipsychotic medications may be

associated with an increase in smoking (McEvoy et al. 1995a), treatment with clozapine may lead to

a decrease (George et al. 1995; McEvoy et al. 1995b). Finally, some other atypical antipsychotic

medications may facilitate the ability of the nicotine patch itself to decrease smoking (George et al.

2000).

HIV and Hepatitis Risks

Patients with schizophrenia, especially those with substance abuse, are at high risk for HIV and

hepatitis B and C (Cournos and Bakalar 1996; Meyer and Nasrallah 2003; Rosenberg et al. 2001). A

cross-sectional Medicaid claims analysis found that patients with schizophrenia spectrum illnesses

were 1.5 times as likely to have a diagnosis of HIV compared to recipients without a diagnosis of

serious mental illness (Blank et al. 2002). Additionally, recent retrospective evaluations of both

large Department of Veterans Affairs and civilian populations indicate that patients with

schizophrenia or severe mental illness have rates of hepatitis C virus (HCV) seropositivity of

approximately 20% (Huckans et al. 2006; Meyer and Nasrallah 2003) and that the rate of HCV

infection in patients with schizophrenia is 11 times higher than found in the general population

(Osher et al. 2003; Rosenberg et al. 2001). Risk factors such as unsafe sexual practices, combined

with multiple partners, place patients with schizophrenia at heightened risk for sexually

transmitted diseases (Sewell 1996). Patients should be asked about their sexual practices and,

when indicated, tested for HIV and hepatitis. Discussions that provide education about safe sex are

important. For those schizophrenic patients with HIV/AIDS or hepatitis, a close collaboration with a

medical specialist is essential, as treatment may be complicated by poor adherence,

neuropsychiatric consequences of antiviral therapies (e.g., interferon), and drug–drug and

drug–disease interactions.

Extrapyramidal Side Effects

The term extrapyramidal side effects (EPS) describes a spectrum of adverse reactions, including

akathisia, parkinsonism, and acute dystonia, induced in some patients by antipsychotic

medications. Parkinsonism and acute dystonia are associated with the degree of dopamine D2

receptor occupancy in the striatum (Kapur and Remington 1996). Thus, high-potency

first-generation antipsychotics, such as haloperidol, have the greatest propensity (especially at

high doses) to cause these side effects, but many second-generation agents, such as risperidone,

olanzapine, and ziprasidone, also may cause EPS in a dose-dependent manner. The CATIE study

found that the rate of drug discontinuation due to reported EPS was 8% in the patient group

treated with the typical antipsychotic perphenazine, with rates of 4% for ziprasidone, 3% for

risperidone and quetiapine, and 2% for olanzapine (Lieberman et al. 2005). Among thePrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

17 of 51

10/05/2009 16:35

second-generation agents, quetiapine and clozapine do not appear to produce clinically significant

parkinsonism or dystonia. In addition, aripiprazole has a low propensity to cause EPS (Ohlsen and

Pilowsky 2005), although there are case reports of akathisia (Cohen et al. 2005) and parkinsonism

(Cohen et al. 2005; Sharma and Sorrell 2006; Ziegenbein et al. 2006) occurring with this drug.

Akathisia, a disturbing sense of inner restlessness and the inability of the patient to stay still, is

associated with seemingly purposeless movements (such as tapping or pacing) that may be

noticeable to the examiner. The restlessness of akathisia may be misdiagnosed as an increase in

psychosis, one that worsens when treated by higher doses of antipsychotic medication. Like other

EPS, akathisia appears less likely to occur with second-generation agents (Glazer 2000b). Although

lowering the dose of the antipsychotic is an obvious treatment for akathisia, addition of a -blocker

(e.g., propranolol) is often effective. Anticholinergic drugs and benzodiazepines are generally not

that effective but can be tried in patients who fail to respond to -blockers, and anticholinergics

also may be useful in patients with coexisting parkinsonism.

Parkinsonism (Osser 1999), characterized by tremor, rigidity, and bradykinesia, can occur early in

treatment, usually within the initial weeks or months. Bradykinesia includes generalized slowing of

movement and a mask-like face (with a loss of facial expression); it may be confused with

depression or negative symptoms. One variant of parkinsonism, akinesia, can coexist with

bradykinesia (but without tremor or rigidity) and may be associated with symptoms of apathy and

fatigue. The “rabbit syndrome” (Casey 1999), occurring after months or years of antipsychotic drug

treatment, is also a variant of parkinsonism and is characterized by a perioral and jaw tremor. As

with other forms of EPS, the second-generation antipsychotics appear less likely to cause

parkinsonism than the older agents (Glazer 2000b), although the rate of parkinsonism may be dose

related with some of the newer agents. Anticholinergic medications are the treatment of choice and

usually are effective. Lower doses of antipsychotics and a switch to an agent less likely to produce

EPS also may be helpful.

Acute dystonia occurs most commonly during the week after initiation of antipsychotics or following

an abrupt and rapid dose increase (Ayd 1961; Barnes and Spence 2000; Remington and Kapur

1996). Age is an important risk factor; dystonia occurs most commonly in children and young

adults, especially in males. The dystonia may appear as torticollis, trismus, tongue protrusion,

pharyngeal constriction, laryngospasm, blepharospasm, oculogyric crisis, or abnormal contractions

of any part of the body. Clinically, in addition to the dystonic muscular contractions that may be

immediately noticeable, the patient may complain of tongue thickening, throat tightening, and

difficulty speaking or swallowing. Acute treatment with either an anticholinergic agent or an

antihistamine is usually highly effective but may need to be repeated at intervals if acute dystonia

recurs (before the dose of the anticholinergic is stabilized). Should respiratory difficulty develop,

medications may need to be given parenterally.

Tardive Dyskinesia and Tardive Dystonia

Tardive dyskinesia, which is a syndrome of potentially irreversible involuntary movements, and

tardive dystonia, which is characterized by sustained muscle contractions, can gradually emerge

after a prolonged period of treatment with antipsychotic medications. Accumulating evidence

suggests that the second-generation antipsychotics are less likely to cause these tardive syndromes

than the first-generation drugs (Jeste et al. 1998; Kane et al. 1993; Marder et al. 2002; Margolese

et al. 2005; Shirzadi and Ghaemi 2006; Tarsy and Baldessarini 2006; Tollefson et al. 1997).

However, since many patients have had exposure to more than one second-generation agent, it is

difficult to determine the risk associated with individual agents. It appears that compared with the

first-generation agents, collectively the second-generation drugs carry one-fifth to one-twelfth the

risk of causing tardive dyskinesia and tardive dystonia (Correll et al. 2004; Kane 2004; Leucht et al.

2003b; Margolese et al. 2005; Tarsy and Baldessarini 2006).

The most common form of tardive dyskinesia involves dyskinetic movements of the orofacial and

buccolingual musculature, manifesting as grimacing, facial tics, lip smacking, chewing, and

wormlike movements of the tongue. Involvement of the neck, axial, and extremity musculature alsoPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

18 of 51

10/05/2009 16:35

may occur in the form of choreoathetoid movements, which on rare occasions may involve

laryngopharyngeal and respiratory muscles. Tardive dystonia may occur earlier in treatment than

tardive dyskinesia and is characterized by slow, sustained twisting movements of the head, neck,

trunk, and extremities; blepharospasm, torticollis, facial grimacing, back arching, and

hyperextension and rotation of the limbs may also be seen (Simpson 2000).

Among the risk factors for tardive dyskinesia, age appears quite important; elderly individuals have

an incidence five to six times higher than that in younger people (Kane 2004). Tardive dyskinesia

occurs more frequently in older female patients (Jeste 2000; Saltz et al. 1991), whereas tardive

dystonia is more common in younger patients and males. Other risk factors for tardive dyskinesia

include mood disorders (Keck et al. 2000), race/ethnicity (African American) (Keck et al. 2000),

high doses of medication (Glazer 2000a, 2000c), previous evidence of parkinsonian side effects

from antipsychotics (Keck et al. 2000), early onset of extrapyramidal syndromes (Kane 2004), and

substance abuse (Miller et al. 2005).

Although no treatment has been proven to be effective for tardive dyskinesia, several management

strategies may be clinically useful. Clinicians should screen patients taking antipsychotic

medications on a regular basis. If tardive dyskinesia develops, switching from a first-generation to

a second-generation drug may be helpful. For those patients who are taking a second-generation

agent, a switch to another second-generation drug may be considered. Among the

second-generation drugs, evidence suggests that clozapine may reduce symptoms of tardive

dyskinesia (Glazer 2000a; Lieberman et al. 1991). Symptoms may also be suppressed, at least

temporarily, by increasing the dosage of the antipsychotic medications that produce tardive

dyskinesia; however, this strategy runs the risk of causing or worsening EPS and possibly

increasing tardive dyskinesia over time. Patients with tardive dyskinesia who are taking

anticholinergic medications should have these medications discontinued, because they can worsen

tardive dyskinesia. Finally, the symptoms of tardive dystonia may be alleviated by reducing the

dosages of the antipsychotics, by switching from first-generation to second-generation agents

(including clozapine), by using anticholinergics, and/or by administering dopamine-depleting

agents, such as reserpine or tetrabenazine (Simpson 2000).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), which occurs in about 1%–2% of patients receiving typical

antipsychotic medication and is potentially fatal in up to 20% of the cases (without treatment), has

been reported to occur during treatment with both the typical (Caroff and Mann 1993) and the

atypical (Ananth et al. 2004; Hasan and Buckley 1998; Wirshing et al. 2000) antipsychotics. Several

factors may increase risk, including intramuscular injections, rapid escalation of high doses of

antipsychotic medication, dehydration, restraint use, and high temperatures. Catatonia and severe

disorganization are clinical symptoms that may be associated with a high risk for NMS (Berardi et

1. 2002). Symptoms of NMS include hyperpyrexia, altered consciousness, muscle rigidity and

dystonia, autonomic nervous system dysfunction, and laboratory tests indicating elevated creatine

phosphokinase, liver enzymes, and white blood cell count. Early detection and rapid treatment of

this medical emergency are crucial and include discontinuation of the antipsychotic, treatment in a

medical setting that can support vital functioning, and in some cases the use of a dopamine agonist

such as bromocriptine or dantrolene, a muscle relaxant (Koppel 1998; Susman 2001).

Hyperprolactinemia

Antipsychotic medications—particularly typical agents, risperidone, and paliperidone—can produce

an increase in serum prolactin levels (Dickson and Glazer 1999; Marder et al. 2004). Although early

studies reported few negative consequences of long-term prolactin elevation (Meltzer 1985), this

topic has received increased attention in recent years. It is well known that hyperprolactinemia

secondary to medical disorders (e.g., pituitary tumor) can produce galactorrhea, hypogonadism

(evidenced by sexual and menstrual dysfunction and diminished gonadal hormone levels), and

osteoporosis, all of which have also been reported in patients with schizophrenia (Abraham et al.

1996; Ghadirian et al. 1982; Riecher-Rossler et al. 1994; Windgassen et al. 1996; Yazigi et al.Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

19 of 51

10/05/2009 16:35

1997). Yet the relationships between antipsychotic-induced hyperprolactinemia and these

conditions, perhaps with the exception of galactorrhea (Windgassen et al. 1996), remain unclear,

with conflicting reports in the literature (Canuso et al. 2002; A. M. Costa et al. 2007; Hummer et al.

2005; Kinon et al. 2006; Kleinberg et al. 1999; O’Keane and Meaney 2005). Interestingly, several

reports suggest that hypoestrogenism in schizophrenia occurs in women with and without

hyperprolactinemia (Bergemann et al. 2005; Canuso et al. 2002; T. J. Huber et al. 2004). Thus,

while prolactin-related hypogonadism may contribute to the increased risk of these conditions, it

appears that patients with schizophrenia may be at inherent risk for hypogonadism. The important

question of whether drug-induced hyperprolactinemia increases long-term breast cancer risk has

also been raised. Although a large claims database analysis found a 16% increase in the risk of

breast cancer in women exposed to dopamine antagonists, the authors concluded that these results

are preliminary and potentially confounded and should not necessarily lead to changes in treatment

strategies (Wang et al. 2002). Finally, a recent retrospective review of pharmacovigilance data

suggested that treatment with potent D2 receptor antagonists, such as risperidone, may be

associated with increased risk for pituitary tumors (Szarfman et al. 2006). Prospective studies are

needed to confirm this association.

Clinicians should inquire about possible adverse effects of hyperprolactinemia and aim to diminish

them. If a patient is symptomatic, prolactin levels should be obtained and medical causes of

hyperprolactinemia ruled out. Prolactin elevation associated with galactorrhea, or sexual and

menstrual dysfunction, may be minimized by dosage reduction or by a medication change to an

atypical antipsychotic with less prolactin-elevating potential (Canuso et al. 1998; Dickson and

Glazer 1999). Because patients with schizophrenia generally require chronic treatment with

antipsychotics, those who have had prolonged hyperprolactinemia may be at an increased risk for

osteoporosis (Abraham et al. 1996) and may be appropriate candidates for screening with bone

densitometry. Female patients should have routine mammography in accordance with the screening

guidelines set forth for all women.

PSYCHIATRIC CONDITIONS COMORBID WITH SCHIZOPHRENIA AND

THEIR TREATMENT

Substance-Related Disorders

Nearly one-half of the patients with schizophrenia are reported to have a lifetime history of an

alcohol or a substance use disorder, compared with 16% of the general population (Regier et al.

1990). Alcohol is the most commonly abused substance in chronically ill patients, followed by

cannabis and cocaine (Selzer and Lieberman 1993; Sevy et al. 1990); first-episode patients appear

more likely to abuse cannabis over other substances (Rolfe et al. 1999). As in the general

population, men with schizophrenia are more likely to abuse substances than are women (Mueser

et al. 1995).

The use of alcohol, marijuana, cocaine, and other substances can cause serious problems for

patients with schizophrenia. Comorbid substance use has a deleterious effect on both physical

health and the long-term course of schizophrenia itself (Grech et al. 1999); use of even small

amounts can produce negative effects (D’Souza et al. 2005; Drake et al. 2001). Patients with

schizophrenia and substance abuse are at increased risk for infectious diseases such as HIV,

hepatitis B, and hepatitis C (Rosenberg et al. 2001); in addition, alcohol and substance use is

associated with clinical worsening, poor functioning, and an increased rate of hospitalizations and

homelessness (Dixon et al. 1990; Drake and Mueser 1996; Hurlburt et al. 1996a; Negrete et al.

1986; Soni and Brownlee 1991). In some studies, more than 50% of the first-episode patients have

been reported to have cannabis use disorder (Rolfe et al. 1999), often complicating the diagnosis of

a psychotic disorder (Addington 1999). Comorbid alcohol and substance use often has an

overwhelmingly negative effect on the ability of patients to function at their highest possible level

(Dickey and Azeni 1996).

Given the negative consequences of substance abuse in these patients, investigators have tried to

understand the basis of such use. One theory, the “self-medication” hypothesis, suggests thatPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

20 of 51

10/05/2009 16:35

alcohol and substances of abuse help to decrease negative symptoms of schizophrenia and the EPS

produced by antipsychotic medications (Glynn and Sussman 1990; Khantzian 1985; Siris 1990).

However, although alcohol and substances of abuse may in fact transiently alleviate negative

symptoms and EPS, our group has suggested that the existence of negative symptoms or EPS of

antipsychotics may not be causally related to the substance use (A. I. Green et al. 1999). Some

studies indicate that patients with few negative symptoms may actually use substances more than

do those with more negative symptoms (Buchanan et al. 1997; Lysaker et al. 1994). Also,

first-episode patients, who have not yet been exposed to antipsychotic medication and who

therefore could not have EPS, are quite likely to use alcohol or substances (A. I. Green et al. 2004).

We (A. I. Green et al. 1999; Roth et al. 2005) have introduced a neurobiological formulation, based

on animal studies (Svensson et al. 1995), suggesting that a deficiency in the dopamine-mediated

mesocorticolimbic brain reward circuit of patients with schizophrenia may underlie the use of

alcohol and substances in these patients. This formulation posits that alcohol and substances of

abuse may ameliorate this deficiency by improving the “signal detection” capability of

dopamine-rich systems, by which they reduce negative symptoms and EPS while enhancing the

reward system (Fadda et al. 1989; Goeders and Smith 1986; A. I. Green et al. 1999). A related

neurobiological formulation also has been proposed by Chambers et al. (2001).

Although obtaining information from patients about the use of substances of abuse should be a

standard part of a medical history, alcohol or substance abuse is often underrecognized and

undertreated in mental health settings (Ananth et al. 1989). Because patients often deny the use of

alcohol and drugs, clinicians also should pursue collateral reports from family members, case

managers, and others involved in the delivery of services to patients. Unfortunately, the traditional

separation of mental health and substance abuse services compounds the problems of detection.

Patients with schizophrenia and a comorbid alcohol or substance use disorder require specialized

treatment for both disorders (Bellack and DiClemente 1999), optimally in programs that provide

integrated mental health and substance abuse treatment, as well as medication management

(Drake and Mueser 2001; Minkoff 1989; Osher and Kofoed 1989). Drake and Mueser (2001)

reported that the treatment of comorbid substance abuse requires long-term comprehensive

services (Osher and Kofoed 1989), including individual treatment planning tailored to the patient’s

ability to engage in treatment and assertive outreach (Drake and Mueser 2000; Ziedonis et al.

2000), with interventions within the social support system. The specific integrated interventions for

substance abuse in patients with schizophrenia with the most evidence are group counseling with

cognitive-behavioral and motivational components (Bellack et al. 2006; Weiss et al. 2007),

contingency management (Drebing et al. 2005; Ries et al. 2004), and, for patients who do not

respond to less intensive interventions, long-term residential programs (Brunette et al. 2004).

Although there is no agreed-upon pharmacological treatment approach for patients with

schizophrenia and comorbid alcohol or substance use disorders (A. I. Green et al. 2007, 2008;

Wilkins 1997), some investigators have been interested in the potential role of atypical

antipsychotics in these patients. The atypical antipsychotic that has been studied most in this

population is clozapine. Three preliminary studies—a naturalistic study (Drake et al. 2000) and two

retrospective studies (A. I. Green et al. 2003; Zimmet et al. 2000)—reported a large reduction in

alcohol use in patients taking clozapine; evidence also was found for a reduction in cannabis and

cocaine use. Two other studies (Buckley et al. 1999; Lee et al. 1998) also have reported this

beneficial effect of clozapine in patients with schizophrenia and comorbid substance use disorder.

Clozapine was also associated with reduced rates of relapse to substance abuse in patients who had

been in remission (Brunette et al. 2006). Randomized trials of clozapine needed to confirm these

preliminary studies are currently under way.

The data concerning the potential effect of the other atypical antipsychotics are even more

preliminary. Reports on risperidone appear to be conflicted (Albanese 2000; A. I. Green et al.

2003), although a report by Smelson et al. (2000) found that cocaine-abusing schizophrenic

patients treated with risperidone experienced less craving, had fewer relapses, and remained in

treatment longer than did those treated with typical antipsychotics. Recently, Rubio et al. (2006)Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

21 of 51

10/05/2009 16:35

reported that the new LAI form of risperidone was more effective in improving substance abuse

than a depot form of the typical agent zuclopenthixol (which is not available in the United States),

but the difference was small and probably not clinically significant. However, a report of data from

a large Veterans Administration treatment group showed no advantage for either risperidone or

olanzapine compared with typical antipsychotics on clinical substance abuse measures (Petrakis et

1. 2006). Two other open prospective studies of olanzapine treatment noted improvements in

substance use, but one of them (Noordsy et al. 2001), which might have been limited by statistical

power, did not find significant advantages of olanzapine over typical antipsychotic treatment

(Littrell et al. 2001; Noordsy et al. 2001). Two randomized trials of olanzapine’s impact on cocaine

craving and use compared to typical antipsychotics also reported conflicting results (Sayers et al.

2005; Smelson et al. 2006). Preliminary research on quetiapine and aripiprazole is promising. Two

open studies of quetiapine (E. S. Brown et al. 2003; Potvin et al. 2006) and of aripiprazole

(Beresford et al. 2005; E. S. Brown et al. 2005) suggest that these medications may be helpful for

alcohol and/or cocaine use disorders in patients with schizophrenia. No research has assessed the

impact of ziprasidone.

Other possible pharmacological options for treatment of alcohol or substance use disorder in

schizophrenia include the following: 1) disulfiram (Kofoed et al. 1986), which one randomized,

placebo-controlled trial (Petrakis et al. 2005) and one open trial (Mueser et al. 2003) suggest is

effective for alcohol dependence in patients with schizophrenia but requires monitoring (Kofoed et

1. 1986); 2) naltrexone, which was found to decrease alcohol use among patients with

schizophrenia in two randomized, placebo-controlled trials (Petrakis et al. 2004, 2005); 3) the

tricyclic antidepressants desipramine or imipramine for the treatment of comorbid cocaine

disorders (Siris et al. 1993; Ziedonis et al. 1992); and 4) bupropion for the treatment of nicotine

dependence in these patients (George et al. 2002). Acamprosate, although shown to be effective for

alcohol dependence in placebo-controlled trials, has yet to be studied in patients with

schizophrenia. Clearly, more studies need to be undertaken to develop optimal pharmacological

strategies for the treatment of these comorbid disorders.

Depression

Schizophrenia is often associated with depressive states, from dysphoria to major depression. The

Epidemiologic Catchment Area study suggests that those with schizophrenia have a 14-fold greater

risk of depression than the general population (Fenton 2001). At various times, depression has

been viewed as an aspect of schizophrenia (McGlashan and Carpenter 1976; Sax et al. 1996), as a

response to psychosis (McGlashan and Carpenter 1976; Sax et al. 1996), or as a state occurring

after the cessation of frank psychotic symptoms (Birchwood et al. 2000). Depressive symptoms can

occur throughout the course of schizophrenia, including in first-episode patients (Hafner et al.

2005; Koreen et al. 1993), but in chronically ill patients in particular, these symptoms appear to be

associated with risk of relapse (Mandel et al. 1982) and suicide (Drake et al. 1986).

Assessing patients with schizophrenia for the presence of depression requires knowledge of the

types of depressive states in patients with schizophrenia and the conditions, such as negative

symptoms and EPS, that can be confused with depression. In detecting depression, the presence of

a core depressed mood and related neurovegetative symptoms should be distinguished from

flatness of affect and anhedonia (McGlashan and Carpenter 1976). Depression occurring during an

exacerbation of psychosis may remit with treatment of the psychosis (Birchwood et al. 2000;

Koreen et al. 1993; Tollefson et al. 1999). However, postpsychotic depression classically develops

after the resolution or improvement of psychotic symptoms, particularly in first-episode patients

(Birchwood et al. 2000; Koreen et al. 1993). Moreover, dysphoria and demoralization frequently

occur in patients with schizophrenia (Iqbal et al. 2000; Siris 2000a), as patients struggle with

illness-related disability, but these symptoms may not be associated with the classical

neurovegetative symptoms of depression (Bartels and Drake 1988).

Treatment of depression in patients with schizophrenia may include both psychopharmacological

and psychosocial components (Siris 2000b). Because depression may presage an increase in Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

22 of 51

10/05/2009 16:35

psychosis, the adequacy of pharmacological treatment of psychotic symptoms should be assessed.

Treatment of depression in acute psychosis may be accomplished through the use of antipsychotic

medication alone, especially the atypical antipsychotics (Banov et al. 1994; Levinson et al. 1999;

Marder et al. 1997; Tollefson et al. 1998). However, major depression developing after the

remission of psychosis often requires more specific intervention, such as treatment with

combinations of antipsychotics and antidepressants or mood stabilizers (Levinson et al. 1999).

Postpsychotic depression may benefit from the addition of tricyclic antidepressants or serotonin

reuptake inhibitors to the antipsychotic medication (Hogarty et al. 1995; Kirli and Caliskan 1998;

Siris et al. 1987). However, demoralization and dysphoria do not appear to be responsive to

antidepressants (Iqbal et al. 2000; Levinson et al. 1999); rather, appropriate psychosocial

interventions (e.g., stress management, job training, cognitive therapy, support) may be most

helpful (Siris 2000b).

Suicide

Suicide is the leading cause of premature death in patients with schizophrenia, who have a 10%

lifetime risk of suicide. Nearly 50% of the patients with schizophrenia attempt suicide during their

lifetime (Black et al. 1985; Tsuang et al. 1999a). The risk of suicide is as high in patients with

schizophrenia as in patients with mood disorder and is 10-fold higher than in the general population

(Baxter and Appleby 1999). Several factors are associated with an increased risk of suicide in

patients with schizophrenia: depression and the diagnosis of schizoaffective disorder

(Harkavy-Friedman et al. 2004; Radomsky et al. 1999), social isolation (Drake et al. 1986; G.

Goldstein et al. 2006; Potkin et al. 2003), and feelings of hopelessness and disappointment over

failure to meet high self-expectations (Kim et al. 2003; Westermeyer et al. 1991). Patients with a

higher level of insight and awareness of their illness may be at increased risk (Amador et al. 1996;

Bourgeois et al. 2004; Crumlish et al. 2005), as may patients with a poor level of functioning

(Kaplan and Harrow 1996).

A history of suicide attempts is one of the strongest predictors of suicide in patients with

schizophrenia (Rossau and Mortensen 1997; Roy 1982a). In a large 2-year prospective study of 980

schizophrenia and schizoaffective disorder patients at high risk for suicide, multivariate analysis

found the number of lifetime suicide attempts, number of hospitalizations to prevent suicide in the

previous 3 years, history of alcohol or substance abuse, baseline anxiety scale score, and severity

of parkinsonism to be the strongest predictors of suicide (Potkin et al. 2003). Moreover, a recent

meta-analysis of 29 case–control and cohort studies indicated that suicide risk factors included

previous depressive disorders, drug abuse, agitation or motor restlessness, fear of mental

disintegration, poor adherence to treatment, and recent loss (Hawton et al. 2005).

Gender also appears to be a risk factor (Rossau and Mortensen 1997); men with schizophrenia

commit suicide at an earlier age than do women with schizophrenia (Roy 1982a). An increased risk

of suicide is present in the early phase of the illness (Drake et al. 1985; Kuo et al. 2005; Ran et al.

2005), especially in those patients with an earlier age at onset of schizophrenia (Gupta et al. 1998).

The risk of suicide appears to peak immediately after admission and shortly after discharge (Qin

and Nordentoft 2005; Rossau and Mortensen 1997), especially in patients who are hospitalized for

short periods (Qin and Nordentoft 2005) and in those who return to a socially isolated environment

(Drake et al. 1986). Patients in an active phase of the illness (Heila et al. 1997) or with positive

symptoms (Kelly et al. 2004) may be at risk, especially if they have prominent symptoms of

suspiciousness and delusions (Fenton et al. 1997).

A national clinical survey conducted in Great Britain, based on a 4-year (1996–2000) sample of

people who died by suicide, found that the deaths of schizophrenia patients were characterized by

more violent methods: they were more likely than others to be young, male, unmarried, and from

an ethnic minority, with high rates of unemployment (Hunt et al. 2006). Moreover, rates of previous

violence and drug abuse were high, and suicide victims were proportionally more likely to be

inpatients at the time of death and to have been noncompliant with medication (Hunt et al. 2006).

In another study (Roy 1982b), half of all patients who committed suicide had been seen in thePrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

23 of 51

10/05/2009 16:35

week prior, and in another study (Heila et al. 1997), between 49% and 96% of the patients had

been seen within 3 months of the suicide.

The treating clinician should regularly evaluate the patient’s condition, assess for suicide risk

factors, and aim to enhance protective factors such as social support and positive coping skills

(Montross et al. 2005). Patients who present with suicidal thoughts or behavior require close

follow-up and intensive outreach. For the isolated or newly diagnosed patient, a clear aftercare plan

(often in a day treatment center) should be in place before discharge from the hospital (Drake et al.

1986; Harkavy-Friedman and Nelson 1997). Improved ward safety, effective substance abuse

treatment, affective symptom control, and ensured medication adherence are all measures that

may prevent suicide (Hawton et al. 2005; Hunt et al. 2006). Additionally, evidence suggests that

community programs for early detection of schizophrenia may reduce suicidality risk (Melle et al.

2006).

Psychopharmacological treatment plays a crucial role in the prevention of suicide. In one study,

more than half of the patients who committed suicide were either medication noncompliant or

prescribed inadequate doses of antipsychotics, and 23% of the sample were thought to be

nonresponsive to treatment (Heila et al. 1999). Moreover, a landmark study of nearly 1,000

patients with schizophrenia and schizoaffective disorder who were at risk for suicide (but who were

not necessarily classically treatment resistant) indicated that treatment with clozapine was more

likely to decrease suicidality than was treatment with olanzapine (Meltzer et al. 2003).

Obsessive-Compulsive Symptoms

Obsessive-compulsive symptoms are seen in 8.8%–30% of patients with schizophrenia (I. Berman

et al. 1995a; Byerly et al. 2005; Cassano et al. 1998; Ongur and Goff 2005). Although

obsessive-compulsive symptoms may be difficult to distinguish from delusions (Eisen et al. 1997),

they are important to identify because they may indicate a poor prognosis, yet they may be

responsive to specialized treatment regimens. Most studies have indicated that

obsessive-compulsive symptoms are associated with unfavorable outcomes—with increased social

isolation, longer hospitalizations, greater psychopathology, and poor treatment response (Fenton

and McGlashan 1986; Hwang et al. 2000; Ongur and Goff 2005). By contrast, a more recent study

(N = 58) suggested that the presence of obsessive-compulsive symptoms does not impact clinical

outcomes (Byerly et al. 2005). The obsessive-compulsive symptoms in schizophrenia are similar to

those found in obsessive-compulsive disorder (Tibbo et al. 2000), although they may not be

ego-dystonic in patients with schizophrenia.

Treatment of obsessive-compulsive schizophrenia may require the use of a tricyclic antidepressant

or a serotonin reuptake inhibitor with a typical antipsychotic (I. Berman et al. 1995b; Chang and

Berman 1999; Poyurovsky et al. 2000). The data regarding the role of atypical agents in these

patients are mixed (Fenton 2001). Some reports suggest that atypical antipsychotics may

exacerbate obsessive-compulsive symptoms, whereas others suggest that they may be helpful

(Baker et al. 1992, 1996; Kopala and Honer 1994; Morrison et al. 1998; Ongur and Goff 2005;

Strous et al. 1999). Although the addition of a serotonin reuptake inhibitor to an atypical

antipsychotic may decrease obsessive-compulsive symptoms in these patients (as the addition of a

serotonin reuptake inhibitor to some typical agents does), the combined use of serotonin reuptake

inhibitors with clozapine, especially, may require care because of the possible increase in blood

levels of clozapine.

FUTURE DIRECTIONS

Novel Pharmacotherapeutic Treatment

Although all existing antipsychotic medications have effects on the dopamine system, other

neurotransmitter systems are increasingly being recognized as possible therapeutic targets. For

instance, the glutamate hypothesis of schizophrenia (Coyle 1996; Goff and Coyle 2001; Javitt and

Zukin 1991; Olney and Farber 1995) suggests that modulation of glutamatergic activity could be a

potential target for pharmacological treatment of schizophrenia. The glutamate hypothesis is, to aPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

24 of 51

10/05/2009 16:35

large extent, derived from the observation that treatment of healthy subjects with

N-methyl-D-aspartate (NMDA) antagonists, such as ketamine and phencyclidine (PCP), produces

symptoms reminiscent of schizophrenia (Adler et al. 1998; Newcomer et al. 1999). Most important,

in addition to the psychotic symptoms, which can be induced by a variety of central nervous system

stimulants or hallucinogens, NMDA antagonists uniquely produce many of the cognitive deficits

associated with schizophrenia (Krystal et al. 1994) and symptoms that resemble the negative

symptoms of the illness (Abi-Saab et al. 2001). Thus, it would follow that drugs that enhance NMDA

receptor function might be beneficial in the treatment of negative symptoms of schizophrenia

(Javitt 2006; Javitt and Coyle 2004).

Because of the possible risks of neurotoxicity as a result of direct stimulation of NMDA receptors,

drugs that indirectly enhance NMDA neurotransmission by modulating other binding sites on the

NMDA receptor complex have been studied. For example, D-cycloserine (a partial agonist) (Goff et

1. 1999), D-serine (Tsai et al. 1998), D-alanine (Tsai et al. 2006), glycine (Heresco-Levy et al.

1996a, 1996b; Javitt et al. 2001), agonists of the glycine binding site (located adjacent to the

NMDA ion channel), and sarcosine (a glycine transporter-1 inhibitor) (Tsai et al. 2004) have been

shown to have therapeutic potential. Preliminary data are quite promising, in that all of these

agents appear to be effective in improving negative symptoms of schizophrenia, although their

effects on positive symptoms, if any, tend to be very modest (Goff and Coyle 2001; Tsai et al.

1998), and it appears that they may not be effective in patients treated with clozapine (Goff et al.

1996; Potkin et al. 1999); but see Javitt et al. 2001).

Non-NMDA glutamate receptors may also be potential targets for treatment. For example, a recent

preliminary study demonstrated that a selective agonist of metabotropic glutamate 2/3 (mGlu2/3)

receptors, used as monotherapy, was efficacious in reducing both positive and negative symptoms

in 196 patients with schizophrenia (Patil et al. 2007). MGlu2/3 agonists, which blunt the effects of

PCP in animals, are thought to work in part by modulating glutamate release (Patil et al. 2007).

This study suggests that agents that do not directly block dopamine receptors may have therapeutic

potential in schizophrenia.

Another novel approach to the treatment of schizophrenia is the development of drugs that act as

partial dopamine agonists. These drugs bind to dopamine receptors, including the presynaptic

autoreceptors, with high affinity but with variable intrinsic activity, depending on the activity level

of the target system (Tamminga 2002). Because of this, they exert a wide range of modulatory

effects on the dopaminergic system. The first FDA-approved drug with this mechanism is

aripiprazole.

Given the increasing evidence suggesting that neurocognitive deficits are pervasive in patients with

schizophrenia and that they are important determinants of long-term functional outcome, there has

been considerable interest in developing compounds that target these deficits. Drugs that may be

effective, at least in theory, in the treatment of neurocognitive deficits include muscarinic agonists,

alpha 7 nicotinic receptor agonists (Martin et al. 2007), ampakines (agonists of the AMPA

[amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] class of glutamate receptors) (Goff and

Coyle 2001), class I metabotropic glutamate receptor agonists (Moghaddam 2004), dopamine D1

receptor agonists (G. V. Williams and Castner 2006), and alpha 2 -aminobutyric acid (GABA) type

A (GABAA) receptor agonists (D. A. Lewis and Gonzalez-Burgos 2006). Although clinical experience

with these drugs is quite limited, there are ongoing clinical trials to test the possible efficacy of at

least some of these compounds.

Early Intervention and Prevention of Schizophrenia

As emphasized earlier in this chapter, some investigators have suggested that early detection and

treatment of first-episode psychosis may improve the long-term prognosis of schizophrenia. In

recent years, there have even been attempts to identify individuals who are in the prodromal phase

of schizophrenia but have not yet developed psychosis (Yung and McGorry 1996b), with the notion

that intervention, including psychopharmacological treatment, during this period of the illness mayPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

25 of 51

10/05/2009 16:35

be able to prevent the onset of full-blown psychosis (McGorry et al. 2002). However, as has been

discussed in this chapter, many of the prodromal symptoms, among which depression and anxiety

are common manifestations, are not specific to schizophrenia and are not uncommonly observed in

otherwise healthy adolescents (McGorry et al. 1995). The issue of misidentification of individuals

who are not at risk for psychosis must be considered. The current challenge is to establish the

predictive validity of specific traits or prodromal symptoms of the diagnosis or recognition of the

prodrome as a syndrome. However, even if these individuals can be reliably identified, the modes of

treatment, including the specific classes of medications, that may be most effective in preventing

the onset of psychosis are at present virtually unknown (Cannon et al. 2007; McGlashan et al.

2007).

Another concept that may help clarify prodrome is the notion of schizotaxia, which was originally

put forward by Meehl (1962, 1989) and reformulated by Faraone et al. (2001) to describe a

constellation of negative symptoms and neuropsychological deficits present in 20%–50% of the

first-degree relatives of patients with schizophrenia. Preliminary findings from treatment of six

such relatives meeting criteria for schizotaxia with low-dose risperidone (up to 2 mg) for 6 weeks

suggested that this treatment may improve the deficits associated with this condition (Tsuang et al.

1999b). If the validity of schizotaxia as a “preschizophrenic” trait could be established (Tsuang et

1. 2000), it would be important to determine whether treatment of schizotaxia in individuals with

prodromal symptoms could actually be associated with a decrease in the incidence of

schizophrenia.

REFERENCES

Abi-Saab WM, D’Souza C, Madonick S, et al: Targeting the glutamate system, in Current Issues in

the Psychopharmacology of Schizophrenia. Edited by Breier A, Tran PV, Herrea JM, et al.

Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 304–332

Abraham G, Friedman RH, Verghese C: Osteoporosis demonstrated by dual energy x-ray

absorptiometry in chronic schizophrenic patients. Biol Psychiatry 40:430–431, 1996 [PubMed]

Addington J: Early intervention strategies for co-morbid cannabis use and psychosis. Presented at

the Inaugural International Cannabis and Psychosis Conference, Melbourne, Australia, February

16–19, 1999

Adler CM, Goldberg TE, Malhotra AK, et al: Effects of ketamine on thought disorder, working

memory, and semantic memory in healthy volunteers. Biol Psychiatry 43:811–816, 1998 [PubMed]

Albanese MJ: Risperidone in substance abusers with bipolar disorder. Presented at the 39th Annual

Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, 2000

Allison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a comprehensive research

synthesis. Am J Psychiatry 156:1686–1696, 1999 [Full Text] [PubMed]

Amador XF, Friedman JH, Kasapis C, et al: Suicidal behavior in schizophrenia and its relationship to

awareness of illness. Am J Psychiatry 153:1185–1188, 1996 [Full Text] [PubMed]

American Diabetes Association, American Psychiatric Association, American Association of Clinical

Endocrinologists, et al: Consensus development conference on antipsychotic drugs and obesity and

diabetes. J Clin Psychiatry 65:267–272, 2004

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th

Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

Ananth J, Vandewater S, Kamal M, et al: Missed diagnosis of substance abuse in psychiatric

patients. Hosp Community Psychiatry 40:297–299, 1989 [PubMed]

Ananth J, Parameswaran S, Gunatilake S, et al: Neuroleptic malignant syndrome and atypical

antipsychotic drugs. J Clin Psychiatry 65:464–470, 2004 [PubMed]

Andreasen NC: Positive vs. negative schizophrenia: a critical evaluation. Schizophr BullPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

26 of 51

10/05/2009 16:35

11:380–389, 1985 [PubMed]

Andreasen NC, Carpenter WT Jr, Kane JM, et al: Remission in schizophrenia: proposed criteria and

rationale for consensus. Am J Psychiatry 162:441–449, 2005 [Full Text] [PubMed]

Angermeyer MC, Kuhn L, Goldstein JM: Gender and the course of schizophrenia: differences in

treated outcomes. Schizophr Bull 16:293–307, 1990 [PubMed]

Ayd FJ Jr: A survey of drug-induced extrapyramidal reactions. JAMA 175:1054–1060, 1961

[PubMed]

Aylward E, Walker E, Bettes B: Intelligence in schizophrenia: meta-analysis of the research.

Schizophr Bull 10:430–459, 1984 [PubMed]

Baddeley AD: Working Memory. Oxford, UK, Oxford University Press, 1986

Baker RW, Chengappa KN, Baird JW, et al: Emergence of obsessive compulsive symptoms during

treatment with clozapine. J Clin Psychiatry 53:439–442, 1992 [PubMed]

Baker RW, Ames D, Umbricht DS, et al: Obsessive-compulsive symptoms in schizophrenia: a

comparison of olanzapine and placebo. Psychopharmacol Bull 32:89–93, 1996 [PubMed]

Banov MD, Zarate CA Jr, Tohen M, et al: Clozapine therapy in refractory affective disorders: polarity

predicts response in long-term follow-up. J Clin Psychiatry 55:295–300, 1994 [PubMed]

Baptista T: Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta

Psychiatr Scand 100:3–16, 1999 [PubMed]

Barnes TRE, Spence SA: Movement disorders associated with antipsychotic drugs: clinical and

biological implications, in Psychopharmacology of Schizophrenia. Edited by Reverly MA, Deakin

JFW. New York, Oxford University Press, 2000, pp 178–210

Bartels SJ, Drake RE: Depressive symptoms in schizophrenia: comprehensive differential diagnosis.

Compr Psychiatry 29:467–483, 1988 [PubMed]

Baxter D, Appleby L: Case register study of suicide risk in mental disorders. Br J Psychiatry

175:322–326, 1999 [PubMed]

Beasley CM Jr, Sutton VK, Hamilton SH, et al: A double-blind, randomized, placebo-controlled trial

of olanzapine in the prevention of psychotic relapse. J Clin Psychopharmacol 23:582–594, 2003

[PubMed]

Bellack AS: Skills training for people with severe mental illness. Psychiatr Rehabil J 27:375–391,

2004 [PubMed]

Bellack AS, DiClemente CC: Treating substance abuse among patients with schizophrenia. Psychiatr

Serv 50:75–80, 1999 [Full Text] [PubMed]

Bellack AS, Mueser KT: Psychosocial treatment for schizophrenia. Schizophr Bull 19:317–336, 1993

[PubMed]

Bellack AS, Bennett ME, Gearon JS, et al: A randomized clinical trial of a new behavioral treatment

for drug abuse in people with severe and persistent mental illness. Arch Gen Psychiatry

63:426–432, 2006 [PubMed]

Berardi D, Dell’Atti M, Amore M, et al: Clinical risk factors for neuroleptic malignant syndrome. Hum

Psychopharmacol 17:99–102, 2002 [PubMed]

Beresford TP, Clapp L, Martin B, et al: Aripiprazole in schizophrenia with cocaine dependence: a

pilot study. J Clin Psychopharmacol 25:363–366, 2005 [PubMed]

Bergemann N, Mundt C, Parzer P, et al: Plasma concentrations of estradiol in women suffering from

schizophrenia treated with conventional versus atypical antipsychotics. Schizophr Res 73:357–366,

2005 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

27 of 51

10/05/2009 16:35

Berman I, Kalinowski A, Berman SM, et al: Obsessive and compulsive symptoms in chronic

schizophrenia. Compr Psychiatry 36:6–10, 1995a

Berman I, Sapers BL, Chang HH, et al: Treatment of obsessive-compulsive symptoms in

schizophrenic patients with clomipramine. J Clin Psychopharmacol 15:206–210, 1995b

Berman KF, Weinberger DR: Neuroimaging studies of schizophrenia, in Neurobiology of Mental

Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford University Press, 1999, pp

246–257

Bernardo M, Ramon Azanza J, Rubio-Terres C, et al: Cost-effectiveness analysis of schizophrenia

relapse prevention: an economic evaluation of the ZEUS

(Ziprasidone-Extended-Use-In-Schizophrenia) study in Spain. Clin Drug Investig 26:447–457, 2006

[PubMed]

Bertolino A, Roffman JL, Lipska BK, et al: Reduced N-acetylaspartate in prefrontal cortex of adult

rats with neonatal hippocampal damage. Cereb Cortex 12:983–990, 2002 [PubMed]

Bilder RM, Goldman RS, Volavka J, et al: Neurocognitive effects of clozapine, olanzapine,

risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J

Psychiatry 159:1018–1028, 2002 [Full Text] [PubMed]

Birchwood M: Early intervention in schizophrenia: theoretical background and clinical strategies. Br

J Clin Psychol 31(pt 3): 257–278, 1992

Birchwood M, Iqbal Z, Chadwick P, et al: Cognitive approach to depression and suicidal thinking in

psychosis, I: ontogeny of post-psychotic depression. Br J Psychiatry 177:516–521, 2000 [PubMed]

Black DW, Warrack G, Winokur G: The Iowa record-linkage study, I: suicides and accidental deaths

among psychiatric patients. Arch Gen Psychiatry 42:71–75, 1985 [PubMed]

Blank MB, Mandell DS, Aiken L, et al: Co-occurrence of HIV and serious mental illness among

Medicaid recipients. Psychiatr Serv 53:868–873, 2002 [Full Text] [PubMed]

Bond GR: Supported employment: evidence for an evidence-based practice. Psychiatr Rehabil J

27:345–359, 2004 [PubMed]

Bondolfi G, Dufour H, Patris M, et al: Risperidone versus clozapine in treatment-resistant chronic

schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry

155:499–504, 1998 [Full Text] [PubMed]

Borgwardt SJ, McGuire PK, Aston J, et al: Structural brain abnormalities in individuals with an

at-risk mental state who later develop psychosis. Br J Psychiatry Suppl 51:s69–s75, 2007

Bourgeois M, Swendsen J, Young F, et al: Awareness of disorder and suicide risk in the treatment of

schizophrenia: results of the international suicide prevention trial. Am J Psychiatry 161:1494–1496,

2004 [Full Text] [PubMed]

Braff DL: Information processing and attention dysfunctions in schizophrenia. Schizophr Bull

19:233–259, 1993 [PubMed]

Braff DL: Psychophysiological and information processing approaches to schizophrenia, in

Neurobiology of Mental Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford

University Press, 1999, pp 258–271

Braff DL, Grillon C, Geyer MA: Gating and habituation of the startle reflex in schizophrenic patients.

Arch Gen Psychiatry 49:206–215, 1992 [PubMed]

Breier A, Schreiber JL, Dyer J, et al: National Institute of Mental Health longitudinal study of chronic

schizophrenia. Prognosis and predictors of outcome. Arch Gen Psychiatry 48:239–246, 1991

[PubMed]

Breier AF, Malhotra AK, Su TP, et al: Clozapine and risperidone in chronic schizophrenia: effects onPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

28 of 51

10/05/2009 16:35

symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 156:294–298,

1999 [Full Text] [PubMed]

Brenner HD, Hodel B, Roder V, et al: Treatment of cognitive dysfunctions and behavioral deficits in

schizophrenia. Schizophr Bull 18:21–26, 1992 [PubMed]

Brown AS, Susser ES, Butler PD, et al: Neurobiological plausibility of prenatal nutritional

deprivation as a risk factor for schizophrenia. J Nerv Ment Dis 184:71–85, 1996 [PubMed]

Brown ES, Nejtek VA, Perantie DC, et al: Cocaine and amphetamine use in patients with psychiatric

illness: a randomized trial of typical antipsychotic continuation or discontinuation. J Clin

Psychopharmacol 23:384–388, 2003 [PubMed]

Brown ES, Jeffress J, Liggin JD, et al: Switching outpatients with bipolar or schizoaffective disorders

and substance abuse from their current antipsychotic to aripiprazole. J Clin Psychiatry 66:756–760,

2005 [PubMed]

Brown GW, Rutter M: The measurement of family activities and relationships: a methodological

study. Human Relations 19:241–263, 1966

Brown S, Inskip H, Barraclough B: Causes of the excess mortality of schizophrenia. Br J Psychiatry

177:212–217, 2000 [PubMed]

Browne S, Clarke M, Gervin M, et al: Determinants of neurological dysfunction in first episode

schizophrenia. Psychol Med 30:1433–1441, 2000 [PubMed]

Brunette MF, Mueser KT, Drake RE: A review of research on residential programs for people with

severe mental illness and co-occurring substance use disorders. Drug Alcohol Rev 23:471–481,

2004 [PubMed]

Brunette MF, Drake RE, Xie H, et al: Clozapine use and relapses of substance use disorder among

patients with co-occurring schizophrenia and substance use disorders. Schizophr Bull 32:637–643,

2006 [PubMed]

Buchanan RW, Strauss ME, Kirkpatrick B, et al: Neuropsychological impairments in deficit vs

nondeficit forms of schizophrenia. Arch Gen Psychiatry 51:804–811, 1994 [PubMed]

Buchanan RW, Strauss ME, Breier A, et al: Attentional impairments in deficit and nondeficit forms of

schizophrenia. Am J Psychiatry 154:363–370, 1997 [Full Text] [PubMed]

Buchanan RW, Ball MP, Weiner E, et al: Olanzapine treatment of residual positive and negative

symptoms. Am J Psychiatry 162:124–129, 2005 [Full Text] [PubMed]

Buckley P, McCarthy M, Chapman P, et al: Clozapine treatment of comorbid substance abuse in

patients with schizophrenia. Schizophr Res 36:272, 1999

Buka SL, Tsuang MT, Torrey EF, et al: Maternal infections and subsequent psychosis among

offspring. Arch Gen Psychiatry 58:1032–1037, 2001 [PubMed]

Bustillo J, Lauriello J, Horan W, et al: The psychosocial treatment of schizophrenia: an update. Am J

Psychiatry 158:163–175, 2001 [Full Text] [PubMed]

Byerly M, Goodman W, Acholonu W, et al: Obsessive compulsive symptoms in schizophrenia:

frequency and clinical features. Schizophr Res 76:309–316, 2005 [PubMed]

Cadenhead KS, Swerdlow NR, Shafer KM, et al: Modulation of the startle response and startle

laterality in relatives of schizophrenic patients and in subjects with schizotypal personality

disorder: evidence of inhibitory deficits. Am J Psychiatry 157:1660–1668, 2000 [Full Text]

[PubMed]

Cannon TD: On the nature and mechanisms of obstetric influences in schizophrenia: a review and

synthesis of epidemiologic studies. Int Rev Psychiatry 9:387–397, 1997

Cannon TD, Rosso IM, Hollister JM, et al: A prospective cohort study of genetic and perinatalPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

29 of 51

10/05/2009 16:35

influences in the etiology of schizophrenia. Schizophr Bull 26:351–366, 2000 [PubMed]

Cannon TD, Cornblatt B, McGorry P: The empirical status of the ultra high-risk (prodromal) research

paradigm. Schizophr Bull 33:661–664, 2007 [PubMed]

Canuso CM, Hanau M, Jhamb KK, et al: Olanzapine use in women with antipsychotic-induced

hyperprolactinemia. Am J Psychiatry 155:1458, 1998 [Full Text] [PubMed]

Canuso CM, Goldstein JM, Wojcik J, et al: Antipsychotic medication, prolactin elevation, and ovarian

function in women with schizophrenia and schizoaffective disorder. Psychiatry Res 111:11–20,

2002 [PubMed]

Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 77:185–202, 1993

[PubMed]

Carpenter WT Jr, Heinrichs DW, Wagman AM: Deficit and nondeficit forms of schizophrenia: the

concept. Am J Psychiatry 145:578–583, 1988 [PubMed]

Carpenter WT Jr, Hanlon TE, Heinrichs DW, et al: Continuous versus targeted medication in

schizophrenic outpatients: outcome results. Am J Psychiatry 147:1138–1148, 1990 [PubMed]

Carpenter WT Jr: New views on the course and treatment of schizophrenia. J Psychiatr Res

32:191–195, 1998 [PubMed]

Carpenter WT Jr, Gold JM: Another view of therapy for cognition in schizophrenia. Biol Psychiatry

51:969–971, 2002 [PubMed]

Carter CS, Perlstein W, Ganguli R, et al: Functional hypofrontality and working memory dysfunction

in schizophrenia. Am J Psychiatry 155:1285–1287, 1998 [Full Text] [PubMed]

Casey DE: Rabbit syndrome, in Movement Disorders in Neurology and Neuropsychiatry. Edited by

Joseph AB, Young RR. Malden, MA, Blackwell Science, 1999, pp 119–122

Cassano GB, Pini S, Saettoni M, et al: Occurrence and clinical correlates of psychiatric comorbidity

in patients with psychotic disorders. J Clin Psychiatry 59:60–68, 1998 [PubMed]

Cassens G, Inglis AK, Appelbaum PS, et al: Neuroleptics: effects on neuropsychological function in

chronic schizophrenic patients. Schizophr Bull 16:477–499, 1990 [PubMed]

Censits DM, Ragland JD, Gur RC, et al: Neuropsychological evidence supporting a

neurodevelopmental model of schizophrenia: a longitudinal study. Schizophr Res 24:289–298, 1997

[PubMed]

Chadwick PDJ, Lowe CF, Horne PJ, et al: Modifying delusions: the role of empirical testing:

innovations in cognitive-behavioral approaches to schizophrenia. Behav Ther 25:35–49, 1994

Chambers RA, Krystal JH, Self DW: A neurobiological basis for substance abuse comorbidity in

schizophrenia. Biol Psychiatry 50:71–83, 2001 [PubMed]

Chang HH, Berman I: Treatment issues for patients with schizophrenia who have

obsessive-compulsive symptoms. Psychiatric Annals 29:529–532, 1999

Cohen ST, Rulf D, Pies R: Extrapyramidal side effects associated with aripiprazole coprescription in

2 patients. J Clin Psychiatry 66:135–136, 2005 [PubMed]

Coldwell CM, Bender WS: The effectiveness of assertive community treatment for homeless

populations with severe mental illness: a meta-analysis. Am J Psychiatry 164:393–399, 2007 [Full

Text] [PubMed]

Combs DR, Adams SD, Penn DL, et al: Social Cognition and Interaction Training (SCIT) for inpatients

with schizophrenia spectrum disorders: preliminary findings. Schizophr Res 91:112–116, 2007

[PubMed]

Conley RR, Kelly DL: Current status of antipsychotic treatment. Curr Drug Targets CNS NeurolPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

30 of 51

10/05/2009 16:35

Disord 1:123–128, 2002 [PubMed]

Correll CU, Leucht S, Kane JM: Lower risk for tardive dyskinesia associated with second-generation

antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 161:414–425, 2004 [Full

Text] [PubMed]

Costa AM, de Lima MS, Faria M, et al: A naturalistic, 9-month follow-up, comparing olanzapine and

conventional antipsychotics on sexual function and hormonal profile for males with schizophrenia. J

Psychopharmacol 21:165–170, 2007 [PubMed]

Costa E, Grayson DR, Guidotti A: Epigenetic downregulation of GABAergic function in schizophrenia:

potential for pharmacological intervention? Mol Interv 3:220–229, 2003 [PubMed]

Costa E, Dong E, Grayson DR, et al: Epigenetic targets in GABAergic neurons to treat schizophrenia.

Adv Pharmacol 54:95–117, 2006 [PubMed]

Cournos F, Bakalar N: AIDS and People With Severe Mental Illness: A Handbook for Mental Health

Professionals. New Haven, CT, Yale University Press, 1996

Covey L, Hughes DC, Glassman AH, et al: Ever-smoking, quitting, and psychiatric disorders:

evidence from the Durham, North Carolina, Epidemiologic Catchment Area. Tobacco Control

3:222–227, 1994

Coyle JT: The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry

3:241–253, 1996 [PubMed]

Crow TJ: The two-syndrome concept: origins and current status. Schizophr Bull 11:471–486, 1985

[PubMed]

Crow TJ, MacMillan JF, Johnson AL, et al: A randomised controlled trial of prophylactic neuroleptic

treatment. Br J Psychiatry 148:120–127, 1986 [PubMed]

Crumlish N, Whitty P, Kamali M, et al: Early insight predicts depression and attempted suicide after

4 years in first-episode schizophrenia and schizophreniform disorder. Acta Psychiatr Scand

112:449–455, 2005 [PubMed]

Csernansky JG, Mahmoud R, Brenner R: A comparison of risperidone and haloperidol for the

prevention of relapse in patients with schizophrenia. N Engl J Med 346:16–22, 2002 [PubMed]

D’Souza DC, Abi-Saab WM, Madonick S, et al: Delta-9-tetrahydrocannabinol effects in schizophrenia:

implications for cognition, psychosis, and addiction. Biol Psychiatry 57:594–608, 2005 [PubMed]

Dalack GW, Healy DJ, Meador-Woodruff JH: Nicotine dependence in schizophrenia: clinical

phenomena and laboratory findings. Am J Psychiatry 155:1490–1501, 1998 [Full Text] [PubMed]

David AS, Malmberg A, Brandt L, et al: IQ and risk for schizophrenia: a population-based cohort

study. Psychol Med 27:1311–1323, 1997 [PubMed]

Davidson M, Harvey PD, Powchik P, et al: Severity of symptoms in chronically institutionalized

geriatric schizophrenic patients. Am J Psychiatry 152:197–207, 1995 [Full Text] [PubMed]

DeLisi LE: Defining the course of brain structural change and plasticity in schizophrenia. Psychiatry

Res 92:1–9, 1999 [PubMed]

DeLisi LE, Sakuma M, Tew W, et al: Schizophrenia as a chronic active brain process: a study of

progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res

74:129–140, 1997 [PubMed]

Dickerson F, Boronow JJ, Ringel N, et al: Neurocognitive deficits and social functioning in

outpatients with schizophrenia. Schizophr Res 21:75–83, 1996 [PubMed]

Dickerson F, Boronow J, Stallings C, et al: Toxoplasma gondii in individuals with schizophrenia:

association with clinical and demographic factors and with mortality. Schizophr Bull 33:737–740,

2007 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

31 of 51

10/05/2009 16:35

Dickey B, Azeni H: Persons with dual diagnoses of substance abuse and major mental illness: their

excess costs of psychiatric care. Am J Public Health 86:973–977, 1996 [PubMed]

Dickson RA, Glazer WM: Neuroleptic-induced hyperprolactinemia. Schizophr Res 35

(suppl):S75–S86, 1999

Dilk MN, Bond GR: Meta-analytic evaluation of skills training research for individuals with severe

mental illness. J Consult Clin Psychol 64:1337–1346, 1996 [PubMed]

Dixon L, Haas G, Weiden P, et al: Acute effects of drug abuse in schizophrenic patients: clinical

observations and patients’ self-reports. Schizophr Bull 16:69–79, 1990 [PubMed]

Dixon L, Weiden P, Delahanty J, et al: Prevalence and correlates of diabetes in national

schizophrenia samples. Schizophr Bull 26:903–912, 2000 [PubMed]

Docherty JP, Van Kammen DP, Siris SG, et al: Stages of onset of schizophrenic psychosis. Am J

Psychiatry 135:420–426, 1978 [PubMed]

Drake RE, Mueser KT: Alcohol-use disorder and severe mental illness. Alcohol Health Res World

20:87–93, 1996

Drake RE, Mueser KT: Psychosocial approaches to dual diagnosis. Schizophr Bull 26:105–118, 2000

[PubMed]

Drake RE, Mueser KT: Substance abuse comorbidity, in Comprehensive Care of Schizophrenia.

Edited by Lieberman JA, Murray RM. London, Martin Dunitz, 2001, pp 243–254

Drake RE, Gates C, Whitaker A, et al: Suicide among schizophrenics: a review. Compr Psychiatry

26:90–100, 1985 [PubMed]

Drake RE, Gates C, Cotton PG: Suicide among schizophrenics: a comparison of attempters and

completed suicides. Br J Psychiatry 149:784–787, 1986 [PubMed]

Drake RE, Xie H, McHugo GJ, et al: The effects of clozapine on alcohol and drug use disorders

among patients with schizophrenia. Schizophr Bull 26:441–449, 2000 [PubMed]

Drake RE, Essock SM, Shaner A, et al: Implementing dual diagnosis services for clients with severe

mental illness. Psychiatr Serv 52:469–476, 2001 [Full Text] [PubMed]

Drebing CE, Van Ormer EA, Krebs C, et al: The impact of enhanced incentives on vocational

rehabilitation outcomes for dually diagnosed veterans. J Appl Behav Anal 38:359–372, 2005

[PubMed]

Eckman TA, Wirshing WC, Marder SR, et al: Technique for training schizophrenic patients in illness

self-management: a controlled trial. Am J Psychiatry 149:1549–1555, 1992 [PubMed]

Eisen JL, Beer DA, Pato MT, et al: Obsessive-compulsive disorder in patients with schizophrenia or

schizoaffective disorder. Am J Psychiatry 154:271–273, 1997 [Full Text] [PubMed]

Elvevag B, Goldberg TE: Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev

Neurobiol 14:1–21, 2000 [PubMed]

Emsley RA, Raniwalla J, Bailey PJ, et al: A comparison of the effects of quetiapine (“Seroquel”) and

haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to

conventional antipsychotic treatment. PRIZE Study Group. Int Clin Psychopharmacol 15:121–131,

2000 [PubMed]

Essock SM, Covell NH, Davis SM, et al: Effectiveness of switching antipsychotic medications. Am J

Psychiatry 163:2090–2095, 2006 [Full Text] [PubMed]

Evins AE, Cather C, Deckersbach T, et al: A double-blind placebo-controlled trial of bupropion

sustained-release for smoking cessation in schizophrenia. J Clin Psychopharmacol 25:218–225,

2005 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

32 of 51

10/05/2009 16:35

Fadda F, Mosca E, Colombo G, et al: Effect of spontaneous ingestion of ethanol on brain dopamine

metabolism. Life Sci 44:281–287, 1989 [PubMed]

Falloon IR, Boyd JL, McGill CW, et al: Family management in the prevention of exacerbations of

schizophrenia: a controlled study. N Engl J Med 306:1437–1440, 1982 [PubMed]

Faraone SV, Chen WJ, Goldstein JM, et al: Gender differences in age at onset of schizophrenia. Br J

Psychiatry 164:625–629, 1994 [PubMed]

Faraone SV, Green AI, Seidman LJ, et al: “Schizotaxia”: clinical implications and new directions for

research. Schizophr Bull 27:1–18, 2001 [PubMed]

Fenton WS: Comorbid conditions in schizophrenia. Curr Opin Psychiatry 14:17–23, 2001

Fenton WS, McGlashan TH: The prognostic significance of obsessive-compulsive symptoms in

schizophrenia. Am J Psychiatry 143:437–441, 1986 [PubMed]

Fenton WS, McGlashan TH, Victor BJ, et al: Symptoms, subtype, and suicidality in patients with

schizophrenia spectrum disorders. Am J Psychiatry 154:199–204, 1997 [Full Text] [PubMed]

Fenton WS, Stover EL, Insel TR: Breaking the log-jam in treatment development for cognition in

schizophrenia: NIMH perspective. Psychopharmacology (Berl) 169:365–366, 2003 [PubMed]

Freedman B, Chapman LJ: Early subjective experience in schizophrenic episodes. J Abnorm Psychol

82:46–54, 1973 [PubMed]

Frith CD, Friston KJ, Herold S, et al: Regional brain activity in chronic schizophrenic patients during

the performance of a verbal fluency task. Br J Psychiatry 167:343–349, 1995 [PubMed]

Fuster JM: Prefrontal neurons in networks of executive memory. Brain Res Bull 52:331–336, 2000

[PubMed]

Geddes JR, Lawrie SM: Obstetric complications and schizophrenia: a meta-analysis. Br J Psychiatry

167:786–793, 1995 [PubMed]

George T, Vessicchio J: Nicotine addiction and schizophrenia. Psychiatr Times 18:39–42, 2001

George TP, Sernyak MJ, Ziedonis DM, et al: Effects of clozapine on smoking in chronic schizophrenic

outpatients. J Clin Psychiatry 56:344–346, 1995 [PubMed]

George TP, Ziedonis DM, Feingold A, et al: Nicotine transdermal patch and atypical antipsychotic

medications for smoking cessation in schizophrenia. Am J Psychiatry 157:1835–1842, 2000 [Full

Text] [PubMed]

George TP, Vessicchio JC, Termine A, et al: A placebo controlled trial of bupropion for smoking

cessation in schizophrenia. Biol Psychiatry 52:53–61, 2002 [PubMed]

Ghadirian AM, Chouinard G, Annable L: Sexual dysfunction and plasma prolactin levels in

neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 170:463–467, 1982 [PubMed]

Gianfrancesco FD, Grogg AL, Mahmoud RA, et al: Differential effects of risperidone, olanzapine,

clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan

database. J Clin Psychiatry 63:920–930, 2002 [PubMed]

Gitlin M, Nuechterlein K, Subotnik KL, et al: Clinical outcome following neuroleptic discontinuation

in patients with remitted recent-onset schizophrenia. Am J Psychiatry 158:1835–1842, 2001 [Full

Text] [PubMed]

Glazer WM: Expected incidence of tardive dyskinesia associated with atypical antipsychotics. J Clin

Psychiatry 61 (suppl 4): 21–26, 2000a

Glazer WM: Extrapyramidal side effects, tardive dyskinesia, and the concept of atypicality. J Clin

Psychiatry 61 (suppl 3):16–21, 2000b

Glazer WM: Review of incidence studies of tardive dyskinesia associated with typical antipsychotics.Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

33 of 51

10/05/2009 16:35

J Clin Psychiatry 61 (suppl 4): 15–20, 2000c

Glynn SM, Sussman S: Why patients smoke. Hosp Community Psychiatry 41:1027–1028, 1990

[PubMed]

Glynn SM, Marder SR, Liberman RP, et al: Supplementing clinic-based skills training with

manual-based community support sessions: effects on social adjustment of patients with

schizophrenia. Am J Psychiatry 159:829–837, 2002 [Full Text] [PubMed]

Goeders NE, Smith JE: Reinforcing properties of cocaine in the medical prefrontal cortex: primary

action on presynaptic dopaminergic terminals. Pharmacol Biochem Behav 25:191–199, 1986

[PubMed]

Goff DC, Tsai G, Manoach DS, et al: D-cycloserine added to clozapine for patients with

schizophrenia. Am J Psychiatry 153:1628–1630, 1996 [Full Text] [PubMed]

Goff DC, Henderson DC, Evins AE, et al: A placebo-controlled crossover trial of D-cycloserine added

to clozapine in patients with schizophrenia. Biol Psychiatry 45:512–514, 1999 [PubMed]

Goff DC, Coyle JT: The emerging role of glutamate in the pathophysiology and treatment of

schizophrenia. Am J Psychiatry 158:1367–1377, 2001 [Full Text] [PubMed]

Goff DC, Sullivan LM, McEvoy JP, et al: A comparison of ten-year cardiac risk estimates in

schizophrenia patients from the CATIE study and matched controls. Schizophr Res 80:45–53, 2005

[PubMed]

Goldberg TE, Hyde TM, Kleinman JE, et al: Course of schizophrenia: neuropsychological evidence for

a static encephalopathy. Schizophr Bull 19:797–804, 1993 [PubMed]

Goldberg TE, Weinberger DR: Effects of neuroleptic medications on the cognition of patients with

schizophrenia: a review of recent studies. J Clin Psychiatry 57 (suppl 9):62–65, 1996

Goldman-Rakic PS: Regional and cellular fractionation of working memory. Proc Natl Acad Sci U S A

93:13473–13480, 1996 [PubMed]

Goldstein G, Haas GL, Pakrashi M, et al: The cycle of schizoaffective disorder, cognitive ability,

alcoholism, and suicidality. Suicide Life Threat Behav 36:35–43, 2006 [PubMed]

Goldstein MJ, Rodnick EH, Evans JR, et al: Drug and family therapy in the aftercare of acute

schizophrenics. Arch Gen Psychiatry 35:1169–1177, 1978 [PubMed]

Gottesman II: Schizophrenia Genesis: The Origins of Madness. New York, WH Freeman, 1991

Granholm E, McQuaid JR, McClure FS, et al: A randomized, controlled trial of cognitive behavioral

social skills training for middle-aged and older outpatients with chronic schizophrenia. Am J

Psychiatry 162:520–529, 2005 [Full Text] [PubMed]

Grech A, Van Os J, Murray RM: Influence of cannabis on the outcome of psychosis. Schizophr Res

36:41, 1999

Green AI, Zimmet SV, Strous RD, et al: Clozapine for comorbid substance use disorder and

schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be

ameliorated by clozapine? Harv Rev Psychiatry 6:287–296, 1999 [PubMed]

Green AI, Patel JK, Goisman RM, et al: Weight gain from novel antipsychotic drugs: need for action.

Gen Hosp Psychiatry 22:224–235, 2000 [PubMed]

Green AI, Burgess ES, Dawson R, et al: Alcohol and cannabis use in schizophrenia: effects of

clozapine vs risperidone. Schizophr Res 60:81–85, 2003 [PubMed]

Green AI, Tohen MF, Hamer RM, et al: First episode schizophrenia-related psychosis and substance

use disorders: acute response to olanzapine and haloperidol. Schizophr Res 66:125–135, 2004

[PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

34 of 51

10/05/2009 16:35

Green AI, Drake RE, Brunette MF, et al: Schizophrenia and co-occurring substance use disorder. Am

J Psychiatry 164:402–408, 2007 [Full Text] [PubMed]

Green AI, Noordsy DL, Brunette MF, et al: Substance abuse and schizophrenia: pharmacotherapeutic

intervention. J Subst Abuse Treat 34:61–71, 2008 [PubMed]

Green MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am J

Psychiatry 153:321–330, 1996 [Full Text] [PubMed]

Green MF: Recent studies on the neurocognitive effects of second-generation antipsychotic

medications. Curr Opin Psychiatry 15:25–29, 2002

Green MF, Nuechterlein KH: Should schizophrenia be treated as a neurocognitive disorder?

Schizophr Bull 25:309–319, 1999 [PubMed]

Green MF, Kern RS, Braff DL, et al: Neurocognitive deficits and functional outcome in schizophrenia:

are we measuring the “right stuff”? Schizophr Bull 26:119–136, 2000 [PubMed]

Gupta S, Black DW, Arndt S, et al: Factors associated with suicide attempts among patients with

schizophrenia. Psychiatr Serv 49:1353–1355, 1998 [Full Text] [PubMed]

Gur RE, Cowell P, Turetsky BI, et al: A follow-up magnetic resonance imaging study of

schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures.

Arch Gen Psychiatry 55:145–152, 1998 [PubMed]

Haas GL, Garratt LS, Sweeney JA: Delay to first antipsychotic medication in schizophrenia: impact

on symptomatology and clinical course of illness. J Psychiatr Res 32:151–159, 1998 [PubMed]

Hafner H, Riecher-Rossler A, Maurer K, et al: First onset and early symptomatology of

schizophrenia. A chapter of epidemiological and neurobiological research into age and sex

differences. Eur Arch Psychiatry Clin Neurosci 242:109–118, 1992 [PubMed]

Hafner H, Maurer K, Loffler W, et al: The influence of age and sex on the onset and early course of

schizophrenia. Br J Psychiatry 162:80–86, 1993 [PubMed]

Hafner H, Maurer K, Loffler W, et al: The epidemiology of early schizophrenia. Influence of age and

gender on onset and early course. Br J Psychiatry Suppl (23):29–38, 1994

Hafner H, Loffler W, Maurer K, et al: Depression, negative symptoms, social stagnation and social

decline in the early course of schizophrenia. Acta Psychiatr Scand 100:105–118, 1999 [PubMed]

Hafner H, Maurer K, Trendler G, et al: The early course of schizophrenia and depression. Eur Arch

Psychiatry Clin Neurosci 255:167–173, 2005 [PubMed]

Hambrecht M, Maurer K, Hafner H, et al: Transnational stability of gender differences in

schizophrenia? An analysis based on the WHO study on determinants of outcome of severe mental

disorders. Eur Arch Psychiatry Clin Neurosci 242:6–12, 1992 [PubMed]

Hamoui N, Kingsbury S, Anthone GJ, et al: Surgical treatment of morbid obesity in schizophrenic

patients. Obes Surg 14:349–352, 2004 [PubMed]

Harding CM, Brooks GW, Ashikaga T, et al: The Vermont longitudinal study of persons with severe

mental illness, II: long-term outcome of subjects who retrospectively met DSM-III criteria for

schizophrenia. Am J Psychiatry 144:727–735, 1987 [PubMed]

Harkavy-Friedman JM, Nelson E: Management of the suicidal patient with schizophrenia. Psychiatr

Clin North Am 20:625–640, 1997 [PubMed]

Harkavy-Friedman JM, Nelson EA, Venarde DF, et al: Suicidal behavior in schizophrenia and

schizoaffective disorder: examining the role of depression. Suicide Life Threat Behav 34:66–76,

2004 [PubMed]

Harrison G: Trajectories of psychosis: towards a new social biology of schizophrenia. Epidemiol

Psichiatr Soc 13:152–157, 2004 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

35 of 51

10/05/2009 16:35

Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological

implications. Lancet 361:417–419, 2003 [PubMed]

Harvey PD, Keefe RE: Cognition and the new antipsychotics. Journal of Advanced Schizophrenia

Brain Research 1:2–8, 1998

Harvey PD, Keefe RS: Studies of cognitive change in patients with schizophrenia following novel

antipsychotic treatment. Am J Psychiatry 158:176–184, 2001 [Full Text] [PubMed]

Harvey PD, Howanitz E, Parrella M, et al: Symptoms, cognitive functioning, and adaptive skills in

geriatric patients with lifelong schizophrenia: a comparison across treatment sites. Am J Psychiatry

155:1080–1086, 1998 [Full Text] [PubMed]

Hasan S, Buckley P: Novel antipsychotics and the neuroleptic malignant syndrome: a review and

critique. Am J Psychiatry 155:1113–1116, 1998 [Full Text] [PubMed]

Hawton K, Sutton L, Haw C, et al: Schizophrenia and suicide: systematic review of risk factors. Br J

Psychiatry 187:9–20, 2005 [PubMed]

Heckers S, Rauch SL, Goff D, et al: Impaired recruitment of the hippocampus during conscious

recollection in schizophrenia. Nat Neurosci 1:318–323, 1998 [PubMed]

Heila H, Isometsa ET, Henriksson MM, et al: Suicide and schizophrenia: a nationwide psychological

autopsy study on age- and sex-specific clinical characteristics of 92 suicide victims with

schizophrenia. Am J Psychiatry 154:1235–1242, 1997 [Full Text] [PubMed]

Heila H, Isometsa ET, Henriksson MM, et al: Suicide victims with schizophrenia in different

treatment phases and adequacy of antipsychotic medication. J Clin Psychiatry 60:200–208, 1999

[PubMed]

Henderson DC, Cagliero E, Gray C, et al: Clozapine, diabetes mellitus, weight gain, and lipid

abnormalities: a five-year naturalistic study. Am J Psychiatry 157:975–981, 2000 [Full Text]

[PubMed]

Hennekens CH, Hennekens AR, Hollar D, et al: Schizophrenia and increased risks of cardiovascular

disease. Am Heart J 150:1115–1121, 2005 [PubMed]

Heresco-Levy U, Javitt DC, Ermilov M, et al: Double-blind, placebo-controlled, crossover trial of

glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 169:610–617,

1996a

Heresco-Levy U, Silipo G, Javitt DC: Glycinergic augmentation of NMDA receptor-mediated

neurotransmission in the treatment of schizophrenia. Psychopharmacol Bull 32:731–740, 1996b

Herz MI, Glazer WM, Mostert MA, et al: Intermittent vs maintenance medication in schizophrenia.

Two-year results. Arch Gen Psychiatry 48:333–339, 1991 [PubMed]

Hinze-Selch D, Daubener W, Eggert L, et al: A controlled prospective study of Toxoplasma gondii

infection in individuals with schizophrenia: beyond seroprevalence. Schizophr Bull 33:782–788,

2007 [PubMed]

Ho BC, Andreasen NC, Flaum M, et al: Untreated initial psychosis: its relation to quality of life and

symptom remission in first-episode schizophrenia. Am J Psychiatry 157:808–815, 2000 [Full Text]

[PubMed]

Hodel B, Brenner HD: Cognitive therapy with schizophrenic patients: conceptual basis, present

state, future directions. Acta Psychiatr Scand Suppl 384:108–115, 1994 [PubMed]

Hogarty GE, Anderson CM, Reiss DJ, et al: Family psychoeducation, social skills training, and

maintenance chemotherapy in the aftercare treatment of schizophrenia, I: one-year effects of a

controlled study on relapse and expressed emotion. Arch Gen Psychiatry 43:633–642, 1986

[PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

36 of 51

10/05/2009 16:35

Hogarty GE, McEvoy JP, Ulrich RF, et al: Pharmacotherapy of impaired affect in recovering

schizophrenic patients. Arch Gen Psychiatry 52:29, 1995 [PubMed]

Hogarty GE, Greenwald D, Ulrich RF, et al: Three-year trials of personal therapy among

schizophrenic patients living with or independent of family, II: effects on adjustment of patients.

Am J Psychiatry 154:1514–1524, 1997a

Hogarty GE, Kornblith SJ, Greenwald D, et al: Three-year trials of personal therapy among

schizophrenic patients living with or independent of family, I: description of study and effects on

relapse rates. Am J Psychiatry 154:1504–1513, 1997b

Hogarty GE, Flesher S, Ulrich R, et al: Cognitive enhancement therapy for schizophrenia: effects of a

2-year randomized trial on cognition and behavior. Arch Gen Psychiatry 61:866–876, 2004

[PubMed]

Hogarty GE, Greenwald DP, Eack SM: Durability and mechanism of effects of cognitive enhancement

therapy. Psychiatr Serv 57:1751–1757, 2006 [Full Text] [PubMed]

Huber G, Gross G, Schuttler R, et al: Longitudinal studies of schizophrenic patients. Schizophr Bull

6:592–605, 1980 [PubMed]

Huber TJ, Borsutzky M, Schneider U, et al: Psychotic disorders and gonadal function: evidence

supporting the oestrogen hypothesis. Acta Psychiatr Scand 109:269–274, 2004 [PubMed]

Huckans MS, Blackwell AD, Harms TA, et al: Management of hepatitis C disease among VA patients

with schizophrenia and substance use disorders. Psychiatr Serv 57:403–406, 2006 [Full Text]

[PubMed]

Hummer M, Malik P, Gasser RW, et al: Osteoporosis in patients with schizophrenia. Am J Psychiatry

162:162–167, 2005 [Full Text] [PubMed]

Hunt IM, Kapur N, Windfuhr K, et al: Suicide in schizophrenia: findings from a national clinical

survey. J Psychiatr Pract 12:139–147, 2006 [PubMed]

Hurlburt MS, Hough RL, Wood PA: Effects of substance abuse on housing stability of homeless

mentally ill persons in supported housing. Psychiatr Serv 47:731–736, 1996a

Hurlburt MS, Wood PA, Hough RL: Providing independent housing for the homeless mentally ill: a

novel approach to evaluating long-term longitudinal housing patterns. Journal of Community

Psychology 24:291–310, 1996b

Huttenlocher PR: Neural Plasticity: The Effects of Environment on the Development of the Cerebral

Cortex. Cambridge, MA, Harvard University Press, 2002

Hwang MY, Morgan JE, Losconzcy MF: Clinical and neuropsychological profiles of

obsessive-compulsive schizophrenia: a pilot study. J Neuropsychiatry Clin Neurosci 12:91–94, 2000

[Full Text] [PubMed]

Hyman SE, Fenton WS: Medicine. What are the right targets for psychopharmacology? Science

299:350–351, 2003 [PubMed]

Ingvar DH, Franzen G: Abnormalities of cerebral blood flow distribution in patients with chronic

schizophrenia. Acta Psychiatr Scand 50:425–462, 1974 [PubMed]

Iqbal Z, Birchwood M, Chadwick P, et al: Cognitive approach to depression and suicidal thinking in

psychosis, II: testing the validity of a social ranking model. Br J Psychiatry 177:522–528, 2000

[PubMed]

Isomaa B, Almgren P, Tuomi T, et al: Cardiovascular morbidity and mortality associated with the

metabolic syndrome. Diabetes Care 24:683–689, 2001 [PubMed]

Jablensky A, Sartorius N, Ernberg G, et al: Schizophrenia: manifestations, incidence and course in

different cultures. A World Health Organization ten-country study. Psychol Med Monogr SupplPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

37 of 51

10/05/2009 16:35

20:1–97, 1992 [PubMed]

Javitt DC: Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in

schizophrenia patients. Curr Opin Psychiatry 19:151–157, 2006 [PubMed]

Javitt DC, Coyle JT: Decoding schizophrenia. Sci Am 290:48–55, 2004 [PubMed]

Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry

148:1301–1308, 1991 [PubMed]

Javitt DC, Silipo G, Cienfuegos A, et al: Adjunctive high-dose glycine in the treatment of

schizophrenia. Int J Neuropsychopharmacol 4:385–391, 2001 [PubMed]

Jeste DV: Tardive dyskinesia in older patients. J Clin Psychiatry 61 (suppl 4):27–32, 2000

Jeste DV, Lacro JP, Bailey A: Lower incidence of tardive dyskinesia with risperidone compared with

haloperidol in older patients. Presented at the 21st Congress of the Collegium Internationale

Neuro-Psychopharmacologicum, Glasgow, Scotland, July 12–16, 1998

Jin H, Meyer JM, Jeste DV: Atypical antipsychotics and glucose dysregulation: a systematic review.

Schizophr Res 71:195–212, 2004 [PubMed]

Johnson DA: Antipsychotic medication: clinical guidelines for maintenance therapy. J Clin

Psychiatry 46:6–15, 1985 [PubMed]

Johnstone EC, Crow TJ, Johnson AL, et al: The Northwick Park Study of first episodes of

schizophrenia, I: presentation of the illness and problems relating to admission. Br J Psychiatry

148:115–120, 1986 [PubMed]

Jolley AG, Hirsch SR, Morrison E, et al: Trial of brief intermittent neuroleptic prophylaxis for

selected schizophrenic outpatients: clinical and social outcome at two years. BMJ 301:837–842,

1990 [PubMed]

Jones C, Cormac I, Silveira da Mota Neto JI, et al: Cognitive behaviour therapy for schizophrenia.

Cochrane Database Syst Rev (4):CD000524, 2004

Jones PB, Barnes TR, Davies L, et al: Randomized controlled trial of the effect on Quality of Life of

second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest

Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63:1079–1087, 2006

[PubMed]

Kampman O, Lehtinen K: Compliance in psychoses. Acta Psychiatr Scand 100:167–175, 1999

[PubMed]

Kane JM: Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence.

J Clin Psychiatry 65 (suppl 9): 16–20, 2004

Kane JM, Rifkin A, Quitkin F, et al: Fluphenazine vs placebo in patients with remitted, acute

first-episode schizophrenia. Arch Gen Psychiatry 39:70–73, 1982 [PubMed]

Kane JM, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic. A

double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796, 1988 [PubMed]

Kane JM, Woerner MG, Pollack S, et al: Does clozapine cause tardive dyskinesia? J Clin Psychiatry

54:327–330, 1993 [PubMed]

Kane JM, Handan G, Malhotra AK: Clozapine, in Current Issues in the Psychopharmacology of

Schizophrenia. Edited by Breier A, Tran PV, Herrea JM, et al. Philadelphia, PA, Lippincott Williams &

Wilkins, 2001, pp 209–223

Kane JM, Khanna S, Rajadhyaksha S, et al: Efficacy and tolerability of ziprasidone in patients with

treatment-resistant schizophrenia. Int Clin Psychopharmacol 21:21–28, 2006 [PubMed]

Kane JM, Meltzer HY, Carson WH Jr, et al: Aripiprazole for treatment-resistant schizophrenia:Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

38 of 51

10/05/2009 16:35

results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin

Psychiatry 68:213–223, 2007 [PubMed]

Kaplan KJ, Harrow M: Positive and negative symptoms as risk factors for later suicidal activity in

schizophrenics versus depressives. Suicide Life Threat Behav 26:105–121, 1996 [PubMed]

Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. Am J

Psychiatry 153:466–476, 1996 [Full Text] [PubMed]

Kapur S, Remington G: Dopamine D(2) receptors and their role in atypical antipsychotic action: still

necessary and may even be sufficient. Biol Psychiatry 50:873–883, 2001 [PubMed]

Kasai K, Shenton ME, Salisbury DF, et al: Progressive decrease of left Heschl gyrus and planum

temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance

imaging study. Arch Gen Psychiatry 60:766–775, 2003a

Kasai K, Shenton ME, Salisbury DF, et al: Progressive decrease of left superior temporal gyrus gray

matter volume in patients with first-episode schizophrenia. Am J Psychiatry 160:156–164, 2003b

Keck PE Jr, McElroy SL, Strakowski SM, et al: Antipsychotics in the treatment of mood disorders and

risk of tardive dyskinesia. J Clin Psychiatry 61 (suppl 4):33–38, 2000

Keefe RS, Bilder RM, Davis SM, et al: Neurocognitive effects of antipsychotic medications in patients

with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64:633–647, 2007 [PubMed]

Kelly DL, Shim JC, Feldman SM, et al: Lifetime psychiatric symptoms in persons with schizophrenia

who died by suicide compared to other means of death. J Psychiatr Res 38:531–536, 2004

[PubMed]

Kendler KS: Overview: a current perspective on twin studies of schizophrenia. Am J Psychiatry

140:1413–1425, 1983 [PubMed]

Kety SS, Rosenthal D, Wender PH: The types and prevalence of mental illness in the biological and

adoptive families of adopted schizophrenics. J Psychiatr Res 1:345–362, 1964

Kety SS, Wender PH, Jacobsen B, et al: Mental illness in the biological and adoptive relatives of

schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark. Arch Gen

Psychiatry 51:442–455, 1994 [PubMed]

Khantzian EJ: The self-medication hypothesis of addictive disorders: focus on heroin and cocaine

dependence. Am J Psychiatry 142:1259–1264, 1985 [PubMed]

Kim CH, Jayathilake K, Meltzer HY: Hopelessness, neurocognitive function, and insight in

schizophrenia: relationship to suicidal behavior. Schizophr Res 60:71–80, 2003 [PubMed]

Kingsbury SJ, Fayek M, Trufasiu D, et al: The apparent effects of ziprasidone on plasma lipids and

glucose. J Clin Psychiatry 62:347–349, 2001 [PubMed]

Kinon BJ: The routine use of atypical antipsychotic agents: maintenance treatment. J Clin

Psychiatry 59 (suppl 19):18–22, 1998

Kinon BJ, Ahl J, Liu-Seifert H, et al: Improvement in hyperprolactinemia and reproductive

comorbidities in patients with schizophrenia switched from conventional antipsychotics or

risperidone to olanzapine. Psychoneuroendocrinology 31:577–588, 2006 [PubMed]

Kirli S, Caliskan M: A comparative study of sertraline versus imipramine in postpsychotic depressive

disorder of schizophrenia. Schizophr Res 33:103–111, 1998 [PubMed]

Kissling WJ, Kane JM, Barnes TRE, et al: Guidelines for neuroleptic relapse prevention in

schizophrenia: towards a consensus view, in Guidelines for Neuroleptic Relapse Prevention in

Schizophrenia. Edited by Kissling WJ. Berlin, Germany, Springer-Verlag, 1991, pp 155–163

Kleinberg DL, Davis JM, de Coster R, et al: Prolactin levels and adverse events in patients treated

with risperidone. J Clin Psychopharmacol 19:57–61, 1999 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

39 of 51

10/05/2009 16:35

Knott V, McIntosh J, Millar A, et al: Nicotine and smoker status moderate brain electric and mood

activation induced by ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Pharmacol

Biochem Behav 85:228–242, 2006 [PubMed]

Kofoed L, Kania J, Walsh T, et al: Outpatient treatment of patients with substance abuse and

coexisting psychiatric disorders. Am J Psychiatry 143:867–872, 1986 [PubMed]

Koller EA, Doraiswamy PM: Olanzapine-associated diabetes mellitus. Pharmacotherapy 22:841–852,

2002 [PubMed]

Koller E, Schneider B, Bennett K, et al: Clozapine-associated diabetes. Am J Med 111:716–723, 2001

[PubMed]

Koller EA, Cross JT, Doraiswamy PM, et al: Risperidone-associated diabetes mellitus: a

pharmacovigilance study. Pharmacotherapy 23:735–744, 2003 [PubMed]

Kopala L, Honer WG: Risperidone, serotonergic mechanisms, and obsessive-compulsive symptoms

in schizophrenia. Am J Psychiatry 151:1714–1715, 1994 [PubMed]

Kopelowicz A, Liberman RP, Zarate R: Recent advances in social skills training for schizophrenia.

Schizophr Bull 32 (suppl 1): S12–S23, 2006

Koppel BS: Neuroleptic malignant syndrome, in Principles and Practices of Emergency Medicine, 4th

Edition. Edited by Schwartz GR, Hanke BK, Mayer TA. Baltimore, MD, Williams & Wilkins, 1998, pp

1155–1605

Koreen AR, Siris SG, Chakos M, et al: Depression in first-episode schizophrenia. Am J Psychiatry

150:1643–1648, 1993 [Full Text] [PubMed]

Kraepelin E: Dementia Praecox and Paraphrenia (1919). New York, Robert E Krieger, 1971

Kramer M, Simpson G, Maciulis V, et al: Paliperidone extended-release tablets for prevention of

symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled

study. J Clin Psychopharmacol 27:6–14, 2007 [PubMed]

Krystal JH, Karper LP, Seibyl JP, et al: Subanesthetic effects of the noncompetitive NMDA

antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine

responses. Arch Gen Psychiatry 51:199–214, 1994 [PubMed]

Kuo CJ, Tsai SY, Lo CH, et al: Risk factors for completed suicide in schizophrenia. J Clin Psychiatry

66:579–585, 2005 [PubMed]

Lane A, Kinsella A, Murphy P, et al: The anthropometric assessment of dysmorphic features in

schizophrenia as an index of its developmental origins. Psychol Med 27:1155–1164, 1997 [PubMed]

Lauriello J, Bustillo J, Keith SJ: A critical review of research on psychosocial treatment of

schizophrenia. Biol Psychiatry 46:1409–1417, 1999 [PubMed]

Lawrie SM, Byrne M, Miller P, et al: Neurodevelopmental indices and the development of psychotic

symptoms in subjects at high risk of schizophrenia. Br J Psychiatry 178:524–530, 2001 [PubMed]

Lee ML, Dickson RA, Campbell M, et al: Clozapine and substance abuse in patients with

schizophrenia. Can J Psychiatry 43:855–856, 1998 [PubMed]

Lehman AF: Vocational rehabilitation in schizophrenia. Schizophr Bull 21:645–656, 1995 [PubMed]

Lehmann HE, Hanrahan GE: Chlorpromazine: new inhibiting agent for psychomotor excitement and

manic states. AMA Arch Neurol Psychiatry 71:227–237, 1954 [PubMed]

Leucht S, Barnes TR, Kissling W, et al: Relapse prevention in schizophrenia with new-generation

antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.

Am J Psychiatry 160:1209–1222, 2003a

Leucht S, Wahlbeck K, Hamann J, et al: New generation antipsychotics versus low-potencyPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

40 of 51

10/05/2009 16:35

conventional antipsychotics: a systematic review and meta-analysis. Lancet 361:1581–1589, 2003b

Leucht S: Amisulpride: a selective dopamine antagonist and atypical antipsychotic: results of a

meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 7 (suppl 1): S15–S20,

2004

Levinson DF, Umapathy C, Musthaq M: Treatment of schizoaffective disorder and schizophrenia with

mood symptoms. Am J Psychiatry 156:1138–1148, 1999 [Full Text] [PubMed]

Lewis DA, Gonzalez-Burgos G: Pathophysiologically based treatment interventions in schizophrenia.

Nat Med 12:1016–1022, 2006 [PubMed]

Lewis DA, Levitt P: Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci

25:409–432, 2002 [PubMed]

Lewis DA, Lieberman JA: Catching up on schizophrenia: natural history and neurobiology. Neuron

28:325–334, 2000 [PubMed]

Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci

6:312–324, 2005 [PubMed]

Lewis SW, Davies L, Jones PB, et al: Randomised controlled trials of conventional antipsychotic

versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia

responding poorly to, or intolerant of, current drug treatment. Health Technol Assess 10:iii–iv,

ix–xi, 1–165, 2006

Liberman RP, Wallace CJ, Blackwell G, et al: Skills training versus psychosocial occupational

therapy for persons with persistent schizophrenia. Am J Psychiatry 155:1087–1091, 1998 [Full

Text] [PubMed]

Liddle PF, Barnes TR, Morris D, et al: Three syndromes in chronic schizophrenia. Br J Psychiatry

Suppl (7):119–122, 1989

Lieberman JA: Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological

perspective. Biol Psychiatry 46:729–739, 1999 [PubMed]

Lieberman JA: Neurobiology and the natural history of schizophrenia. J Clin Psychiatry 67:e14,

2006

Lieberman JA, Saltz BL, Johns CA, et al: The effects of clozapine on tardive dyskinesia. Br J

Psychiatry 158:503–510, 1991 [PubMed]

Lieberman JA, Jody D, Geisler S, et al: Time course and biologic correlates of treatment response in

first-episode schizophrenia. Arch Gen Psychiatry 50:369–376, 1993 [PubMed]

Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with

chronic schizophrenia. N Engl J Med 353:1209–1223, 2005 [PubMed]

Littrell KH, Petty RG, Hilligoss NM, et al: Olanzapine treatment for patients with schizophrenia and

substance abuse. J Subst Abuse Treat 21:217–221, 2001 [PubMed]

Loebel AD, Lieberman JA, Alvir JM, et al: Duration of psychosis and outcome in first-episode

schizophrenia. Am J Psychiatry 149:1183–1188, 1992 [PubMed]

Loh C, Meyer JM, Leckband SG: A comprehensive review of behavioral interventions for weight

management in schizophrenia. Ann Clin Psychiatry 18:23–31, 2006 [PubMed]

Lysaker P, Bell M, Beam-Goulet J, et al: Relationship of positive and negative symptoms to cocaine

abuse in schizophrenia. J Nerv Ment Dis 182:109–112, 1994 [PubMed]

Macleod J, Davey Smith G, Hickman M: Does cannabis use cause schizophrenia? Lancet 367:1055,

2006 [PubMed]

Mandel MR, Severe JB, Schooler NR, et al: Development and prediction of postpsychotic depressionPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

41 of 51

10/05/2009 16:35

in neuroleptic-treated schizophrenics. Arch Gen Psychiatry 39:197–203, 1982 [PubMed]

Manoach DS, Press DZ, Thangaraj V, et al: Schizophrenic subjects activate dorsolateral prefrontal

cortex during a working memory task, as measured by fMRI. Biol Psychiatry 45:1128–1137, 1999

[PubMed]

Marder SR: Integrating pharmacological and psychosocial treatments for schizophrenia. Acta

Psychiatr Scand Suppl (407): 87–90, 2000

Marder SR: Drug initiatives to improve cognitive function. J Clin Psychiatry 67 (suppl 9):31–35;

discussion 36–42, 2006

Marder SR, Wirshing WC, Mintz J, et al: Two-year outcome of social skills training and group

psychotherapy for outpatients with schizophrenia. Am J Psychiatry 153:1585–1592, 1996 [Full

Text] [PubMed]

Marder SR, Davis JM, Chouinard G: The effects of risperidone on the five dimensions of

schizophrenia derived by factor analysis: combined results of the North American trials. J Clin

Psychiatry 58:538–546, 1997 [PubMed]

Marder SR, Essock SM, Miller AL, et al: The Mount Sinai conference on the pharmacotherapy of

schizophrenia. Schizophr Bull 28:5–16, 2002 [PubMed]

Marder SR, Essock SM, Miller AL, et al: Physical health monitoring of patients with schizophrenia.

Am J Psychiatry 161:1334–1349, 2004 [Full Text] [PubMed]

Margolese HC, Chouinard G, Kolivakis TT, et al: Tardive dyskinesia in the era of typical and atypical

antipsychotics, part 2: incidence and management strategies in patients with schizophrenia. Can J

Psychiatry 50:703–714, 2005 [PubMed]

Martin LF, Leonard S, Hall MH, et al: Sensory gating and alpha-7 nicotinic receptor gene allelic

variants in schizoaffective disorder, bipolar type. Am J Med Genet B Neuropsychiatr Genet

144:611–614, 2007

May PR, Tuma AH, Dixon WJ: For better or worse? Outcome variance with psychotherapy and other

treatments for schizophrenia. J Nerv Ment Dis 165:231–239, 1978

McEvoy JP, Freudenreich O, Levin ED, et al: Haloperidol increases smoking in patients with

schizophrenia. Psychopharmacology (Berl) 119:124–126, 1995a

McEvoy J, Freudenreich O, McGee M, et al: Clozapine decreases smoking in patients with chronic

schizophrenia. Biol Psychiatry 37:550–552, 1995b

McEvoy JP, Meyer JM, Goff DC, et al: Prevalence of the metabolic syndrome in patients with

schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness

(CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr

Res 80:19–32, 2005 [PubMed]

McEvoy JP, Lieberman JA, Stroup TS, et al: Effectiveness of clozapine versus olanzapine, quetiapine,

and risperidone in patients with chronic schizophrenia who did not respond to prior atypical

antipsychotic treatment. Am J Psychiatry 163:600–610, 2006 [Full Text] [PubMed]

McGlashan TH: The profiles of clinical deterioration in schizophrenia. J Psychiatr Res 32:133–141,

1998 [PubMed]

McGlashan TH: Duration of untreated psychosis in first-episode schizophrenia: marker or

determinant of course? Biol Psychiatry 46:899–907, 1999 [PubMed]

McGlashan TH, Carpenter WT Jr: Postpsychotic depression in schizophrenia. Arch Gen Psychiatry

33:231–239, 1976 [PubMed]

McGlashan TH, Addington J, Cannon T, et al: Recruitment and treatment practices for help-seeking

“prodromal” patients. Schizophr Bull 33:715–726, 2007 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

42 of 51

10/05/2009 16:35

McGorry PD, McFarlane C, Patton GC, et al: The prevalence of prodromal features of schizophrenia

in adolescence: a preliminary survey. Acta Psychiatr Scand 92:241–249, 1995 [PubMed]

McGorry PD, Yung AR, Phillips LJ, et al: Randomized controlled trial of interventions designed to

reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold

symptoms. Arch Gen Psychiatry 59:921–928, 2002 [PubMed]

McGurk SR, Mueser KT, Feldman K, et al: Cognitive training for supported employment: 2–3 year

outcomes of a randomized controlled trial. Am J Psychiatry 164:437–441, 2007 [Full Text]

[PubMed]

Mednick SA, Machon RA, Huttunen MO, et al: Adult schizophrenia following prenatal exposure to an

influenza epidemic. Arch Gen Psychiatry 45:189–192, 1988 [PubMed]

Meehl PE: Schizotaxia, schizotypy, schizophrenia. Am Psychol 17:827–838, 1962

Meehl PE: Schizotaxia revisited. Arch Gen Psychiatry 46:935–944, 1989 [PubMed]

Melle I, Johannesen JO, Friis S, et al: Early detection of the first episode of schizophrenia and

suicidal behavior. Am J Psychiatry 163:800–804, 2006 [Full Text] [PubMed]

Meltzer HY: Long-term effects of neuroleptic drugs on the neuroendocrine system. Adv Biochem

Psychopharmacol 40:59–68, 1985 [PubMed]

Meltzer HY: Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin

hypothesis of schizophrenia. Psychopharmacology (Berl) 99 (suppl):S18–S27, 1989

Meltzer HY, Alphs L, Green AI, et al: Clozapine treatment for suicidality in schizophrenia:

International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82–91, 2003 [PubMed]

Meyer JM, Koro CE: The effects of antipsychotic therapy on serum lipids: a comprehensive review.

Schizophr Res 70:1–17, 2004 [PubMed]

Meyer J, Nasrallah H: Medical Illness and Schizophrenia. American Psychiatric Publishing, 2003

Miller DD, McEvoy JP, Davis SM, et al: Clinical correlates of tardive dyskinesia in schizophrenia:

baseline data from the CATIE schizophrenia trial. Schizophr Res 80:33–43, 2005 [PubMed]

Minkoff K: An integrated treatment model for dual diagnosis of psychosis and addiction. Hosp

Community Psychiatry 40:1031–1036, 1989 [PubMed]

Moghaddam B: Targeting metabotropic glutamate receptors for treatment of the cognitive

symptoms of schizophrenia. Psychopharmacology (Berl) 174:39–44, 2004 [PubMed]

Moghaddam B, Jackson M: Effect of stress on prefrontal cortex function. Neurotox Res 6:73–78,

2004 [PubMed]

Montero I, Hernandez I, Asencio A, et al: Do all people with schizophrenia receive the same benefit

from different family intervention programs? Psychiatry Res 133:187–195, 2005 [PubMed]

Montross LP, Zisook S, Kasckow J: Suicide among patients with schizophrenia: a consideration of

risk and protective factors. Ann Clin Psychiatry 17:173–182, 2005 [PubMed]

Morrison D, Clark D, Goldfarb E, et al: Worsening of obsessive-compulsive symptoms following

treatment with olanzapine. Am J Psychiatry 155:855, 1998 [Full Text] [PubMed]

Mortensen PB, Norgaard-Pedersen B, Waltoft BL, et al: Early infections of Toxoplasma gondii and

the later development of schizophrenia. Schizophr Bull 33:741–744, 2007 [PubMed]

Mueser KT, Bennett M, Kushner MG: Epidemiology of substance use disorders among persons with

chronic mental illnesses, in Double Jeopardy: Chronic Mental Illness and Substance Abuse. Edited

by Lehman AF, Dixon L. New York, Harwood Academic Publishers, 1995, pp 9–25

Mueser KT, Bond GR, Drake RE, et al: Models of community care for severe mental illness: a review

of research on case management. Schizophr Bull 24:37–74, 1998 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

43 of 51

10/05/2009 16:35

Mueser KT, Noordsy DL, Fox L, et al: Disulfiram treatment for alcoholism in severe mental illness.

Am J Addict 12:242–252, 2003 [PubMed]

Mueser KT, Meyer PS, Penn DL, et al: The Illness Management and Recovery program: rationale,

development, and preliminary findings. Schizophr Bull 32 (suppl 1):S32–S43, 2006

Mukherjee S, Decina P, Bocola V, et al: Diabetes mellitus in schizophrenic patients. Compr

Psychiatry 37:68–73, 1996 [PubMed]

Muller P, Bandelow B, Gaebel W, et al: Intermittent medication, coping and psychotherapy.

Interactions in relapse prevention and course modification. Br J Psychiatry Suppl (18):140–144,

1992

Murray RM: Neurodevelopmental schizophrenia: the rediscovery of dementia praecox. Br J

Psychiatry Suppl (25):6–12, 1994

Negrete JC, Knapp WP, Douglas DE, et al: Cannabis affects the severity of schizophrenic symptoms:

results of a clinical survey. Psychol Med 16:515–520, 1986 [PubMed]

Nelson HE, Pantelis C, Carruthers K, et al: Cognitive functioning and symptomatology in chronic

schizophrenia. Psychol Med 20:357–365, 1990 [PubMed]

Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al: Ketamine-induced NMDA receptor

hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology

20:106–118, 1999 [PubMed]

Noordsy DL, O’Keefe C, Mueser KT, et al: Six-month outcomes for patients who switched to

olanzapine treatment. Psychiatr Serv 52:501–507, 2001 [Full Text] [PubMed]

Nuechterlein KH, Dawson ME: Information processing and attentional functioning in the

developmental course of schizophrenic disorders. Schizophr Bull 10:160–203, 1984 [PubMed]

O’Donnell P, Lewis BL, Weinberger DR, et al: Neonatal hippocampal damage alters

electrophysiological properties of prefrontal cortical neurons in adult rats. Cereb Cortex

12:975–982, 2002 [PubMed]

O’Keane V, Meaney AM: Antipsychotic drugs: a new risk factor for osteoporosis in young women

with schizophrenia? J Clin Psychopharmacol 25:26–31, 2005 [PubMed]

Ohlsen RI, Pilowsky LS: The place of partial agonism in psychiatry: recent developments. J

Psychopharmacol 19:408–413, 2005 [PubMed]

Olney JW, Farber NB: Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry

52:998–1007, 1995 [PubMed]

Ongur D, Goff DC: Obsessive-compulsive symptoms in schizophrenia: associated clinical features,

cognitive function and medication status. Schizophr Res 75:349–362, 2005 [PubMed]

Osher FC, Kofoed LL: Treatment of patients with psychiatric and psychoactive substance abuse

disorders. Hosp Community Psychiatry 40:1025–1030, 1989 [PubMed]

Osher FC, Goldberg RW, McNary SW, et al: Substance abuse and the transmission of hepatitis C

among persons with severe mental illness. Psychiatr Serv 54:842–847, 2003 [Full Text] [PubMed]

Osser DN: Neuroleptic-induced pseudoparkinsonism, in Movement Disorders in Neurology and

Neuropsychiatry. Edited by Joseph AB, Young RR. Malden, MA, Blackwell Science, 1999, pp 61–68

Osser DN, Najarian DM, Dufresne RL: Olanzapine increases weight and serum triglyceride levels. J

Clin Psychiatry 60:767–770, 1999 [PubMed]

Pantelis C, Velakoulis D, McGorry PD, et al: Neuroanatomical abnormalities before and after onset

of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361:281–288, 2003

[PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

44 of 51

10/05/2009 16:35

Park S, Holzman PS: Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry

49:975–982, 1992 [PubMed]

Park S, Holzman PS, Goldman-Rakic PS: Spatial working memory deficits in the relatives of

schizophrenic patients. Arch Gen Psychiatry 52:821–828, 1995 [PubMed]

Patil ST, Zhang L, Martenyi F, et al: Activation of mGlu2/3 receptors as a new approach to treat

schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107, 2007 [PubMed]

Penn DL, Mueser KT: Research update on the psychosocial treatment of schizophrenia. Am J

Psychiatry 153:607–617, 1996 [Full Text] [PubMed]

Penn DL, Addington J, Pinkham A: Social cognitive impairments, in Textbook of Schizophrenia.

Edited by Lieberman JA, Stroup TS, Perkins DO. Washington, DC, American Psychiatric Publishing,

2006, pp 261–274

Perala J, Suvisaari J, Saarni SI, et al: Lifetime prevalence of psychotic and bipolar I disorders in a

general population. Arch Gen Psychiatry 64:19–28, 2007 [PubMed]

Petrakis IL, O’Malley S, Rounsaville B, et al: Naltrexone augmentation of neuroleptic treatment in

alcohol abusing patients with schizophrenia. Psychopharmacology (Berl) 172:291–297, 2004

[PubMed]

Petrakis IL, Poling J, Levinson C, et al: Naltrexone and disulfiram in patients with alcohol

dependence and comorbid psychiatric disorders. Biol Psychiatry 57:1128–1137, 2005 [PubMed]

Petrakis IL, Leslie D, Finney JW, et al: Atypical antipsychotic medication and substance use-related

outcomes in the treatment of schizophrenia. Am J Addict 15:44–49, 2006 [PubMed]

Pfohl B, Winokur G: The evolution of symptoms in institutionalized hebephrenic/catatonic

schizophrenics. Br J Psychiatry 141:567–572, 1982 [PubMed]

Phillips SD, Burns BJ, Edgar ER, et al: Moving assertive community treatment into standard practice.

Psychiatr Serv 52:771–779, 2001 [Full Text] [PubMed]

Pietzcker A, Gaebel W, Kopcke W: Intermittent versus maintenance neuroleptic long-term

treatment in schizophrenia: 2 year results of German multicenter study. J Psychiatr Res

27:321–339, 1993

Pilling S, Bebbington P, Kuipers E, et al: Psychological treatments in schizophrenia, II:

meta-analyses of randomized controlled trials of social skills training and cognitive remediation.

Psychol Med 32:783–791, 2002 [PubMed]

Pilowsky LS, Kerwin RW, Murray RM: Schizophrenia: a neurodevelopmental perspective.

Neuropsychopharmacology 9:83–91, 1993 [PubMed]

Pitschel-Walz G, Leucht S, Bauml J, et al: The effect of family interventions on relapse and

rehospitalization in schizophrenia—a meta-analysis. Schizophr Bull 27:73–92, 2001 [PubMed]

Porteous DJ, Thomson P, Brandon NJ, et al: The genetics and biology of DISC1—an emerging role in

psychosis and cognition. Biol Psychiatry 60:123–131, 2006 [PubMed]

Potkin SG, Jin Y, Bunney BG, et al: Effect of clozapine and adjunctive high-dose glycine in

treatment-resistant schizophrenia. Am J Psychiatry 156:145–147, 1999 [Full Text] [PubMed]

Potkin SG, Alphs L, Hsu C, et al: Predicting suicidal risk in schizophrenic and schizoaffective

patients in a prospective two-year trial. Biol Psychiatry 54:444–452, 2003 [PubMed]

Potvin S, Stip E, Lipp O, et al: Quetiapine in patients with comorbid schizophrenia-spectrum and

substance use disorders: an open-label trial. Curr Med Res Opin 22:1277–1285, 2006 [PubMed]

Poyurovsky M, Dorfman-Etrog P, Hermesh H, et al: Beneficial effect of olanzapine in schizophrenic

patients with obsessive-compulsive symptoms. Int Clin Psychopharmacol 15:169–173, 2000

[PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

45 of 51

10/05/2009 16:35

Qin P, Nordentoft M: Suicide risk in relation to psychiatric hospitalization: evidence based on

longitudinal registers. Arch Gen Psychiatry 62:427–432, 2005 [PubMed]

Radomsky ED, Haas GL, Mann JJ, et al: Suicidal behavior in patients with schizophrenia and other

psychotic disorders. Am J Psychiatry 156:1590–1595, 1999 [Full Text] [PubMed]

Ran MS, Xiang MZ, Mao WJ, et al: Characteristics of suicide attempters and nonattempters with

schizophrenia in a rural community. Suicide Life Threat Behav 35:694–701, 2005 [PubMed]

Rapp CA, Goscha RJ: The principles of effective case management of mental health services.

Psychiatr Rehabil J 27:319–333, 2004 [PubMed]

Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental disorders with alcohol and other drug

abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264:2511–2518, 1990

[PubMed]

Remington G, Kapur S: Neuroleptic-induced extrapyramidal symptoms and the role of combined

serotonin/dopamine antagonist. J Clin Psychiatry 14:14–24, 1996

Remington G, Kapur S, Zipursky R: APA Practice guideline for schizophrenia: risperidone

equivalents. American Psychiatric Association. Am J Psychiatry 155:1301–1302, 1998 [Full Text]

[PubMed]

Riecher-Rossler A, Hafner H, Stumbaum M, et al: Can estradiol modulate schizophrenic

symptomatology? Schizophr Bull 20:203–214, 1994 [PubMed]

Ries RK, Dyck DG, Short R, et al: Outcomes of managing disability benefits among patients with

substance dependence and severe mental illness. Psychiatr Serv 55:445–447, 2004 [Full Text]

[PubMed]

Ripoll N, Bronnec M, Bourin M: Nicotinic receptors and schizophrenia. Curr Med Res Opin

20:1057–1074, 2004 [PubMed]

Robinson DG, Woerner MG, Alvir JM, et al: Predictors of treatment response from a first episode of

schizophrenia or schizoaffective disorder. Am J Psychiatry 156:544–549, 1999 [Full Text] [PubMed]

Rog DJ: The evidence on supported housing. Psychiatr Rehabil J 27:334–344, 2004 [PubMed]

Rolfe TJ, McGory P, Cooks J, et al: Cannabis use in first episode psychosis: incidence and short-term

outcome. Schizophr Res 36:313, 1999

Rosenberg SD, Goodman LA, Osher FC, et al: Prevalence of HIV, hepatitis B, and hepatitis C in

people with severe mental illness. Am J Public Health 91:31–37, 2001 [PubMed]

Rosenheck RA, Leslie DL, Sindelar J, et al: Cost-effectiveness of second-generation antipsychotics

and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry

163:2080–2089, 2006 [Full Text] [PubMed]

Ross CA, Margolis RL, Reading SA, et al: Neurobiology of schizophrenia. Neuron 52:139–153, 2006

[PubMed]

Rossau CD, Mortensen PB: Risk factors for suicide in patients with schizophrenia: nested

case-control study. Br J Psychiatry 171:355–359, 1997 [PubMed]

Rosso IM, Bearden CE, Hollister JM, et al: Childhood neuromotor dysfunction in schizophrenia

patients and their unaffected siblings: a prospective cohort study. Schizophr Bull 26:367–378, 2000

[PubMed]

Roth RM, Brunette MF, Green AI: Treatment of substance use disorders in schizophrenia: a unifying

neurobiological mechanism? Curr Psychiatry Rep 7:283–291, 2005 [PubMed]

Roy A: Risk factors for suicide in psychiatric patients. Arch Gen Psychiatry 39:1089–1095, 1982a

Roy A: Suicide in chronic schizophrenia. Br J Psychiatry 141:171–177, 1982bPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

46 of 51

10/05/2009 16:35

Rubio G, Martinez I, Ponce G, et al: Long-acting injectable risperidone compared with

zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity. Can J

Psychiatry 51:531–539, 2006 [PubMed]

Russell AJ, Munro JC, Jones PB, et al: Schizophrenia and the myth of intellectual decline. Am J

Psychiatry 154:635–639, 1997 [Full Text] [PubMed]

Sacco KA, Termine A, Seyal A, et al: Effects of cigarette smoking on spatial working memory and

attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen

Psychiatry 62:649–659, 2005 [PubMed]

Salisbury DF, Kuroki N, Kasai K, et al: Progressive and interrelated functional and structural

evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry 64:521–529, 2007

[PubMed]

Saltz BL, Woerner MG, Kane JM, et al: Prospective study of tardive dyskinesia incidence in the

elderly. JAMA 266:2402–2406, 1991 [PubMed]

Sax KW, Strakowski SM, Keck PE Jr, et al: Relationships among negative, positive, and depressive

symptoms in schizophrenia and psychotic depression. Br J Psychiatry 168:68–71, 1996 [PubMed]

Sayers SL, Campbell EC, Kondrich J, et al: Cocaine abuse in schizophrenic patients treated with

olanzapine versus haloperidol. J Nerv Ment Dis 193:379–386, 2005 [PubMed]

Saykin AJ, Gur RC, Gur RE, et al: Neuropsychological function in schizophrenia. Selective

impairment in memory and learning. Arch Gen Psychiatry 48:618–624, 1991 [PubMed]

Saykin AJ, Shtasel DL, Gur RE, et al: Neuropsychological deficits in neuroleptic naive patients with

first-episode schizophrenia. Arch Gen Psychiatry 51:124–131, 1994 [PubMed]

Schooler NR: Relapse and rehospitalization: comparing oral and depot antipsychotics. J Clin

Psychiatry 64 (suppl 16):14–17, 2003

Schooler NR: Relapse prevention and recovery in the treatment of schizophrenia. J Clin Psychiatry

67 (suppl 5):19–23, 2006

Schooler NR, Keith SJ, Severe JB, et al: Relapse and rehospitalization during maintenance

treatment of schizophrenia. The effects of dose reduction and family treatment. Arch Gen

Psychiatry 54:453–463, 1997 [PubMed]

Schooler NR, Rabinowitz J, Davidson M, et al: Risperidone and haloperidol in first-episode

psychosis: a long-term randomized trial. Am J Psychiatry 162:947–953, 2005 [Full Text] [PubMed]

Schultz SK, Miller DD, Oliver SE, et al: The life course of schizophrenia: age and symptom

dimensions. Schizophr Res 23:15–23, 1997 [PubMed]

Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38, 2002

[PubMed]

Selemon LD, Goldman-Rakic PS: The reduced neuropil hypothesis: a circuit based model of

schizophrenia. Biol Psychiatry 45:17–25, 1999 [PubMed]

Sellwood W, Barrowclough C, Tarrier N, et al: Needs-based cognitive-behavioural family

intervention for carers of patients suffering from schizophrenia: 12-month follow-up. Acta Psychiatr

Scand 104:346–355, 2001 [PubMed]

Selzer JA, Lieberman JA: Schizophrenia and substance abuse. Psychiatr Clin North Am 16:401–412,

1993 [PubMed]

Sevy S, Kay SR, Opler LA, et al: Significance of cocaine history in schizophrenia. J Nerv Ment Dis

178:642–648, 1990 [PubMed]

Sewell DD: Schizophrenia and HIV. Schizophr Bull 22:465–473, 1996 [PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

47 of 51

10/05/2009 16:35

Sharma A, Sorrell JH: Aripiprazole-induced parkinsonism. Int Clin Psychopharmacol 21:127–129,

2006 [PubMed]

Shirzadi AA, Ghaemi SN: Side effects of atypical antipsychotics: extrapyramidal symptoms and the

metabolic syndrome. Harv Rev Psychiatry 14:152–164, 2006 [PubMed]

Simon AE, Cattapan-Ludewig K, Zmilacher S, et al: Cognitive functioning in the schizophrenia

prodrome. Schizophr Bull 33:761–771, 2007 [PubMed]

Simpson GM: The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 61 (suppl

4):39–44, 2000

Siris SG: Pharmacological treatment of substance-abusing schizophrenic patients. Schizophr Bull

16:111–122, 1990 [PubMed]

Siris SG: Depression in schizophrenia: perspective in the era of “atypical” antipsychotic agents. Am

J Psychiatry 157:1379–1389, 2000a

Siris SG: Management of depression in schizophrenia. Psychiatric Annals 30:13–19, 2000b

Siris SG, Morgan V, Fagerstrom R, et al: Adjunctive imipramine in the treatment of postpsychotic

depression. A controlled trial. Arch Gen Psychiatry 44:533–539, 1987 [PubMed]

Siris SG, Mason SE, Bermanzohn PC, et al: Adjunctive imipramine in substance-abusing dysphoric

schizophrenic patients. Psychopharmacol Bull 29:127–133, 1993 [PubMed]

Smelson DA, Williams J, Kaune M, et al: Reduced cue-elicited cocaine craving and relapses following

treatment with risperidone. Presented at the 153rd Annual Meeting of the American Psychiatric

Association, Chicago, IL, May 13–18, 2000

Smelson DA, Ziedonis D, Williams J, et al: The efficacy of olanzapine for decreasing cue-elicited

craving in individuals with schizophrenia and cocaine dependence: a preliminary report. J Clin

Psychopharmacol 26:9–12, 2006 [PubMed]

Soni SD, Brownlee M: Alcohol abuse in chronic schizophrenics: implications for management in the

community. Acta Psychiatr Scand 84:272–276, 1991 [PubMed]

Spence SA, Hirsch SR, Brooks DJ, et al: Prefrontal cortex activity in people with schizophrenia and

control subjects. Evidence from positron emission tomography for remission of “hypofrontality”

with recovery from acute schizophrenia. Br J Psychiatry 172:316–323, 1998 [PubMed]

Spencer T, Biederman J, Wilens T, et al: Is attention-deficit hyperactivity disorder in adults a valid

disorder? Harv Rev Psychiatry 1:326–335, 1994 [PubMed]

Spohn HE, Strauss ME: Relation of neuroleptic and anticholinergic medication to cognitive functions

in schizophrenia. J Abnorm Psychol 98:367–380, 1989 [PubMed]

Stanton JM: Weight gain associated with neuroleptic medication: a review. Schizophr Bull

21:463–472, 1995 [PubMed]

Stefansson H, Steinthorsdottir V, Thorgeirsson TE, et al: Neuregulin 1 and schizophrenia. Ann Med

36:62–71, 2004 [PubMed]

Stein LI, Test MA: Alternative to mental hospital treatment, I: conceptual model, treatment

program, and clinical evaluation. Arch Gen Psychiatry 37:392–397, 1980 [PubMed]

Steinberg ML, Williams JM, Ziedonis DM: Financial implications of cigarette smoking among

individuals with schizophrenia. Tob Control 13:206, 2004 [PubMed]

Stroup TS, Lieberman JA, McEvoy JP, et al: Effectiveness of olanzapine, quetiapine, risperidone, and

ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical

antipsychotic. Am J Psychiatry 163:611–622, 2006 [Full Text] [PubMed]

Stroup TS, Lieberman JA, McEvoy JP, et al: Effectiveness of olanzapine, quetiapine, and risperidonePrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

48 of 51

10/05/2009 16:35

in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J

Psychiatry 164:415–427, 2007 [Full Text] [PubMed]

Strous RD, Patel JK, Zimmet S, et al: Clozapine and paroxetine in the treatment of schizophrenia

with obsessive-compulsive features. Am J Psychiatry 156:973–974, 1999 [Full Text] [PubMed]

Stuss DT, Benson DF: The Frontal Lobes. New York, Raven Press, 1986

Susman VL: Clinical management of neuroleptic malignant syndrome. Psychiatr Q 72:325–336,

2001 [PubMed]

Svensson TH, Mathe JM, Andersson JL, et al: Mode of action of atypical neuroleptics in relation to

the phencyclidine model of schizophrenia: role of 5-HT2 receptor and alpha 1-adrenoceptor

antagonism [corrected]. J Clin Psychopharmacol 15:11S–18S, 1995

Szarfman A, Tonning JM, Levine JG, et al: Atypical antipsychotics and pituitary tumors: a

pharmacovigilance study. Pharmacotherapy 26:748–758, 2006 [PubMed]

Szymanski S, Lieberman JA, Alvir JM, et al: Gender differences in onset of illness, treatment

response, course, and biologic indexes in first-episode schizophrenic patients. Am J Psychiatry

152:698–703, 1995 [Full Text] [PubMed]

Tamminga CA: Principles of the pharmacotherapy of schizophrenia, in Neurobiology of Mental

Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford University Press, 1999, pp

272–290

Tamminga CA: Partial dopamine agonists in the treatment of psychosis. J Neural Transm

109:411–420, 2002 [PubMed]

Tarrier N, Barrowclough C, Vaughn C, et al: The community management of schizophrenia. A

controlled trial of a behavioural intervention with families to reduce relapse. Br J Psychiatry

153:532–542, 1988 [PubMed]

Tarrier N, Kinney C, McCarthy E, et al: Two-year follow-up of cognitive—behavioral therapy and

supportive counseling in the treatment of persistent symptoms in chronic schizophrenia. J Consult

Clin Psychol 68:917–922, 2000 [PubMed]

Tarsy D, Baldessarini RJ: Epidemiology of tardive dyskinesia: is risk declining with modern

antipsychotics? Mov Disord 21:589–598, 2006 [PubMed]

Tibbo P, Kroetsch M, Chue P, et al: Obsessive-compulsive disorder in schizophrenia. J Psychiatr Res

34:139–146, 2000 [PubMed]

Tollefson GD, Beasley CM Jr, Tamura RN, et al: Blind, controlled, long-term study of the comparative

incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry

154:1248–1254, 1997 [Full Text] [PubMed]

Tollefson GD, Sanger TM, Lu Y, et al: Depressive signs and symptoms in schizophrenia: a

prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 55:250–258, 1998

[PubMed]

Tollefson GD, Andersen SW, Tran PV: The course of depressive symptoms in predicting relapse in

schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone. Biol

Psychiatry 46:365–373, 1999 [PubMed]

Tollefson GD, Birkett MA, Kiesler GM, et al: Double-blind comparison of olanzapine versus clozapine

in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry 49:52–63,

2001 [PubMed]

Toomey R, Faraone SV, Seidman LJ, et al: Association of neuropsychological vulnerability markers

in relatives of schizophrenic patients. Schizophr Res 31:89–98, 1998 [PubMed]

Tran PV, Dellva MA, Tollefson GD, et al: Oral olanzapine versus oral haloperidol in the maintenancePrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

49 of 51

10/05/2009 16:35

treatment of schizophrenia and related psychoses. Br J Psychiatry 172:499–505, 1998 [PubMed]

Tsai G, Yang P, Chung LC, et al: D-serine added to antipsychotics for the treatment of schizophrenia.

Biol Psychiatry 44:1081–1089, 1998 [PubMed]

Tsai G, Lane HY, Yang P, et al: Glycine transporter I inhibitor, N-methylglycine (sarcosine), added

to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55:452–456, 2004 [PubMed]

Tsai GE, Yang P, Chang YC, et al: D-alanine added to antipsychotics for the treatment of

schizophrenia. Biol Psychiatry 59:230–234, 2006 [PubMed]

Tsankova N, Renthal W, Kumar A, et al: Epigenetic regulation in psychiatric disorders. Nat Rev

Neurosci 8:355–367, 2007 [PubMed]

Tsuang MT, Winokur G, Crowe RR: Morbidity risks of schizophrenia and affective disorders among

first degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J

Psychiatry 137:497–504, 1980 [PubMed]

Tsuang MT, Fleming JA, Simpson JC: Suicide and schizophrenia, in The Harvard Medical School

Guide to Suicide Assessment and Intervention. Edited by Jacobs DG. San Francisco, CA,

Jossey-Bass, 1999a, pp 287–299

Tsuang MT, Stone WS, Seidman LJ, et al: Treatment of nonpsychotic relatives of patients with

schizophrenia: four case studies. Biol Psychiatry 45:1412–1418, 1999b

Tsuang MT, Stone WS, Faraone SV: Towards the prevention of schizophrenia. Biol Psychiatry

48:349–356, 2000 [PubMed]

van Haren NE, Pol HE, Schnack HG, et al: Progressive brain volume loss in schizophrenia over the

course of the illness: evidence of maturational abnormalities in early adulthood. Biol Psychiatry

63:106–113, 2007

van Os J, Drukker M, a Campo J, et al: Validation of remission criteria for schizophrenia. Am J

Psychiatry 163:2000–2002, 2006

Varsamis J, Adamson JD: Early schizophrenia. Can Psychiatr Assoc J 16:487–497, 1971 [PubMed]

Volavka J, Czobor P, Sheitman B, et al: Clozapine, olanzapine, risperidone, and haloperidol in the

treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry

159:255–262, 2002 [Full Text] [PubMed]

Waddington JL: Schizophrenia: developmental neuroscience and pathobiology. Lancet

341:531–536, 1993 [PubMed]

Waddington JL, Buckley PF, Scully PJ, et al: Course of psychopathology, cognition and

neurobiological abnormality in schizophrenia: developmental origins and amelioration by

antipsychotics? J Psychiatr Res 32:179–189, 1998 [PubMed]

Walker E, Lewis N, Loewy R, et al: Motor dysfunction and risk for schizophrenia. Dev Psychopathol

11:509–523, 1999 [PubMed]

Wang PS, Walker AM, Tsuang MT, et al: Dopamine antagonists and the development of breast

cancer. Arch Gen Psychiatry 59:1147–1154, 2002 [PubMed]

Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia.

Arch Gen Psychiatry 44:660–669, 1987 [PubMed]

Weinberger DR: On the plausibility of “the neurodevelopmental hypothesis” of schizophrenia.

Neuropsychopharmacology 14:1S–11S, 1996

Weinberger DR, Berman KF, Zec RF: Physiologic dysfunction of dorsolateral prefrontal cortex in

schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry 43:114–124, 1986

[PubMed]Print: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

50 of 51

10/05/2009 16:35

Weinberger DR, McClure RK: Neurotoxicity, neuroplasticity, and magnetic resonance imaging

morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 59:553–558,

2002 [PubMed]

Weiner E, Ball MP, Summerfelt A, et al: Effects of sustained-release bupropion and supportive group

therapy on cigarette consumption in patients with schizophrenia. Am J Psychiatry 158:635–637,

2001 [Full Text] [PubMed]

Weiss RD, Griffin ML, Kolodziej ME, et al: A randomized trial of integrated group therapy versus

group drug counseling for patients with bipolar disorder and substance dependence. Am J

Psychiatry 164:100–107, 2007 [Full Text] [PubMed]

Werneke U, Taylor D, Sanders TA: Options for pharmacological management of obesity in patients

treated with atypical antipsychotics. Int Clin Psychopharmacol 17:145–160, 2002 [PubMed]

Westermeyer JF, Harrow M, Marengo JT: Risk for suicide in schizophrenia and other psychotic and

nonpsychotic disorders. J Nerv Ment Dis 179:259–266, 1991 [PubMed]

Wilkins JN: Pharmacotherapy of schizophrenia patients with comorbid substance abuse. Schizophr

Bull 23:215–228, 1997 [PubMed]

Williams GV, Castner SA: Under the curve: critical issues for elucidating D1 receptor function in

working memory. Neuroscience 139:263–276, 2006 [PubMed]

Williams JM, Ziedonis DM, Foulds J: A case series of nicotine nasal spray in the treatment of tobacco

dependence among patients with schizophrenia. Psychiatr Serv 55:1064–1066, 2004 [Full Text]

[PubMed]

Windgassen K, Wesselmann U, Schulze Monking H: Galactorrhea and hyperprolactinemia in

schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology 33:142–146,

1996 [PubMed]

Wirshing DA, Spellberg BJ, Erhart SM, et al: Novel antipsychotics and new onset diabetes. Biol

Psychiatry 44:778–783, 1998 [PubMed]

Wirshing DA, Wirshing WC, Kysar L, et al: Novel antipsychotics: comparison of weight gain

liabilities. J Clin Psychiatry 60:358–363, 1999 [PubMed]

Wirshing DA, Erhart SM, Pierre JM: Nonextrapyramidal side effects of novel antipsychotics. Curr

Opin Psychiatry 13:45–50, 2000

Wirshing DA, Boyd JA, Meng LR, et al: The effects of novel antipsychotics on glucose and lipid

levels. J Clin Psychiatry 63:856–865, 2002 [PubMed]

Wirshing DA, Pierre JM, Erhart SM, et al: Understanding the new and evolving profile of adverse

drug effects in schizophrenia. Psychiatr Clin North Am 26:165–190, 2003 [PubMed]

Wyatt RJ: Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17:325–351, 1991

[PubMed]

Wyatt RJ: Early intervention for schizophrenia: can the course of the illness be altered? Biol

Psychiatry 38:1–3, 1995 [PubMed]

Wyatt RJ, Damiani LM, Henter ID: First-episode schizophrenia. Early intervention and medication

discontinuation in the context of course and treatment. Br J Psychiatry Suppl 172:77–83, 1998

[PubMed]

Wykes T, Reeder C, Corner J, et al: The effects of neurocognitive remediation on executive

processing in patients with schizophrenia. Schizophr Bull 25:291–307, 1999 [PubMed]

Yazigi RA, Quintero CH, Salameh WA: Prolactin disorders. Fertil Steril 67:215–225, 1997 [PubMed]

Yung AR, McGorry PD: The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N

Z J Psychiatry 30:587–599, 1996aPrint: Chapter 55. Treatment of Schizophrenia http://www.psychiatryonline.com/popup.aspx?aID=423573&print=yes…

51 of 51

10/05/2009 16:35

Yung AR, McGorry PD: The prodromal phase of first-episode psychosis: past and current

conceptualizations. Schizophr Bull 22:353–370, 1996b

Zakzanis KK: Neuropsychological correlates of positive vs. negative schizophrenic symptomatology.

Schizophr Res 29:227–233, 1998 [PubMed]

Ziedonis D, Richardson T, Lee E, et al: Adjunctive desipramine in the treatment of cocaine abusing

schizophrenics. Psychopharmacol Bull 28:309–314, 1992 [PubMed]

Ziedonis D, Williams J, Corrigan P, et al: Management of substance abuse in schizophrenia.

Psychiatr Ann 30:67–75, 2000

Ziedonis D, Williams JM, Smelson D: Serious mental illness and tobacco addiction: a model program

to address this common but neglected issue. Am J Med Sci 326:223–230, 2003 [PubMed]

Ziegenbein M, Sieberer M, Calliess IT, et al: Aripiprazole-induced extrapyramidal side effects in a

patient with schizoaffective disorder. Aust N Z J Psychiatry 40:194–195, 2006 [PubMed]

Zimmet SV, Strous RD, Burgess ES, et al: Effects of clozapine on substance use in patients with

schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol

20:94–98, 2000 [PubMed]

Zipursky RB, Lim KO, Sullivan EV, et al: Widespread cerebral gray matter volume deficits in

schizophrenia. Arch Gen Psychiatry 49:195–205, 1992 [PubMed]

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.