About Course
INTRODUCTION
Psychiatry has experienced a rapid metamorphosis since the 1970s in its methods of treatment. The
move from a largely psychoanalytic orientation toward a more biological stance radically changed not
only its basic approaches to patients but also the professional identities of psychiatrists. For most older
psychiatrists, the transformation in the 1980s and 1990s was not easy. At first, keeping up with ever
expanding information on biological theories, new laboratory tests, computerization, new medications,
and new additional uses for old medications was in itself a full-time occupation—one that often allowed
little time or energy for integrating current information into daily practice. Moreover, the proliferation
of biological and psychopharmacological information occurred so rapidly that the task of integrating
biological and psychotherapeutic approaches became ever more difficult. By now, however, the most
arduous parts of the transition are over for most practitioners, and over the past two or more decades
a cadre of psychiatrists, well versed in psychopharmacology, has been trained.
Some academics and practitioners have argued that psychopharmacological approaches have become
the essence of psychiatry, whereas for many years others insisted that these drugs merely masked
underlying diseases, worked against conflict resolution, interfered with therapy, and so forth. Our
impression has been that most practitioners today have developed more balanced, practical
approaches, combining elements of both psychotherapy and psychopharmacology. In an odd way,
academic psychiatry, with its sometimes hypertrophied and polarized approaches, lagged behind
clinical practice. Indeed, we believe intuitively that psychiatry as a medical subspecialty is
incorporating aspects of psychosocial, psychobiological, and psychopharmacological theories to form a
truly new psychiatry.
One major reason for this is that although psychotropic drugs exert profound and beneficial effects on
cognition, mood, and behavior, they often do not change the underlying disease process, which is
frequently highly sensitive to intrapsychic, interpersonal, and psychosocial stressors. As a rule,
beneficial outcomes can be achieved only by simultaneously reducing symptoms and promoting the
capacity of the individual to adapt to the exigencies of his or her life. Strikingly, some practitioners of
internal medicine have embraced psychosocial principles to help treat illnesses such as hypertension,
rheumatoid arthritis, and juvenile diabetes. Similarly, psychiatrists who embrace psychopharmacology
as the be-all and end-all will probably find themselves in the same position as internists who feel that
prescribing thiazides is a simple solution to hypertensive illness. Conversely, practitioners of
psychoanalysis should not expect that approach to cure or significantly reduce vegetative symptoms in
endogenously depressed patients. Rather, they need to realize the potential benefits of alternative
treatments—particularly psychotropic medication.
For practitioners who did not have extensive experience, the transition to a more pharmacological
practice was not without difficulties. A favorable clinical outcome after prescribing a psychotropic drug
does reinforce confidence in psychopharmacological approaches. Practically speaking, since favorable
outcomes can often be effected more quickly with a psychopharmacological approach than with
psychotherapy, confidence in psychopharmacology could be achieved more readily. The selective
serotonin reuptake inhibitors (SSRIs), with their ease of use and wide therapeutic effects, helped
practitioners become effective pharmacological treaters.
Although this book is primarily a guide to psychopharmacology, it should not lead the reader to
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need to comprehensively evaluate and understand psychiatric patients. Our primary purpose is to
provide the reader-practitioner with basic and practical information regarding the many classes of
psychiatric medications. This book is written as a practical, usable clinical guide to the selection and
prescription of appropriate drug therapies for individual patients, drawing on our own clinical
experience as well as on the scientific literature. It is not a series of meticulously documented review
papers; therefore, statements in the text are sometimes not individually referenced. However, each
chapter is followed by a list of selected relevant articles and books for readers who want to go beyond
the material presented here. Starting with the fourth edition, in response to some readers’
suggestions, we increased the number of references, both cited in the text and listed in the
bibliographies of individual chapters. We also added new sections and provided summary tables to act
as quicker reference sources.
GENERAL ADVICE
The less experienced practitioner of psychopharmacology can follow a number of practical steps to help
develop skills and achieve favorable outcomes. Generally speaking, we recommend that practitioners
concentrate first on one or two drugs per drug class and become fully familiar with how to use them
(dosage, side effects, etc.). One’s armamentarium of medication can then be widened over time and
through further experience. SSRIs have been widely used in clinical practice since 1990. All clinicians
should become familiar with this class of agents. Still, other classes are effective and should be
mastered as well.
The physician should have available some key resource materials, such as textbooks on
psychopharmacology and the Physicians’ Desk Reference (PDR). (Some helpful titles are found in
Appendix B at the end of this manual.) These materials can be supplemented with pharmacology
newsletters, which provide useful current information.
Moreover, practitioners should be familiar with a number of books directed at the lay audience that can
help supplement information provided to patients (see Appendix B at the end of this manual).
It is also a good idea to identify local psychopharmacological consultants who can provide second
opinions when needed—for example, if patients fail to respond or if they experience severe side
effects.
PRACTICE GUIDELINES
Since the early 1990s, practice gudelines have been developed by professional societies as well as
academic leaders. Such guidelines can be helpful, since they are generally based on evidence in the
literature. Unfortunately, there are limitations imposed by overreliance on these guidelines. For one,
available evidence in the published literature may be for agents that are not the most effective for
treating specific patients. Second, evidence often breaks down when the practitioner encounters a lack
of response to the initial therapy, leaving him or her to fall back once again on clinical experience or
judgment. Third, evidence is often based on the consensus opinions of experts. These opinions are
helpful but are not necessarily accurate. In the end, there is still a need for considerable art in the
practice of medicine.
LEGAL, ETHICAL, AND ECONOMIC ISSUES
It seems prudent to discuss briefly a number of legal, ethical, and economic issues that arise in
psychopharmacology. Because a comprehensive discussion of all these is beyond the scope of this
manual, the reader is referred elsewhere for specific information (see Appendix B).
Informed consent has become an increasingly important issue in medicine. Standard medical practice
has long called for informing patients of the benefits versus the risks of various surgical and medical
procedures. In the past decade, greater attention has been paid to the question of informed consent;
for psychiatry, however, several key problems quickly arise. For one, psychiatrists must wrestle with
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medication prescribed or to interpret the provided information in a reflective and beneficial way.
Obviously, this issue is particularly pressing with psychotic patients, and legal guardianship may be
required at times to effect adequate informed consent. Fortunately, these patients represent a minority
of the average practitioner’s patient population.
Paranoid but competent patients present practical problems that are best overcome by creating a solid
working relationship. Such patients are less commonly encountered than are highly anxious, obsessive,
or agitated patients, who are prone to a phobic approach to medication. The practitioner at first glance
may view informed consent in such cases as an insurmountable obstacle. Practically speaking,
however, such patients will be anxious even if the practitioner does not inform them of side effects.
Indeed, disclosing the facts often relieves their anxiety. It also connotes a respect for the severity of
their illness and the need to assume some risks mutually.
Should the physician inform the patient of every side effect listed in the PDR or merely highlight the
most common ones? Some courts have judged that physicians may be liable if they do not tell the
patient of every side effect. Practically speaking, most clinicians do not do so—for several reasons,
including the time involved and concern for unduly frightening the patient. The latter is particularly
relevant when one reflects on the fact that package-insert information lists virtually all side effects ever
reported in drug trials, even if they were not due to the drug, plus side effects observed only or mainly
with similar drugs. Still, we are impressed that patients not only have ready access to copies of the
PDR and consumer guides to medications but also commonly use them. In a sense, these practices
begin to obviate the physician’s apparent problem. Physicians need to enter into an open dialogue with
all patients regarding the benefits and side effects of medication, even (or particularly) patients who
are self-taught. Patients who read the PDR need to be informed of the relative probability of the
occurrence of one or another side effect. For example, patients should be made to realize that a dry
mouth as the result of a tricyclic antidepressant (TCA) is to be expected, but that agranulocytosis or
anaphylaxis is extremely rare. Our experience is that patients are reassured by the physician’s belief
(and hope) that these side effects will not be encountered. Today, package inserts often include tables
comparing side effects in patients treated with a given drug with those observed with a placebo. This
places the issues in a much better perspective. Some physicians routinely give patients written
materials (often a separate sheet for each medication) that spell out the medication’s relative risks.
This works well, but only if the practitioner feels comfortable with this approach and it becomes truly
routine in his or her practice.
For many years until the introduction of atypical antipsychotics, a particularly difficult problem revolved
around the informed consent regarding the risk of developing tardive dyskinesia, an unfortunate side
effect generally due to long-term treatment with the more typical antipsychotic medications (see
Chapter 4: “Antipsychotic Drugs”). Tardive dyskinesia is less of a real risk in psychiatric practice today.
It was shown to affect some 14% of patients receiving maintenance therapy with standard neuroleptic
medication for 3 or more years, and it may have been more common in patients with affective
disorders than in those with schizophrenia. Thus, practitioners had to be particularly conservative in
administering neuroleptics to patients who did not demonstrate frequent or chronic psychotic episodes.
However, because chronic psychotic disorders do unfortunately exist, even prudent practice with first
line antipsychotics could not eliminate the risk of tardive dyskinesia. Newer antipsychotics offer greater
promise for reducing the risk of this problem, although the risk has not been completely eliminated.
What should the physician tell the patient about tardive dyskinesia, and when? Here, a variety of
approaches have been developed. One is to inform the patient and/or the family of the risk of tardive
dyskinesia before prescribing typical neuroleptics. This may be too anxiety provoking and impractical,
particularly for acutely psychotic patients, because tardive dyskinesia is generally a long-term side
effect and there is a pressing need to help the patient quickly. Another approach is to broach the
subject of the risk of tardive dyskinesia after approximately 4–6 weeks of treatment with a typical
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The risk with atypical antipsychotics is low.
Should one obtain written verification of informed consent? Here, too, different approaches have
emerged. Some institutions and practitioners have adopted formal, written informed consent. Others
have followed traditional verbal informed-consent procedures and have placed written documentation
of the interchange in the patient’s record. Still others have routinely provided the patient with
additional written information (beyond that provided in the PDR) regarding the risks of tardive
dyskinesia or other side effects but have not asked the patient to provide written informed consent.
Each of these approaches has its advantages and its proponents. Currently, we recommend that 1)
practitioners and institutions adopt some formal, documented disclosure of the risk of tardive
dyskinesia with typical neuroleptics, 2) they combine this with conservative administration of typical
neuroleptics (in terms of both time and dosage), and 3) they and the patient cooperate in monitoring
the patient for the emergence of dyskinetic movements. Much of this issue is less relevant today, since
initiation of long-term therapy with typical antipsychotics is relatively uncommon in this country.
With the release of clozapine, psychiatrists needed to seriously consider adopting a standard
documented informed-consent procedure for this potentially lethal but therapeutically unique drug.
Patients who are incompetent to give informed consent should have a guardian who provides the
consent. Clozapine-like agents, such as olanzapine, without the apparent risks for agranulocytosis have
largely obviated the problem, but there are still patients with refractory conditions who require
clozapine therapy.
Although the atypical antipsychotics are safer in some ways than were first-generation agents, weight,
insulin resistance (metabolic syndrome), and diabetes are major worries with some of these agents,
particularly olanzapine and clozapine. Diabetic ketoacidosis is a rare but serious side effect that has
garnered a great deal of attention. More common, however, is the weight gain seen with several of the
newer compounds, with a possible loss of insulin sensitivity. Patients who begin taking these agents
should be monitored closely for both weight gain and insulin resistance. Patients should be warned
about such side effects if the agent is thought to have an increased risk (e.g., clozapine, olanzapine).
As indicated in Chapter 4 (“Antipsychotic Drugs”), the offending agent may need to be discontinued.
Since the early 1990s, physicians have been increasingly faced with the dilemma of prescribing
standard drugs for indications that have not been approved by the U.S. Food and Drug Administration
(FDA) or at doses that are higher than those recommended in the PDR. In some instances when this
practice is followed, drugs can be misprescribed, and this can obviously be dangerous. In many other
instances, considerable clinical or research data that have emerged point to potentially great benefits
to many patients, but package-insert information may not have been changed because of economic or
regulatory factors. For example, imipramine has for many years been commonly prescribed to both
outpatients and inpatients at a dosage of 300 mg/day. Still, the package insert states that outpatients
should not receive more than 225 mg/day. In part, this reflects the fact that approved dosage
regimens were determined on the basis of data generated many years ago, when a greater proportion
of seriously depressed patients were treated as inpatients and before plasma levels were applied (see
Chapter 3: “Antidepressants”). It is unlikely that the package insert will ever be changed. Additional
studies designed to document further the efficacy and safety of higher dosages would be too costly for
drug manufacturers, who can no longer hope to recoup the costs of such study because the patents for
the drug have long since expired. One pharmaceutical manufacturer several years ago applied for and
was granted FDA approval to raise the maximum daily dose of its nortriptyline compound (Pamelor)
from 100 to 150 mg/day. A manufacturer of an identical nortriptyline compound, Aventyl, did not
apply, and this product still calls for only a 100-mg maximum daily dose. Thus, we had and still have
on the U.S. market two identical nortriptylines with different maximum daily doses.
Examples of so-called nonapproved uses in previous editions of this manual included the use of
imipramine and phenelzine in treating agoraphobia or panic disorder and the use of carbamazepine in
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valproic acid for maintenance therapy in bipolar disorder, SSRIs in treating body dysmorphic disorder
and related disorders, and bupropion in treating attention-deficit disorder. A growing body of data
supports the effectiveness of these drugs for these indications, but market conditions and regulatory
guidelines may result in some, or even all, of these drugs’ not being granted official new indications.
One generally nonapproved indication for SSRIs has been adolescent depression. The FDA has warned
that efficacy data for this class and for venlafaxine are limited and that these agents carry a risk for
increasing suicidal behavior. Fluoxetine appears to be an exception on both counts. We thus
recommend initially using fluoxetine in adolescents with depression. Should patients not respond,
alternatives can be considered, and if an alternative agent is used, the practitioner should provide clear
documentation. The risks and benefits of these agents need to be discussed with young patients and
their parents whenever possible. Since the FDA instituted a black box warning about the potential risk
of using antidepressants in adolescents and children, prescription rates by pediatricians have dropped
by approximately 20% (Nemeroff et al. 2007). Suicide rates among the young may be rising. A recent
report by Gibbons et al. (2006) points to a significant rise in suicide rates in younger male adolescents
(about age 15 years) in the Netherlands after institution of the warning. These data indicate that
discussion of side effects without discussing potential benefits can have unfortunate results.
Is the practitioner at legal risk in prescribing drugs for nonapproved indications? Generally, the
American Medical Association and the FDA have taken the position that the use of any marketed drug
for nonapproved indications or at higher dosages for individual patients is within the purview of the
clinician. PDR is not an official textbook of medical practice, but rather a compendium of drug
information for marketing purposes. It sets limitations on what pharmaceutical companies can claim for
their products. Malpractice is based on failure to practice within community norms. Still, many
clinicians will not easily accept the risk of being sued—even if such a suit may have little merit—by a
patient who experiences an untoward reaction to a standard drug used for a nonapproved indication or
to a dose of a drug that is higher than the recommended maximum dose.
What are the solutions? Until various forces (both patients and physicians) come to the fore to effect a
change in the system for widening indications or for redefining maximum doses, each clinician must
decide whether to assume the risk. However, although clinicians may attempt a conservative approach,
they will at some point encounter patients who will require alternative treatments. One possible aid is
to acquire outside consultation from more expert psychopharmacologists or from other practitioners in
the community. Another is to explain the scope of the problem to patients, providing them with
available published reports on positive benefits and documenting these actions in their records. Some
physicians will ask for written documentation that the patient has been informed. In the end, there are
no simple solutions, and the physician will at some point be faced with this problem.
Another issue faces psychiatrists who treat patients with treatment-resistant conditions. Many
antidepressant and antipsychotic drugs are available in Canada or in European countries. Before
clomipramine received FDA approval in 1989, Canadian drugstores were mailing the drug regularly to
the United States after receiving a prescription and a check from the patient. With the growth of
pressure from patients with AIDS, the FDA and the U.S. Customs Service appear to view favorably (or
at least passively) the importation of a 3-month supply of drugs not available in the United States for
the treatment of an individual patient. Well-established drugs such as mianserin, older monoamine
oxidase inhibitors (iproniazid, nialamide), and newer drugs such as moclobemide and tianeptine are
available in Canada and Europe, and psychiatrists or patients may be able to obtain them through
pharmacies, colleagues, friends, or relatives there.
Many patients received Canadian clomipramine for years without our ever hearing of a malpractice
suit. Nevertheless, the possibility exists. In 1987, Dr. Robert Dupont wrote to the American Psychiatric
Association’s malpractice insurers to ask whether his malpractice insurance would cover him if he were
to be sued for an adverse effect from clomipramine imported from Canada. He was told he would not
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was appropriate. Psychiatrists who want to treat patients with imported drugs not approved in the
United States should consider the risks to themselves as well as to their patients. We recommend
having the patient sign an informed-consent document if a foreign medication is to be used.
Information on this issue can be obtained from the FDA Web site (www.fda.gov). King (1998)
discusses these issues and outlines the procedures for obtaining FDA and investigational new drug
application approval, primarily for investigational agents.
One important facet of psychopharmacological practice is to document various steps in treatment:
diagnosis, drug dose regimen, other medications, informed consent, and so forth. Practical tips have
been articulated in a paper by Lamb (2001).
Managed care has had a tremendous impact on psychiatric practice. Building on the initial success of
psychopharmacology, it has in a sense reshaped psychiatric practice—primarily along pharmacological
lines. By providing limited benefits, it has forced psychiatrists to emphasize drug treatment. This has
been a somewhat shortsighted approach, resulting in many patients’ receiving limited care. Moreover,
the limited sessions and the avoidance of hospitalization lead at times to unrealistic expectations by
patients and their families and inordinate pressure on providers. Although psychopharmacological
approaches imply ease of care for a large caseload of patients, providers must keep in mind that
responses to treatment are gradual at best and that any short-term successes must be followed by the
continuation and maintenance phases of treatment.
Cost containment has led many health plans to prefer generic compounds over proprietary drugs. We
are frequently asked about the advisability of prescribing generic compounds. For many years, the FDA
has required only that a manufacturer demonstrate that a given dose of a compound will produce blood
levels within 20%–30% of those produced by the proprietary form. Obviously, for some medications
(e.g., TCAs) this standard can prove problematic. Lower blood levels of a TCA may result in the
patient’s not achieving therapeutic levels when treated with traditional doses. Moreover, switching to
an equivalent dose of a generic compound in patients who have responded to a given dosage of
a standard antidepressant may result in loss of therapeutic effect. Differences between generic and
proprietary forms can go in both directions. Use of the generic form could lead to higher, potentially
toxic blood levels. In August 2001, fluoxetine became available in a generic formulation. Fluoxetine
produces relatively high concentrations in blood and brain, and generic forms did not prove to be
problematic. Similarly, we have not heard of problems with generic paroxetine. A few years ago, this
issue came to the fore again with the concern that some generic cardiac medications may not have
offered efficacy equal to that seen with the brand product. It is conceivable that, in the future, efficacy
will need to be demonstrated for generic formulations.
As the second edition of this manual was being written, the FDA had ordered that a number of generic
benzodiazepine compounds be removed from the market because they had fallen below minimum
standards. Thus, quality control of the manufacturing of generic compounds may not necessarily meet
acceptable standards. However, there may be significant variability between different batches of the
same proprietary drug as well, and large pharmaceutical companies have had other problems with the
manufacturing of proprietary compounds. In recent years, generic compounds appear closer in
equivalency to their proprietary counterparts.
In previous editions, we recommended that physicians start their patients on proprietary compounds
(particularly in the case of TCAs) and adjust dosages until therapeutic benefit was achieved and side
effects were limited. Generic compounds could then be used for maintenance therapy. Blood levels for
the specific medication, if available, could be obtained while the patient was still being treated with the
proprietary compound—before switching to the generic—and rechecked while the patient was taking
the equivalent dose of the generic if the patient lost therapeutic benefit or experienced side effects. We
now feel less staunchly about this, in part because a good deal of practice today is with generic
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Another consequence of cost containment is health plans’ insistence that patients obtain 3-month
supplies of medications, generally during maintenance therapy. Obviously, for patients with a history of
abuse of medications or suicidal behavior or with medications with narrow safety margins, this
requirement can prove problematic. We recommend using good clinical sense in deciding how many
pills or capsules to prescribe. Frequently, local pharmacies will work with physicians and patients to
come to a clinically and economically sound compromise (e.g., agreeing to hold supplies in patients’
names but dispensing in 1- to 2-week quantities). However, this practice is a problem with mail-order
drugs that are made available through health insurance plans. Again, newer medications tend to have
wide safety margins, and the problem has to a large extent been obviated.
There has been recent controversy about the propriety of states and municipal governments condoning
the large-scale importation of pharmaceuticals approved in the United States from Canada and other
countries. The FDA has opposed this attempt to reduce costs in part because the origin, safety, and
efficacy of medications imported from Canada cannot be verified (for further infomation, see the FDA
Web site: www.fda.gov/importeddrugs). At the time of writing, this issue is unresolved.
In this book, we provide practical information regarding many different psychotropic drugs.
Information regarding dosages is for adult patients (ages 18–60 years) unless otherwise noted. We
have included information derived from our reading of the psychiatric literature as well as from our
own clinical practice. We attempt to indicate, whenever possible, the uses that officially have not been
approved by the FDA for marketing purposes, but we also attempt to provide readers with sufficient
data to aid them in deciding whether or how they may want to prescribe specific drugs. In so doing, we
are not endorsing the use of these specific drugs but are realistically attempting to place a drug in its
proper perspective. We believe real-world psychiatric practice dictates that we give the practitioner
information based either on the scientific literature or on common clinical use, even though a drug’s
indications may not yet have been changed or—perhaps because of economic reasons—may never be
changed. Information about specific agents should be checked against the PDR and package inserts to
ensure accuracy before prescribing for specific patients.
BIBLIOGRAPHY
Applebaum PS: Legal and ethical aspects of psychopharmacologic practice, in Clinical
Psychopharmacology, 2nd Edition. Edited by Bernstein JC. Boston, MA, Wright PSG, 1984
Erickson SH, Bergman JJ, Schneeweiss R, et al: The use of drugs for unlabeled indications. JAMA
243:1543–1546, 1980 [PubMed]
FDA does not approve uses of drugs (editorial). JAMA 252:1054–1055, 1984
Gibbons RD: Efficacy and safety of antidepressants for depression and suicide risk in youth and adults:
results of new analyses. Neuropsychopharmacology 31 (suppl 1): S50, 2006
Gutheil TG: Liability issues and malpractice prevention, in Handbook of Clinical Psychopharmacology.
Edited by Tupin JP, Shader RI, Harnett DS. Northvale, NJ, Jason Aronson, 1988, pp 439–453
King SM: Legal and risk management concerns relating to the use of non-FDA approved drugs in the
practice of psychiatry. Rx for Risk 6(2):1–7, 1998
Lamb K: Risk management and medication prescribing/administering. Rx for Risk 9(1):1–3, 2001
Nemeroff CB, Kalali A, Keller MB, et al: Impact of publicity concerning pediatric suicidality data on
physician practice patterns in the United States. Arch Gen Psychiatry 64:466–472, 2007 [PubMed]
Nonapproved uses of FDA-approved drugs. JAMA 211:1705, 1970
Slovenko R: Update on legal issues associated with tardive dyskinesia. J Clin Psychiatry 61 (suppl
4):45–57, 2000
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http://www.psychiatryonline.com/popup.aspx?aID=231521&print=yes_chapterUse of approved drugs for unlabeled indications. FDA Drug Bulletin, April 1982 [entire issue]
Use of drugs for unapproved indications: your legal responsibility. FDA Drug Bulletin, October 1972
[entire issue]
Copyright © 2008 American Psychiatric Publishing, Inc. All Rights Reserved.
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Course Content
Introduction to Psychopharmacology
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History of Psychopharmacology
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Basic Neuroscience Concepts
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Classification of Psychiatric Medications
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Introduction to Psychopharmacology Quiz
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Ethical Considerations in Psychopharmacology
Basic Pharmacokinetics and Pharmacodynamics
Major Classes of Psychotropic Medications
Integrating Psychopharmacology into Treatment Plans
Ethical Considerations and Future Directions in Psychopharmacology
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