Chapter 27. Classic Antipsychotic Medications

Chapter 27. Classic Antipsychotic Medications

HISTORY AND DISCOVERY

Prior to the introduction of classic antipsychotic medications in the 1950s, treatment for psychotic disorders primarily consisted of humane containment and supportive care. A variety of remedies

without empirical support were popular in different cultures for brief periods of time but went out of vogue because they were ineffective. One approach to the treatment of psychosis that survived

through the ages was the use of reserpine as a folk medicine in India. In the Ayurveda (the traditional Indian medical system originating 5,000 years ago), Sarpagundha (Rauwolfia serpentina,

Indian snakeroot, from which reserpine is derived) was recommended as the treatment for “unmada” (psychosis). In the early 1950s, reserpine was found to improve psychosis and reduce violent

behavior in clinical trials among aggressive mentally ill patients in state hospitals in New York and California, and this led to its introduction as an antipsychotic in 1954 (2 years after

chlorpromazine). However, reserpine’s popularity declined after 1957 because of its high level of side effects and low safety index. Although the use of reserpine has been completely discontinued

in some countries (e.g., the United Kingdom) because of its significant drug interactions and adverse effects, it is available in the United States, where it is still used, albeit very infrequently, as an

alternative or augmentation treatment in patients with schizophrenia refractory to other antipsychotic treatment.

Chlorpromazine, the first of the “classic” antipsychotics, heralded a pharmacological revolution in psychiatry with its introduction in 1952. The discovery of chlorpromazine was serendipitous and

owes much to the need of Allied forces during World War II to find a synthetic antimalarial treatment, given that access to many quinine-producing areas of the world had been blocked by Japanese

forces. Paul Ehrlich had noted in 1891 that methylene blue, a phenothiazine derivative, effectively treated symptoms of malaria (Travis 1991). A new group of compounds was synthesized by

substituting chains on the central nitrogen atom of the phenothiazine ring. Although these phenothiazine derivatives were found to be inactive as antimalarial drugs, they were noted to have

potent antihistaminic properties.

Scientists at Rhône-Poulenc in France found that one of the aminoalkyl phenothiazines, promethazine, had more pronounced sedative properties than other antihistamines. This effect was noted in

1949 by Henri Laborit, an anesthesiologist and surgeon in the French navy who had researched various synthetic antihistamines as a way of “potentiating” anesthetics for use in surgical patients to

decrease the morbidity and mortality from surgically induced shock. Promethazine was one of the agents he tested. His observation that administration of a “lytic cocktail” (a mixture of a narcotic,

sedating, and hypnotic drug) to induce an “artificial hibernation” was successful in decreasing patient anxiety led to a further search by the Rhône-Poulenc scientists for other phenothiazine

derivatives with similar effects. Paul Charpentier, a company chemist and phenothiazine specialist, had synthesized a new phenothiazine, chlorpromazine, which was first tested by S. Couvoisier in

rodents and dogs in 1950. It was found to prolong barbiturate-induced sleep, to prevent apomorphine-induced emesis, and to inhibit conditioned avoidance–escape responses. When Laborit used

this drug on his surgical patients, he noted that some of them, without losing consciousness, became very relaxed and appeared indifferent to what was occurring around them. He later referred to

this effect as a “chemical lobotomy.”

On the basis of these observations, Laborit recommended the drug to his psychiatric colleagues at the Val-de-Grace military hospital in Paris. Their success in treating a young male patient with

mania at the Sainte-Anne mental hospital in Paris was noted by two French psychiatrists, Jean Delay and Pierre Deniker. In March 1952, they began the treatment of a small group of hospitalized

psychotic patients with chlorpromazine alone. Delay and Deniker reported the drug’s amazing treatment successes at the June 1952 meeting of the Medical Psychological Society. The use of

chlorpromazine quickly spread to Canada, where Heinz Lehmann at the Verdun Hospital in Montreal treated a large cohort of acute schizophrenic patients with the drug. After 4–5 weeks of

treatment, many of the patients were practically symptom-free.

In the United States, chlorpromazine was first used by psychiatrist William Long, medical director of McLean Hospital in Boston. Subsequently, the results of a successful open-label trial in

September 1953 by a psychiatrist, Willis Bower, also at McLean, were published in the New England Journal of Medicine in October 1954. The definitive evidence of chlorpromazine’s efficacy was

established following completion of a large controlled study by the U.S. Veterans Administration Collaborative Study Group in 1960.

After the successes of chlorpromazine, numerous other phenothiazines were synthesized and tested. Many other drugs, which were slightly different in structure from the phenothiazines but

nonetheless effective as antipsychotics, were also produced. These included drugs such as haloperidol and thiothixene. The last of these drugs approved by the U.S. Food and Drug Administration

(FDA) was molindone, introduced in 1975. Of the 51 classic antipsychotics (representing 8 different chemical classes) available in the world (Table 27–1), 12 are currently available in the United

States.

TABLE 27–1. First-generation antipsychotics (n = 51)

1. Phenothiazines
2. Aliphatic side chain (low/medium-potency agents)

Chlorproethazine, chlorpromazine, cyamemazine, levomepromazine, promazine, triflupromazine

1. Piperidine side chain (low/medium-potency agents)

Mesoridazine, pericyazine, piperacetazine, pipotiazine, propericiazine, sulforidazine, thioridazine

1. Piperazine side chain (medium/high-potency agents)

Acetophenazine, butaperazine, dixyrazine, fluphenazine, perazine, perphenazine, prochlorperazine, thiopropazate, thioproperazine, trifluoperazine

1. Butyrophenones (high-potency agents)

Benperidol, bromperidol, droperidol, fluanisone, haloperidol, melperone, moperone, pipamperone, timiperone, trifluperidol

III. Thioxanthenes (low/medium-potency agents)

Chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol

1. Dihydroindolones (low/medium-potency agents)

Molindone, oxypertine

1. Dibenzepines (low/medium-potency agents)

Clotiapine, loxapine

1. Diphenylbutylpiperidines (high-potency agents)

Fluspirilene, penfluridol, pimozide

VII. Benzamides (low-potency agents)

Nemonapride, sulpiride, sultopride, tiapride

VIII. Iminodibenzyl (medium-potency agents)

Clocapramine, mosapramine

The ability of chlorpromazine and other conventional antipsychotics to suppress psychotic symptoms (delusions, hallucinations, and bizarre behavior) had a profound impact on chronically

hospitalized psychiatric populations worldwide. Massive numbers of psychiatric patients were discharged from state hospitals to the community. This period of deinstitutionalization led to a

decrease in the number of patients in state and county mental hospitals in the United States from 559,000 in 1955 to 338,000 in 1970 to 107,000 in 1988, an 80% decrease over 30 years. Initially,

this led to enthusiasm about the possibility that patients with schizophrenia and other psychoses would be able to function well in the community. However, it soon became apparent that

improvement with antipsychotic treatment was incomplete, and common lack of compliance, with subsequent relapses, led to frequent rehospitalization (i.e., the “revolving door phenomenon”).

Many patients stopped their medications shortly after hospital discharge, preferring life with psychosis to intolerable movement disorders. Depot preparations introduced in the 1970s helped

reduce the rate of relapse due to noncompliance. However, only a minority of patients received depot antipsychotics, and the search for a safer class of drugs with better tolerability eventually led

to the development of the second-generation (atypical) antipsychotics (SGAs).

Shortly after the widespread use of chlorpromazine, psychiatrists began observing that treated patients frequently manifested signs and symptoms of parkinsonism. Along with other side effects

such as dystonia and akathisia, these are collectively referred to as extrapyramidal side effects (EPS) because they involve involuntary muscle movements. In a 1961 report, the prevalence of

antipsychotic-induced EPS was estimated at 40%. Because of the high rate of movement disorders associated with antipsychotic treatment, many psychiatrists believed EPS to be an unavoidable

accompaniment of antipsychotic action; in fact, the onset of some EPS was considered to indicate achievement of a necessary dose (neuroleptic threshold). The first report of persistent orobuccal

movements (later labeled tardive dyskinesia) came from France in 1959. The pervasiveness and significant adverse consequences of short-term and long-term motor side effects associated with

classic antipsychotic drugs led to a search for antipsychotic drugs that would be as efficacious but without the risk of EPS.

Clozapine, a dibenzodiazepine synthesized in 1959, was the first antipsychotic drug without EPS (i.e., atypical). It was first marketed in 1972 in Europe but was withdrawn in some countries in

1975 after several reports of fatalities secondary to agranulocytosis. Clozapine was not introduced in the United States until 1989, after convincing studies demonstrated its efficacy in

neuroleptic-refractory patients, but with the requirement for mandatory weekly leukocyte counts. Several other atypical agents have been launched in the past 15 years and are reported to bePrint: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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associated with far lower levels of EPS and a broader spectrum of efficacy (see Chapters 28, 29, 30, 31, 32, and 33 in this textbook). Since then, use of the classic antipsychotics (also referred to as

traditional, conventional, or first-generation antipsychotics [FGAs]) has steadily declined, especially in the United States—they currently aggregate less than 10% of all antipsychotic prescriptions

in the country.

SGAs have increasingly replaced FGAs around the world and have almost completely supplanted FGAs in the United States because of their presumed greater efficacy and better safety/tolerability

profiles. However, results of recent government-sponsored studies in the United States (Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE]) and the United Kingdom (Cost Utility of

the Latest Antipsychotic Drugs in Schizophrenia Study [CUtLASS]) have challenged the current worldview of the greater effectiveness of SGAs over FGAs and are reinvigorating interest in the utility

and clinical applicability of classic antipsychotics.

STRUCTURE–ACTIVITY RELATIONS

Phenothiazines

Members of the phenothiazine class of classic antipsychotics share the same basic phenothiazine ring but differ in substitutions at both their R1 and R2 positions (Figure 27–1). Based on the side

chain attached to the nitrogen atom in the middle ring (R1), the phenothiazines are further subdivided into three subtypes: aliphatic, piperidine, and piperazine phenothiazines. There is much more

variety in the substitutions at the second carbon atom; generally more negatively charged (electrophilic) groups tend to result in stronger binding to dopamine receptors. These electrophilic groups

weaken the aromatic bonds within the phenothiazine ring by partially drawing bonding electrons into their orbit.

FIGURE 27–1. Chemical structures of various classic antipsychotics.Print: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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Aliphatic Phenothiazines

The aliphatic phenothiazines share a dimethylamide substitution at their tenth carbon. Chlorpromazine (Thorazine or Largactil) is the prototypical member of this class and remains the aliphatic

phenothiazine most widely used throughout the world. With a chlorine atom attached to its second carbon, chlorpromazine is heavily sedating because of its high level of anticholinergic, anti-

-adrenergic, and antihistaminergic actions.

Piperidine Phenothiazines

Piperidine phenothiazines are named for the presence of a piperidine ring at their tenth carbon. Although members of this group have similar efficacy and side effects compared with aliphatic

phenothiazines, they are notable for having a less potent effect on nigrostriatal dopamine2 (D2) receptors and a higher level of anticholinergic activity; consequently they are associated with a

lower frequency of EPS. Thioridazine (Mellaril) and its metabolite, mesoridazine (Serentil), are the only piperidines available within the United States. The use of these agents has been virtually

extinguished by a black box warning about significant QTc prolongation that was added to their product label in 2000.

Piperazine Phenothiazines

With a substitution of a piperazine group at the tenth carbon of a phenothiazine, the piperazines have greatly increased D2 blockade and a lower affinity to muscarinic, -adrenergic, and

histaminergic receptors. Some of the most potent conventional antipsychotics available in the United States, including fluphenazine (Prolixin), perphenazine (Trilafon), and trifluoperazine

(Stelazine), belong to this class. The well-known antiemetic prochlorperazine (Compazine) is also part of this class; although approved for the treatment of psychosis, it is rarely utilized as an

antipsychotic.

Thioxanthenes

Structurally and pharmacologically similar to the phenothiazines, the thioxanthenes also differ widely in their pharmacological profiles based on similar side-chain substitutions (see Figure 27–1).

For instance, chlorprothixene shares the same dimethylamide and chloride substitution as chlorpromazine, with which it also shares its pharmacological profile. Thiothixene (Navane) has both a

piperazine side chain and a strongly electrophilic substitution [SO2N(CH3)CH3], thus sharing the pharmacological profile of the piperazines. Of further interest, the thioxanthene ring, which differs

from the phenothiazine ring by having a carbon atom at its tenth position, has two optically active isomers, or enantiomers. Of the two isomers of the ring, the cis isomer exerts greater

dopaminergic receptor blockade than the trans isomer.

Butyrophenones

The butyrophenone class has a piperidine ring with a three-carbon chain ending in a carbonyl-substituted p-fluorobenzene ring. Butyrophenones differ on the basis of the substitutions present

within their piperidine rings (see Figure 27–1). Haloperidol, arguably the best-known classic antipsychotic, is the most widely used member of this class. Sharing a similar pharmacological profile

but having a lower level of activity within the nigrostriatal pathway, another phenothiazine, droperidol, is available only in an intramuscular form for the indication of nausea. Both haloperidol and

droperidol are strong dopamine receptor antagonists and show little antimuscarinic, antihistaminergic, and antiadrenergic activity. Although widely used in the past as an antipsychotic, droperidol

is approved by the FDA only for use as an antiemetic, and its use has recently declined due to its QTc-prolonging effects.

Spiperone, one of the most potent dopamine antagonists in existence, is utilized as a D2, dopamine3 (D3), and dopamine4 (D4) receptor radiolabel for research purposes exclusively.

Dibenzoxazepines

Loxapine, the only FDA-approved agent within the dibenzoxazepine class, is composed of a tricyclic ring structure with a seven-member central ring. It has a piperazine side chain and chlorine at

position R2 (see Figure 27–1). It exhibits an intermediate level of D2 blockade, as well as some serotonin2 (5-HT2) antagonism. Its side-effect profile is characterized by intermediate sedation and

autonomic effects. Loxapine has the distinction of being the most “atypical” of the classic antipsychotics because it is structurally similar to the dibenzodiazepine clozapine. Another notable feature

of loxapine is that one of its metabolites, amoxapine, is marketed as an antidepressant with antipsychotic effects.

Dihydroindoles

Molindone is the only member of the dihydroindoles available in the United States. Sharing a similar structure with the indoleamines (see Figure 27–1), such as serotonin, molindone has the

distinction of being the only classic antipsychotic not associated with any weight gain or a lowering of the seizure threshold.

Diphenylbutylpiperidines

Pimozide, the only agent within the diphenylbutylpiperidine class available in the United States, is approved only for the treatment of Tourette’s syndrome and has the distinction of possessing the

highest selectivity and potency for dopamine D2 receptors among the conventional antipsychotics. It significantly prolongs the QTc interval, and this has limited its utilization. Derived from

benperidol, pimozide shares many characteristics of the butyrophenones (see Figure 27–1).

Benzamides and Iminodibenzyl Agents

Sulpiride, the prototypical substituted benzamide, is a relatively selective dopamine D2 antagonist and lacks significant activity on cholinergic, histaminergic, or noradrenergic receptors. Because of

this relative selectivity and a lower propensity to cause EPS, sulpiride is one of the more common classic antipsychotics utilized in Europe (e.g., it was utilized in about half the patients assigned to

receive an FGA in the CUtLASS study). Structurally related to metoclopramide, sulpiride has also been used for the treatment of peptic ulcer and vertigo. No classic antipsychotic agent from either

the benzamide or the iminodibenzyl classes is available in the United States.

PHARMACOLOGICAL PROFILE

The classic conventional antipsychotic drugs have a multitude of effects on various physiological variables through their antagonistic actions on different neurotransmitter systems. The

antipsychotic effects of these agents are believed to occur primarily through antagonism of D2-type dopaminergic receptors. Historically, blockade of D2 receptors was believed to be indispensablePrint: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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for the treatment of psychosis, although the efficacy of weak D2 blockers such as clozapine called this theory into question at one time. The major therapeutic, as well as adverse, effects of D

antagonism have been conceptualized in the context of the major dopaminergic tracts present in the brain, which include the mesocortical, mesolimbic (A10), tuberoinfundibular (A12), and

nigrostriatal (A8 and A9) tracts (Figure 27–2).

FIGURE 27–2. Dopaminergic pathways of the brain.

Although the effects of D2 blockade on the mesocortical and mesolimbic dopaminergic systems are believed to represent the putative mechanism of action of conventional antipsychotics, excessive

blockade of these tracts is also believed to result in a number of adverse cognitive and behavioral side effects. Such side effects are frequently observed in both animals and human subjects. One

such side effect is ataraxia, a state of relative indifference to the environment leading to behavioral inhibition and diminished emotional responsiveness. Inhibition of conditioned avoidance and

other learned behaviors is observed in rodent models. Although operant-conditioned reward-seeking behaviors are diminished in rat models, one notable exception is the relative increase in

cocaine self-administration. One might argue that this correlates with reported anhedonia in human subjects, as well as an increase in cocaine abuse often present within the human population

treated with conventional antipsychotics. D2 receptor antagonism in the mesocortical dopaminergic pathway leads to a blunting of cognition (bradyphrenia) and avolition–apathy—sometimes

referred to as the neuroleptic-induced deficit syndrome—that can be difficult to differentiate from the primary negative symptoms of schizophrenic illness itself. Although conventional

antipsychotics exhibit a robust “tranquilizing” action, they do not induce a state of coma or anesthesia even at very high doses.

Blockade of the tuberoinfundibular tract projecting to the hypothalamus and pituitary gland results in multiple neuroendocrine side effects processed through the pituitary gland. Although

dopamine is involved in enhancing the release of most pituitary hormones, it is actually responsible for the tonic inhibition of prolactin release. With significant dopaminergic blockade of the

tuberoinfundibular tract, prolactin release is no longer prevented, and the release of other pituitary hormones is no longer enhanced. High levels of prolactin combined with decreased levels of

follicle-stimulating hormone and luteinizing hormone often result in amenorrhea, galactorrhea, gynecomastia, decreased bone density, impaired libido, and erectile dysfunction.

High levels of D2 dopaminergic blockade within the nigrostriatal system, which projects to the basal ganglia and caudate, produce some of the most undesirable side effects of conventional

antipsychotics. Movement disorders and EPS such as akathisia, resting tremor, rigidity, and hypokinesia were once believed to be necessary “evidence” of a therapeutic antipsychotic dosage.

However, the advent of the new-generation antipsychotics that are associated with minimal EPS conclusively dispensed with this misconception. At higher levels of D2 blockade, one may also

observe a generalized dystonia, catalepsy, and a rigid, immobile catatonic state that may be accompanied by waxy flexibility.

Classic antipsychotic agents have varying degrees of activity at serotonergic, cholinergic, noradrenergic, histaminergic, and other nondopaminergic receptors. Although it is unclear whether any of

these activities contribute to or interfere with their efficacy in the treatment of psychotic symptoms, they clearly result in a variety of adverse effects. Because of differences in the pharmacological

activity of different classic antipsychotic agents at these receptors, there are predictable differences in their side-effect profiles.

PHARMACOKINETICS AND DISPOSITION

Generally, the pharmacokinetic profiles of the conventional antipsychotics remain poorly understood. Many hundreds of potential metabolites remain undiscovered, even for some of the extensively

studied agents. The physiological activity of several metabolites has also not been precisely defined. However, several general statements can be made concerning the classic antipsychotics as a

group.

Administration and Absorption

Many of the conventional antipsychotics are available in both oral and intramuscular formulations. Although relatively common in the past, intravenous usage of the parenteral forms of haloperidol,

chlorpromazine, and other antipsychotics is not FDA approved. Oral administration of the conventional antipsychotics results in adequate but variable absorption. Calcium-containing food or

antacids, coffee, and heavy nicotine use may decrease absorption from the gastrointestinal tract. Peak plasma levels with oral preparations are generally reached in 1–4 hours, with these levels

being reached slightly more rapidly with liquid concentrates. All of the agents are highly lipophilic, leading to increased distribution in brain tissue relative to plasma. Oral preparations are

extensively metabolized in the liver during their first pass through portal circulation by undergoing any number of transformations, including glucuronidation, oxidation, reduction, and methylation.

Steady-state levels are reached in a period of four to five times the half-life of the drug in question.

Intramuscular administration results in faster, more predictable absorption, with peak plasma levels in 30–60 minutes and clinical efficacy as rapidly as 15 minutes. With intramuscular or

intravenous administration, plasma levels may be as high as four times those of the oral route because of circumvention of the hepatic first-pass metabolism.

Although 10 classic antipsychotics are available in a long-acting (depot) formulation around the world, haloperidol and fluphenazine are the only antipsychotics currently available in such a

formulation in the United States. Although fluphenazine was the first antipsychotic to be released in a long-acting form as an enanthate ester, the longer-lasting decanoate forms of both

haloperidol and fluphenazine later became more popular secondary to a lower frequency of side effects. In a decanoate preparation, the antipsychotic drug is esterified to a lipid side chain and

suspended in sesame oil. The injection is administered into a major muscle, and the drug is slowly released to the bloodstream through the oil over time. As the esterified version of the drug

diffuses into other tissues, the ester chain is hydrolyzed, resulting in the smooth release of the drug in question. This results in the smooth and progressive release of these long-acting agents

between scheduled injections. Fluphenazine decanoate can be given every 2–3 weeks on the basis of its half-life of 7–10 days, while haloperidol decanoate may be given every 3–4 weeks because

of its longer half-life. These preparations require from 3 to 6 months (four to five times the half-life) to reach steady-state levels and are eliminated slowly from the body, with plasma

concentrations detectable for many months after discontinuation of the drug. Their bioavailability relative to oral administration is twofold greater.

Distribution

Most of the conventional antipsychotics are highly protein-bound (85%–90%). This feature is of importance when other highly protein-bound medications are used concomitantly because of the

risk of increasing levels of free or unbound drugs into the toxic range. The antipsychotic drugs are highly lipophilic, which allows unbound portions of the drug to readily cross the blood–brain

barrier with concentrations twofold higher in the brain than in the peripheral circulation. The drugs also readily cross the placenta to the fetus in pregnancy. The lipophilic properties of these drugs

also allow for large amounts of the drugs to be stored in bodily tissues (i.e., fat, lungs, liver, kidneys, and spleen), leading to high apparent volumes of distribution, generally in the 10- to 40-L/kg

range. This property prevents them from being removed from the body effectively via dialysis in cases of overdose.

Metabolism

The conventional antipsychotics are metabolized in the liver by hydroxylation and demethylation to forms that are more soluble and readily excreted by the kidneys and in the feces. Many of these

compounds undergo further glucuronidation and remain active as dopamine receptor antagonists. Because of the many active metabolites of the antipsychotic agents, it has not been possible to

obtain meaningful correlations between plasma levels and clinical response. Factors such as age, genetic variability among individuals, and coadministration of other drugs cause plasma levels to

diverge widely (10- to 20-fold) among individuals.

The majority of conventional antipsychotics are metabolized by the cytochrome P450 (CYP) enzyme subfamilies. Since 2D6 is important for the metabolism of many of these antipsychotics, genetic

variation in the rate of 2D6 metabolism should be considered, especially since most conventional antipsychotics inhibit 2D6 as well. It is estimated that 5%–10% of Caucasians poorly metabolize

medications through the CYP2D6 pathway, and a higher proportion among African Americans as well. Ultrarapid 2D6 metabolizers have been described in other populations. CYP1A2 and 3A4

subfamily enzymes are also involved in the metabolism of some classic antipsychotics, and this may be relevant to understanding drug–drug interactions of those agents.Print: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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Excretion

The major routes of excretion of the classic antipsychotics are through urine and feces by way of bile. These drugs are also excreted in sweat, saliva, tears, and breast milk. Elimination half-life

varies from 18 to 40 hours for these drugs. Lower doses of antipsychotics are generally needed in elderly patients because of decreased renal clearance. Because of the long elimination half-lives of

these agents, once-a-day dosing is possible for each of these agents following stabilization.

MECHANISM OF ACTION

Initial hypotheses centered on the role of dopamine as the major factor in the pathophysiology of psychosis. Carlsson and Lindqvist (1963) first demonstrated an increase in dopamine metabolites

following antipsychotic administration. This increase was shown to be a result of dopaminergic blockade, resulting in an increased rate of turnover. Reserpine reduces dopaminergic activity by

blocking the uptake and storage of dopamine into synaptic vesicles by inhibiting the vesicular monoamine transporters (VMATs). Amphetamine intoxication served as a drug-induced model of the

positive symptoms of schizophrenia. Drugs that blocked dopaminergic receptors, specifically the D2 receptor, were noted to have greater efficacy and potency as antipsychotics. Since dopaminergic

agonists exacerbate psychosis and dopaminergic blockade treats it, dopamine has held central importance in our conceptualization of the neuropharmacology of schizophrenia. Initially, dopamine

turnover appears to be increased, as measured by an increase in central nervous system (CNS) metabolites such as homovanillic acid. It is thought that ultimate efficacy may result when this trend

is reversed by subsequent receptor supersensitization and ultimate decreases in dopaminergic turnover. The time course of the antipsychotic effect of these agents suggests that both the initial

and persistent dopamine D2 receptor blockade and the more gradually developing depolarization blockade are relevant to antipsychotic action.

The contrast between the efficacies of promazine and chlorpromazine lies in chlorpromazine’s tighter affinity to the D2 receptor. Although structurally related to chlorpromazine, promazine, with its

weak binding to the D2 receptor, resulted in poor antipsychotic efficacy beyond mere sedation. However, although chlorpromazine is more potent than promazine, it remains one of the least potent

D2 receptor antagonists. A 100-mg dose of chlorpromazine is roughly equivalent to 5 mg of trifluoperazine and 2 mg of haloperidol. The potency of a classic antipsychotic is determined by its

affinity for the D2 receptor. High-potency agents with the greatest D2 affinity are utilized in single-digit total daily doses, whereas low-potency agents are utilized in triple-digit total daily doses.

As additional antipsychotic drugs were developed, the goal of minimizing the sedative, anticholinergic, and autonomic side-effect profiles common among lower-potency antipsychotics was met by

the development of drugs that more potently block D2 receptors, such as the butyrophenones. EPS were considered a sign of therapeutic antipsychotic dosage by early clinicians, who failed to

realize the serious impact on the patients of long-term EPS associated with excessive D2 blockade. Decades later, positron emission tomography (PET) data revealed that a D

65%–70% correlates with maximal antipsychotic efficacy, with prolactin elevation appearing beyond 72% D2 occupancy and EPS appearing beyond 78% D2 occupancy without any increase in

benefits at higher rates of occupancy. Despite the fact that classic antipsychotic agents have been utilized in the treatment of schizophrenia and other psychotic disorders for over half a century, it

is still unclear if this 65%–70% occupancy has to be continuously maintained or intermittently achieved (tight versus loose D2 receptor binding). The importance of 5-HT2A

amelioration of EPS was later incorporated into the design of the SGAs discussed elsewhere in this text (see Chapters 28, 29, 30, 31, 32, and 33).

INDICATIONS AND EFFICACY

Schizophrenia and Schizoaffective Disorder

Conventional antipsychotics are best known for the treatment and maintenance of the psychotic (also known as positive) symptoms of schizophrenia. The major putative mechanism of action is via

D2 blockade of the mesolimbic and mesocortical tracts. In many individuals, this blockade results in a measurable decrease in the positive symptoms of schizophrenia, including hallucinations,

delusions, and behavioral disorganization. However, negative and cognitive symptoms of schizophrenia respond less robustly. In fact, they may be worsened by blockade of mesocortical tracts that

play roles in cognition and hedonic reinforcement.

The failure to improve the negative symptoms of schizophrenia is one of the major drawbacks of the classic antipsychotics. In fact, the EPS induced by the FGAs can worsen negative and cognitive

symptoms by inducing bradykinesia and bradyphrenia. Another major limitation is the lack of improvement of positive symptoms (i.e., refractoriness) in about 25% of schizophrenia patients and

partial response (i.e., treatment resistance) in another 25%. The discovery that clozapine is more effective than classic antipsychotics in treatment-refractory patients and is devoid of the risk of

EPS and tardive dyskinesia led to the introduction of the SGAs. Six additional SGAs (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone) have been introduced in the

United States, and they have almost completely supplanted FGAs because of their presumed greater efficacy and better safety/tolerability. However, the greater costs of SGAs, the concern that

their benefits were not being realized consistently, and the realization that most of our recent information about these agents derives from industry-sponsored clinical trials (the results of which

often contain discrepancies) led to the implementation of two large-scale government-sponsored studies in the United States (CATIE) and the United Kingdom (CUtLASS) between 1999 and 2004.

Although findings of both of these studies indicate an absence of any greater effectiveness of SGAs over FGAs on preliminary review, a closer examination of the study samples and design provides

additional insights about how classic and atypical antipsychotics might compare (Table 27–2).

TABLE 27–2. Comparison of CUtLASS band I and CATIE phase I

Cost Utility of the Latest Antipsychotic Drugs in

Schizophrenia Study (CUtLASS), band I

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), phase

I

Subjects

Diagnosis of schizophrenia

75%

100%

Mental illness duration (chronic illness) 14 years

16 years

First-episode patients (excluded)

Very few (13% of total)

Excluded (0% of total)

Baseline antipsychotic

82% on FGA

15% on FGA

Baseline Positive and Negative Syndrome Scale (PANSS) total

score (moderate illness on average)

72.2

75.7

Methods

When conducted

1999–2003

2001–2004

Study duration

12 months

18 months

Randomized assignment to

FGA or SGA class (50%)(50% FGA on sulpiride) One of 5 agents (4 SGAs, 1 FGA)(20% FGA)

Antipsychotic switching (both are switching studies) All patients switched agents49% switched class51% stayed in

same class

15% continued on same agent57% actually switched agents28%

antipsychotic-free at baseline and started new agent

Comparison groups

FGA versus SGA arms

Five antipsychotic arms

Primary outcome measure

Quality of life

All-cause antipsychotic discontinuation

Clinical care and primary outcome assessment Medication blinded to raters but not to patients and physicians Medication blinded to patients and physicians

Note. In both studies, patients were at low risk for developing extrapyramidal side effects (EPS) because of inclusion/exclusion criteria and process of study. In both studies, baseline EPS ratings were low despite

chronicity and the fact that most patients were receiving antipsychotic treatment. FGA = first-generation antipsychotic; SGA = second-generation antipsychotic.

Source. Adapted from Tandon et al. 2008.

In phase I of CATIE, 1,460 patients with schizophrenia were assigned to treatment with either an FGA (perphenazine) or one of four SGAs (risperidone, olanzapine, quetiapine, and ziprasidone),

and duration of treatment on the originally assigned medication was assessed over an 18-month period. After control for important variables, no differences in rates of all-cause discontinuation

between perphenazine and various SGAs were noted; in fact, no significant differences were observed with reference to symptomatology, cognition, social function, or motor side effects. In band I

of CUtLASS, 227 patients with psychotic illness (75% of patients with schizophrenia) were assigned to treatment with either an FGA (one of 11) or an SGA (one of 4), and quality of life was

assessed after 12 months of treatment. No difference in quality of life or any other outcome measure was noted between patients assigned to the two groups. Results of these two studies appear

to indicate that there are no differences in effectiveness between classic and atypical antipsychotics. Although a variety of methodological issues have been discussed with reference to these

studies, one key attribute that should be noted is the fact that study inclusion/exclusion criteria and logistics led to patients in both studies being at low risk for EPS. Baseline EPS ratings of

patients in both studies were low. It was in the context of this study sample that the two studies did not discern any advantage for SGAs over FGAs. Given that the essential distinction between

SGAs and FGAs is based on the lower liability of atypical antipsychotics to cause EPS (Figure 27–3), the two studies had low assay sensitivity in regard to this difference; in fact, neither study

detected any difference in EPS rates or anticholinergic use between classic and atypical antipsychotics.

FIGURE 27–3. Clinical benefits of low extrapyramidal side effect (EPS) risk.Print: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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What CATIE and CUtLASS tell us is that avoiding EPS and anticholinergic use during effective antipsychotic therapy may explain the broader spectrum of efficacy sometimes observed with atypical

versus classic antipsychotic agents. The lower risk of tardive dyskinesia observed with SGAs also appears to be driven by these agents’ greater ability to achieve an equivalent antipsychotic effect

without EPS. The principal advantage of SGAs over FGAs thus appears to be the greater ease of the former in providing an adequate antipsychotic effect without causing EPS or requiring use of an

anticholinergic to treat or prevent EPS. In patients at high risk for developing EPS, this difference is magnified, whereas in patients at low risk for developing EPS, this difference is minimized. In a

substantial proportion of patients, however, this difference will likely be meaningful, and an antipsychotic effect without EPS can be achieved with less difficulty (because of the broader window;

Figure 27–4) with an SGA rather than an FGA. It is true that previous industry-sponsored studies magnified the SGA–FGA difference by utilizing high doses of the high-potency agent haloperidol as

the FGA comparator and that this difference is smaller when more temperate doses of lower-potency FGAs are utilized. It is equally true that these differences were minimized in CATIE and

CUtLASS by sample characteristics of low risk of EPS. The findings from CATIE and CUtLASS confirm broadly held clinical impressions that different agents are associated with different adverse

effects, which can make it challenging to achieve maximum efficacy while also maximizing safety and tolerability. However, it is these very differences among the antipsychotic agents, along with

heterogeneity in individual response and vulnerabilities, that may allow optimization of antipsychotic treatment. Different agents at different doses may provide the best balance for individual

patients.

FIGURE 27–4. Dose–response curves of classic versus atypical antipsychotic agents for antipsychotic effects versus extrapyramidal side effects.

Source. Adapted from Jibson and Tandon 1998.

Substance-Induced Psychosis

As noted previously, conventional agents can reverse the psychosis associated with acute and chronic amphetamine intoxication as well as that associated with cocaine use. However, the risk of

acute dystonia must be considered in these populations, as dopamine receptor down-regulation is common, resulting in greater sensitivity to rapid D2 blockade. Results in treatment of psychosis

secondary to drugs acting in nondopaminergic mechanisms (such as hallucinogens) are less satisfactory, although there may be some role for the classic antipsychotics in treating phencyclidine

(PCP) psychosis.

Personality Disorders

Although any personality disorder can be associated with transient psychotic features emerging under stressful conditions, Cluster B disorders are most often associated with this phenomenon.

Treatment for the transient psychotic episodes has included short-term use of a high-potency antipsychotic. Although many symptoms of personality disorders may be amenable to such

pharmacological treatment, long-term conventional antipsychotic treatment has not been recommended, since core personality structure is largely resistant to pharmacological therapy and there is

a risk of tardive dyskinesia with long-term conventional antipsychotic therapy.

Affective Disorders

The utility of antipsychotic agents in the treatment of affective disorders with psychotic features is well known. However, their utility in the treatment of nonpsychotic depression is described as

well. When profoundly negative views of oneself, the world, and the future become severe, the boundaries between psychotic and nonpsychotic depression can become blurred. Several

conventional antipsychotics (such as thioridazine) are FDA approved for the treatment of depression and anxiety without overt psychosis. However, they are rarely used for this purpose anymore

because of the availability of other, more effective, and better-tolerated agents. The utility of conventional agents as adjuncts to mood stabilizers in the treatment of patients with bipolar spectrum

disorders has been well described, both in the acute management of mania and in the maintenance of severe and psychotic bipolar disorder. However, the newer atypical antipsychotics have largely

replaced conventional antipsychotics in the management of bipolar disorder.

Tourette’s Syndrome

The tics present within Tourette’s syndrome are believed to be due to a hyperdopaminergic state that is amenable to treatment by dopamine receptor antagonists. Pimozide is the only conventional

antipsychotic with this indication, which is its only FDA-approved indication.

Huntington’s Disease

Although there is no cure for Huntington’s disease, the psychosis and choreiform movements associated with this disease may be ameliorated by dopamine receptor antagonism. Several

conventional antipsychotics carry FDA indications for treatment of this disease.

Nausea, Emesis, and Hiccups

The lower-potency antipsychotics exert a potent antiemetic effect through histamine1 (H1) receptor antagonism. This effect is closely related to their original role in reducing perioperative stress

and emesis. Many well-known antiemetics, such as promethazine (Phenergan), are phenothiazines with a short-chain substitution. In addition, chlorpromazine is approved as oral, intramuscular,

or intravenous therapy of intractable hiccups, depending on severity.

SIDE EFFECTS AND TOXICOLOGY

As noted earlier, it is the side-effect profile that serves to differentiate the conventional antipsychotics from one another rather than their efficacy in treating psychosis. They serve as antagonists

at four major neurotransmitter receptor systems in the CNS: the dopamine type 2 receptor family (D2, D3, and D4), muscarinic cholinergic receptors (M1), -adrenergic receptors (a

histamine receptors (H1) (Table 27–3).Print: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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TABLE 27–3. Relative affinities of classic antipsychotics to various neurotransmitter receptors

Chlorpromazine Thioridazine Perphenazine Trifluoperazine Fluphenazine Thiothixene Haloperidol Loxapine Molindone

D1

High — High High High Moderate High High Low

D2

High Very high Very high Very high Very high Very high Very high Very high Very high

D3

Very high Very high Unknown Unknown Very high Unknown Very high Unknown Unknown

D4

Very high Very high Unknown High Very high Unknown Very high Very high Low

H1

High High Very high Moderate High Very high Low High Very low

M1

High High Low Low Low Low Low Moderate None

1

Very high Very high High High High Moderate Low High Low

2

Moderate Very high Moderate Low Low Moderate Low Low Moderate

5-HT1 Low Low Low Low Low Low Low Low Low

5-HT2 Very high Very high Very high Very high Very high Very high High Very high Low

Their therapeutic response in ameliorating the positive symptoms of schizophrenia is believed to be due to D2 blockade in the mesolimbic dopamine tract (Table 27–4). Blockade of D

the mesocortical, nigrostriatal, and tuberoinfundibular systems leads to the tract-related side effects described earlier in this chapter (see section “Mechanism of Action”). Lower-potency agents,

such as chlorpromazine, require higher doses to achieve therapeutic efficacy and therefore have a greater effect on other receptor systems. They have more antihistaminergic, anticholinergic, and

antiadrenergic actions. However, they have fewer D2-related side effects because of their lower affinity to D2 receptors and relatively high anticholinergic activity. Higher-potency agents, such as

haloperidol, produce more D2-related movement disorders and prolactin elevation but otherwise have a cleaner side-effect profile, having fewer anticholinergic, antiadrenergic, and

antihistaminergic side effects. Anticholinergic action often leads to dry mouth (xerostomia), blurred vision (mydriasis), constipation, urinary retention, sinus tachycardia, prolonged QRS interval,

confusion, impaired cognition, paralytic ileus exacerbation of open-angle glaucoma, and drowsiness. Antagonism of 1-adrenergic receptors is associated with orthostatic hypotension, QTc

prolongation, reflex tachycardia, dizziness, incontinence, and sedation. Antagonism of 2 receptors can be associated with retrograde ejaculation and priapism. Antagonism of H

sedation, drowsiness, and weight gain. The frequencies of adverse reactions of classic antipsychotic agents are summarized in Table 27–5.

TABLE 27–4. Clinical implications of blockade of different receptors

Receptor Possible benefits

Possible side effects

Dopamine D2

Antipsychotic effect, efficacy on positive symptoms, efficacy on

agitation

EPS, dystonia, parkinsonism, akathisia, tardive dyskinesia

Prolactin elevation and other endocrine effects, leading to sexual and menstrual dysfunction, galactorrhea, gynecomastia, and

bone changes

Serotonin 5-HT2A

Reduced EPS

Not definitely known

Serotonin 5-HT2C

Not definitely known

Weight gain

Acetylcholine

(muscarinic)

Reduced EPS

Central (memory impairment, confusion), cardiac (sinus tachycardia, other arrhythmias), and peripheral (blurred vision, dry

mouth, constipation)

Anticholinergic side effects

Histamine H1

Sedation, weight gain

Noradrenergic alpha1

Dizziness, postural hypotension

Note. EPS = extrapyramidal side effects.

TABLE 27–5. Incidence of adverse reactions to classic antipsychotics at therapeutic doses

Phenothiazines

Butyrophenone Dibenzoxazepine Dihydroindole Diphenylbutylpiperidine

Chlorpromazine Mesoridazine Thioridazine Fluphenazine Perphenazine Trifluoperazine Haloperidol Loxapine Molindone Pimozide

Drowsiness,

sedation

High High High Low Moderate Low

Low High High Moderate

Insomnia,

agitation

Low Low Low Low Low Low

Moderate Low Low Low

Extrapyramidal

effects

Parkinsonism Low–Moderate Low–Moderate Low High Moderate Moderate–High

High Moderate Moderate–High Moderate

Akathisia Low Moderate Low High Moderate High

High Moderate High Moderate

Dystonic

reactions

Low Low Low High Moderate Moderate

High Moderate Moderate Low

Cardiovascular

effects

Orthostatic

hypotension

High High High Low Low Low–Moderate

Low Moderate Low Low

Tachycardia Moderate Moderate High Low Low Low

Low Moderate Low Low

ECG

abnormalities

Moderate Low Moderate Low Low Low

Low Low Low Low

Cardiac

arrhythmias

Low Moderate Moderate Low Low Low

Moderate Low Low Low

Anticholinergic

effects

High High High Low Low Low

Low Moderate Moderate Low

Endocrine

effects

Sexual

dysfunction

Moderate Moderate High Moderate Moderate Moderate

Moderate Low Low Low

Galactorrhea Moderate Moderate Moderate High Moderate Moderate

High Moderate Moderate Low

Weight gain High High High Moderate Moderate Moderate

Low Moderate Low Low

Skin reactions

Photosensitivity Moderate Low Moderate Low Low Low

Low Low Low Low

Rashes Moderate Low Moderate Low Low Low

Low Low Low Low

Pigmentation High Low Low Low Low Low

Low Low Low Low

Ocular effectsPrint: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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Phenothiazines

Butyrophenone Dibenzoxazepine Dihydroindole Diphenylbutylpiperidine

Chlorpromazine Mesoridazine Thioridazine Fluphenazine Perphenazine Trifluoperazine Haloperidol Loxapine Molindone Pimozide

Lenticular

pigmentation

Low Low Low Low Low Low

Low Low Low Low

Pigmentary

retinopathy

Low Low Moderate Low Low Low

Low Low Low Low

Other

Blood dyscrasias Low–Moderate Low Low Low Low Low

Low Low Low Low

Hepatic disorder Low Low Low Low Low Low

Low Low Low Low

Seizures Moderate Moderate Moderate Low Low Low

Low Low Low Low

Cognitive Side Effects

CNS side effects of conventional antipsychotics can be subclassified into cognitive and neuromuscular side effects. Cognitive effects include sedation, confusion, disturbed concentration, memory

impairment, and delirium. Antihistaminergic and anticholinergic actions lead to the sedation and slowed mentation. These effects, which are most pronounced in the lower-potency agents (e.g.,

chlorpromazine), are most severe earlier in treatment, with some tolerance developing over time. Anticholinergic delirium is the most common cause of medication-induced delirium. Since delirium

results in high rates of morbidity and mortality (over 20% mortality), this potential side effect is important, especially in populations of individuals who are more sensitive to anticholinergic

medications, such as the elderly. In addition, every antipsychotic—especially the low-potency drugs—can potentially lower the seizure threshold.

Extrapyramidal Side Effects

Neuromuscular CNS side effects are due to antagonism of D2 receptors in the nigrostriatal dopaminergic pathway. Generally, antipsychotics manifest EPS when dopaminergic blockade exceeds

75%–80% of D2 receptors. EPS effects are most frequent with the high-potency agents such as haloperidol.

Acute-Onset EPS

Acute-onset EPS include medication-induced parkinsonism, acute dystonia, and akathisia. Antipsychotic-induced parkinsonism occurs in 15% of patients after several weeks of treatment. It is more

common in patients older than 40 years, although it can occur at any age. Symptoms are identical to those of Parkinson’s disease and include muscle stiffness (lead-pipe rigidity), cogwheel rigidity,

shuffling gait, stooped posture, drooling, bradykinesia, resting tremor, masked facies, and akinesia. Slowed, restricted movements of the body and face may be mistakenly diagnosed as being due

to depression or the negative symptoms of schizophrenia. It is estimated that up to 10% of patients may experience an acute dystonic episode, which usually occurs within the first few hours or

days of treatment. It is more common in men younger than 30 years and women younger than 25 years, in recent cocaine users, and when intramuscular doses of high-potency antipsychotics are

used.

Dystonia is an acute sustained, painful muscular contraction that may manifest as either generalized or focal in effect on the musculature. Potential areas of involvement include the tongue

(protrusions, twisting), jaw, neck (spasmodic retrocollis or torticollis), and back (opisthotonos). If the dystonia involves the eyes, it results in a symmetrical or unilateral upward lateral movement

called an oculogyric crisis. Unlike previously mentioned dystonias, an oculogyric crisis can also occur late in treatment with antipsychotics. A laryngeal dystonia can result in sudden death

secondary to a patient’s inability to breathe. Resurgent dopamine activity in the basal ganglia that occurs when the CNS level of the antipsychotic begins to decrease is thought to be the mechanism

of action. Dystonia can be extremely uncomfortable and frightening for patients and can lead to noncompliance with medication for fear of recurrence. Treatment of dystonia requires rapid

diagnosis and intravenous administration of antihistaminergic or anticholinergic agents. Anticholinergic agents are often initiated with high-potency antipsychotics in an effort to avoid this side

effect, but long-term use may increase the risk of developing tardive dyskinesia.

Akathisia is a subjective feeling of motor restlessness in which patients feel an irresistible urge to move continuously. It is described as an unpleasant sensation and may result in dysphoria.

Akathisia can occur at any time during treatment and is the most prevalent EPS. It frequently leads to noncompliance with medications and is believed to increase suicide risk in some patients.

Late-Onset EPS

Tardive dyskinesia is characterized by a persistent syndrome of involuntary choreoathetoid movements of the head, limbs, and trunk. It generally takes at least 3–6 months of exposure to

antipsychotics before the disorder develops. Perioral movements involving buccolingual masticatory musculature are the most common early manifestation of tardive dyskinesia.

Tardive dyskinesia has an estimated yearly incidence of 5% among adults and as high as 25% in the elderly who receive continuous conventional antipsychotic therapy and has been a major source

of litigation in past psychiatric practice. The risk of developing tardive dyskinesia is reported to increase with age and to be higher in certain ethnic groups; female gender, presence of mood

disorders, and early onset of EPS have also been associated with increased risk of tardive dyskinesia.

Tardive dyskinesia may be masked by continuing dopamine blockade and has a variable course following development. Over time, spontaneous resolution or improvement has been described in

some individuals. There is no single effective treatment, although treatment with clozapine has been reported to improve symptoms. Tardive dyskinesia is thought to be secondary to upregulation

of postsynaptic dopamine receptors in the basal ganglia secondary to long-term dopamine blockade. Cases of tardive dyskinesia have been described with every antipsychotic, although

high-potency conventional agents are the most closely related causative agents. Other tardive syndromes include tardive dystonia, tardive akathisia, and tardive pain.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a poorly understood syndrome that usually occurs within hours or days of initiation of antipsychotic treatment. This syndrome is characterized by

muscular rigidity, hyperpyrexia (101–107°F), autonomic instability (hypo- or hypertension, tachycardia, diaphoresis, pallor), and altered consciousness. NMS has an estimated incidence of

0.02%–2% and carries a mortality rate of 20%–30%. Death often occurs secondary to dysrhythmias, renal failure secondary to rhabdomyolysis, aspiration pneumonia, or respiratory failure.

Laboratory findings include elevated creatine phosphokinase (CPK), elevated white blood cell count, elevated liver enzymes, myoglobinemia, and myoglobinuria. The syndrome can last up to 10–14

days.

Treatment requires immediate discontinuation of the offending antipsychotic and supportive care with aggressive intravenous hydration. In the past, mild cases of NMS were treated with

intravenous bromocriptine, while more severe cases were treated with intravenous dantrolene. However, evidence-based studies of NMS treatment have never been performed because of its

infrequent occurrence.

NMS is more common in men than in women and occurs more often within the summer months. Risk factors include dehydration, poor nutrition, presence of mood disorders or organic brain

syndromes, rapid titration, use of physical restraints, and intramuscular usage. Although onset of NMS is possible at any point during treatment, a significant proportion of the cases of NMS

manifest during the first 2 weeks of antipsychotic treatment.

Cardiac Effects

-Adrenergic antagonism is associated with orthostatic hypotension with reflex tachycardia, with tolerance possibly developing later in the treatment course. Orthostasis is important because of an

increase in falls and related injuries. Serious hypotension should never be treated with epinephrine, since this hypotension is mediated through intense receptor blockade and diffuse vascular

dilation. Administration of epinephrine may only exacerbate this problem by causing further vascular dilation through its receptor stimulation. If necessary, agents such as norepinephrine should

be used, as this type of agent will stimulate only -adrenergic receptors, reversing vasodilation.

Recent studies involving several conventional antipsychotics have drawn attention to the risk of cardiac dysrhythmias, which is especially prominent with use of lower-potency conventional

antipsychotics. High dosage, rapid titration, intramuscular administration, and especially intravenous administration may be associated with a lengthening of the QRS or QTc intervals, with

resulting risk of serious dysrhythmias such as torsades de pointes and ventricular fibrillation. Recent studies involving thioridazine have raised concerns about piperidine antipsychotics and have

led to a decrease in their use, despite an infrequent incidence of fatal dysrhythmias in clinical practice. In reality, torsades de pointes is rarely encountered during treatment with conventional

antipsychotics, although some speculate that a syndrome of unexplained sudden death described with all conventional antipsychotics may be related to sudden dysrhythmias.

Gastrointestinal Side Effects

As expected, the anticholinergic actions of conventional agents include dry mouth, nausea, vomiting, and constipation that can progress to paralytic ileus. Antihistaminergic action is associated

with medication-related weight gain, which greatly increases the patient’s risk of developing diabetes.

Cholestatic jaundice is a hypersensitivity reaction described with the aliphatic phenothiazines, especially chlorpromazine (incidence of 0.1%). This reaction typically manifests during the first 1–2

months of treatment and presents with nausea, malaise, fever, pruritus, abdominal pain, and jaundice, with resulting elevations in levels of bilirubin and alkaline phosphatase. This condition rarely

lasts more than 2–4 weeks after discontinuation.

Weight Gain, Diabetes Mellitus, and Dyslipidemia

With the introduction of atypical antipsychotics, several of which cause significant weight gain, there is renewed awareness of the metabolic side effects associated with antipsychotic therapy suchPrint: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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as obesity, elevated cholesterol and triglyceride levels, and an increased risk of diabetes mellitus. These metabolic changes increase the risk of ischemic heart disease and contribute to the

increased mortality observed in schizophrenia. Antihistaminergic action is associated with medication-related weight gain, which greatly increases the patient’s risk of developing diabetes.

Diabetes is currently described as a worldwide epidemic. Serotonin 5-HT2C receptor blockade also significantly contributes to weight gain; anticholinergic and 5-HT2A antagonism may also

contribute. There are significant differences among FGAs with reference to their propensity to cause these metabolic adverse effects. Molindone is the least likely to cause weight gain, whereas

thioridazine and chlorpromazine are among the most likely to do so. In general, high-potency agents cause less weight gain and related metabolic adverse effects than low-potency agents do.

Genitourinary Side Effects

Renal effects secondary to blockade of M1 receptors include urinary hesitancy or retention that can lead to a comparable increase in urinary tract infections in both genders. As mentioned

previously, antagonism of tuberoinfundibular dopaminergic tracts increases prolactin secretion. Hyperprolactinemia causes both endocrine and sexual side effects, including gynecomastia,

galactorrhea, diminished libido, erectile dysfunction, amenorrhea, decreased bone density, menstrual irregularities, infertility, delayed ovulation, anorgasmia, and possibly increased risk of breast

cancer.

Sexual difficulties, including erectile dysfunction, retrograde ejaculation (due to blockade of 2-adrenergic receptors), anorgasmia, and occasionally priapism, can also occur.

Hematological Side Effects

Hematological effects of conventional antipsychotics include transient leukopenia (white blood cell [WBC] count <3,500/mm3 ), which is common but not usually problematic, and agranulocytosis

(WBC count <500/mm3 ), a life-threatening problem. Agranulocytosis occurs most often during the first 3 months of treatment, with an incidence of 1 in 500,000. It is more common in white

women older than 40 years. The mortality rate related to this agranulocytosis may be as high as 30%. Aliphatic and piperidine phenothiazines are the most common causal agents among the

conventional antipsychotics. Rarely, thrombocytopenic or nonthrombocytopenic purpura, hemolytic anemia, and pancytopenia may occur.

Ocular Side Effects

In addition to direct anticholinergic effects such as blurred vision (mydriasis and cycloplegia) and exacerbation of open-angle glaucoma, direct optic toxicity has been described. The conventional

antipsychotics are associated with several kinds of optical pathology, including pathology of the lens, cornea, and retina.

Lenticular opacities have been reported with some phenothiazines, including perphenazine, chlorpromazine, and thioridazine. An irreversible increase in retinal pigmentation has been described

with thioridazine when high dosages are used (>800 mg/day). This retinal pigmentation, which can progress even after drug discontinuation, can lead to reduced visual acuity and even blindness.

Early symptoms include poor night vision and secondary nocturnal confusion. Two reports of ocular pathology in young schizophrenic inpatients and outpatients who were treated predominantly

with the older antipsychotics demonstrated a high rate of overall ocular pathology (82%) and a much higher rate of lenticular opacities (22%–26%) than the general population in the third decade

of life (0.2%). The high rate of lenticular opacities in patients with schizophrenia is striking and may be due in part to antipsychotic treatment but is also related to other known risk factors, such as

diabetes, smoking, exposure to ultraviolet radiation, stress, and facial trauma.

Dermatological Side Effects

Cutaneous side effects of conventional antipsychotics involve hypersensitivity rashes—most commonly maculopapular erythematous rashes of the trunk, face, neck, and extremities—and

photosensitivity reactions that can lead to severe sunburn. Care must be taken with injectable versions of many antipsychotics because of direct dermatological toxicity if the skin or subcutaneous

layers are exposed. Prolonged use of chlorpromazine can lead to blue-gray discoloration in body areas exposed to sunlight.

Adverse Effects in Special Populations

In general, there have been few controlled studies of conventional antipsychotics within the pediatric population and almost none during pregnancy and the peripartum period. Currently, with the

availability of atypical antipsychotics, most of the conventional agents have fallen into disuse in pediatric populations. The only conventional antipsychotic agent FDA approved for use during

childhood is pimozide, for the indication of Tourette’s syndrome.

It is ethically problematic to design controlled studies involving pediatric populations and women during pregnancy because of the long-term and serious side effects associated with conventional

agents. However, safety concerns in the peripartum mother sometimes require the use of antipsychotics to ameliorate psychosis (whether it was preexisting or developed peripartum), delirium,

and extremes of affective syndromes. Potential threats of the drugs to the mother, fetus, and/or children must be carefully weighed against the potentially life-threatening nature of severe

psychiatric pathology. Although no formal drug trials have been performed, haloperidol has been the most widely used antipsychotic in the peripartum period, with the best empirical track record of

safety during that time. However, one must be mindful that haloperidol has been shown to cross the placenta and to be present within breast milk. Also, animal models have demonstrated

complications such as decreased gestational size and infant withdrawal syndromes. Chlorpromazine should not be used during pregnancy, due to a relatively worse empirical side-effect profile,

including gray baby syndrome. Use of antipsychotics during pregnancy should be undertaken only with careful consideration of the risks, benefits, and alternatives with the obstetrical specialist

who is managing the remainder of the patient’s prenatal care.

Geriatric populations pose a special challenge because of the increased sensitivity to all side effects of antipsychotics, impaired hepatic and renal metabolism of these agents, increased risk of

delirium, increased use of other medications, and increased risk of tardive dyskinesia. Annual incidence of tardive dyskinesia in the elderly seems to increase exponentially with age and is

estimated to be as high as 10-fold greater than the incidence in younger patients. Increasing permeability of the blood–brain barrier with age and an increase in adverse side effects both

necessitate much lower dosing of conventional antipsychotics, as well as routine consideration of taper and discontinuation of these agents. Alternative means of managing elderly patients, such as

other medical, behavioral, and environmental means of management, should be sought on a continuing basis. If antipsychotic therapy is still required, cautious utilization and diligent monitoring

are essential.

Summary of Side Effects

The antagonistic action of the conventional antipsychotics on D2 receptors in the nigrostriatal, mesocortical, and tuberoinfundibular tracts, as well as blockade of adrenergic, histaminic, and

muscarinic cholinergic receptors, produces many undesirable side effects involving multiple body systems. The lower-potency agents cause more peripheral side effects and less dopaminergic

tract–related pathology, while the reverse is true of the higher-potency agents.

DRUG–DRUG INTERACTIONS

Careful consideration of a patient’s existing drug regimen should be given prior to the initiation of antipsychotic therapy. Except under very special circumstances, antipsychotics should be used in

monotherapy, after selection of the appropriate agent. Clear rationales should be provided, and target symptoms should be identified and monitored routinely. Oral forms of medications should be

used whenever possible, and the patient’s medical condition should be routinely monitored and patients should have physical exams regularly.

Protein Binding

Since conventional antipsychotics are tightly protein bound, care must be taken when these medications are administered with other highly protein-bound medications. Mutual displacement of

medications such as phenytoin, digoxin, warfarin, and valproate could lead to a short-term increase in serum levels of these drugs and of the conventional antipsychotic, with a long-term decrease

to subtherapeutic levels through increased elimination.

Cytochrome P450 Inhibition

As mentioned previously, conventional antipsychotics are primarily hepatically metabolized through the cytochrome P450 2D6 and 3A4 enzymes. In addition, each inhibits the 2D6 enzyme to some

degree. Care must be taken when these agents are coadministered with such potent 2D6 inhibitors as fluoxetine, paroxetine, cimetidine, erythromycin, and certain class IC antiarrhythmics, such as

quinidine. Similarly, potent 3A4 inhibitors, such as nefazodone, fluoxetine, fluvoxamine, and ketoconazole, should be used with care. Inhibitors of 2D6 and 3A4, as well as competitive substrates,

should be used carefully with conventional antipsychotics because of their potential to increase plasma levels and subsequent side effects. Also, consideration should be given when other drugs

that are primarily metabolized by 2D6 are coadministered with conventional agents, because of their potential to increase serum levels of these drugs, including tricyclic antidepressants, selective

serotonin reuptake inhibitors, some antiarrhythmics, and several -blockers. CYP1A2, induced by nicotine and inhibited by estrogen, plays a role in metabolizing some antipsychotics. The

complexity of these and other potential drug interactions requires a psychiatrist who is familiar with general medicine if these medicines are to be used competently and safely. Needless patient

suffering and lawsuits are the only alternative.

Other Interactions

A syndrome of neurotoxic encephalopathy has been described on coadministration of lithium with haloperidol or thioridazine. Care should be taken if these agents are coadministered, especially in

individuals older than 50 years.

CONCLUSION

Despite the presence of some serious side effects, the conventional antipsychotics revolutionized the practice of psychiatry and the treatment of the severely mentally ill throughout the world. They

remain effective agents despite their burdensome side-effect profiles. However, as time progresses, newer atypical antipsychotics appear to have eclipsed these agents to a large extent, as newer

short-acting intramuscular and depot formulations have been introduced. It is estimated that less than 10% of current antipsychotic prescriptions in the United States are for conventional agents.

The recognition of weight gain and related metabolic adverse effects in conjunction with atypical antipsychotic therapy, along with the results of CATIE and CUtLASS indicating little difference in

effectiveness between classic and atypical agents, has reinvigorated interest in conventional agents. As the metabolic profiles of both classic and atypical agents are better elucidated, it is

conceivable that there may be a resurgence in the use of classic agents if they are found to provide a more benign metabolic profile than atypical agents. Motor side effects and the narrowerPrint: Chapter 27. Classic Antipsychotic Medications http://www.psychiatryonline.com/popup.aspx?aID=428724&print=yes…

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antipsychotic–EPS dose window will continue to be limiting factors.

As models of psychosis and antipsychotics are further refined, additional neurotransmitter systems will be addressed in the pathology of schizophrenia and psychosis. Unfortunately, early attempts

to treat schizophrenia and reduce side effects by blocking a single neurotransmitter system were unsuccessful. The next generation of drugs following atypical antipsychotics will likely address

glutamatergic and cholinergic systems to target cognitive deficits and certain neurophysiological aberrations, such as poor prepulse inhibition. Clearly, much work remains, as the enigma of

psychopathology of the human mind is unraveled. Conventional antipsychotics will always be remembered for their vital role as the foundation of antipsychotic pharmacotherapy and the main

impetus for the remarkable neuropharmacological progress in psychiatric neuroscience over the second half of the twentieth century. They retain an important, if limited, role in our antipsychotic

armamentarium in the first decade of the twenty-first century.

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