29.1 General Principles of Psychopharmacology
911
patient variables. Nevertheless, it is possible that some drugs
have a niche in which they can be uniquely helpful for a sub-
group of patients, without demonstrating any overall superior-
ity in efficacy. No drug is universally effective, and no evidence
indicates the unambiguous superiority of any single agent as a
treatment for any major psychiatric disorders. The only excep-
tion, clozapine (Clozaril), has been approved by the FDA as a
treatment for cases of treatment-refractory schizophrenia.
Decisions about drug selection and use are made on a case-
by-case basis, relying on the individual judgment by the physi-
cian. Other factors in drug selection are the characteristics of
the drug and the nature of the patients illness. Each of these
components affects the probability of a successful outcome.
Drug Factors
Pharmacodynamics
The time course and intensity of a drug’s effects are referred to
as its
pharmacodynamics.
Major pharmacodynamic consider-
ations include receptor mechanisms, the dose–response curve,
the therapeutic index, and the development of tolerance, depen-
dence, and withdrawal phenomena. Drug mechanism of action
is subsumed under pharmacodynamics. The clinical response to
a drug, including adverse reactions, results from an interaction
between that drug and a patient’s susceptibility to those actions.
Pharmacogenetic studies are beginning to identify genetic
polymorphisms linked to individual differences in treatment
response and sensitivity to side effects.
Mechanisms
The mechanisms through which most psychotropic drugs
produce their therapeutic effects remain poorly understood.
Standard explanations focus on ways that drugs alter synaptic
concentrations of dopamine, serotonin, norepinephrine, hista-
mine,
g
-aminobutyric acid (GABA), or acetylcholine. These
changes are said to result from receptor antagonists or agonists,
interference with neurotransmitter reuptake, enhancement of
neurotransmitter release, or inhibition of enzymes. Specific
drugs are associated with permutations or combinations of these
actions. For example, a drug can be an agonist for a receptor,
thus stimulating the specific biological activity of the receptor,
or an antagonist, thus inhibiting the biological activity. Some
drugs are partial agonists, because they are not capable of fully
activating a specific receptor. Some psychotropic drugs also
produce clinical effects through mechanisms other than receptor
interactions. For example, lithium (Eskalith) can act by directly
inhibiting the enzyme inositol-1-phosphatase. Some effects are
closely linked to a specific synaptic effect. For example, most
medications that treat psychosis share the ability to block the
dopamine type 2 (D
2
) receptor. Similarly, benzodiazepine ago-
nists bind a receptor complex that contains benzodiazepine and
GABA receptors.
Further illustrating the fact that the mechanisms of action
of psychotropic drugs remain only partially understood are
observations that medications that do not directly target mono-
amine neurotransmitters can be remarkably effective in treating
some psychiatric disorders. For example, ketamine (Ketalar), an
anesthetic agent that targets glutamate, can rapidly and dramati-
cally alleviate symptoms of depression when given as a slow
infusion. Another example involves the antibiotic minocycline
(Solodyn), which has been shown to have antidepressant effects.
Along with other findings, this suggests that the immune system
and inflammatory responses may underlie some mood disorders.
Accounts of so-called mechanisms of action should never-
theless be kept in perspective. Explanations of how psychotropic
drugs actually work that focus on synaptic elements represent
an oversimplification of a complex series of events. If merely
raising or lowering levels of neurotransmitter activity is associ-
ated with the clinical effects of a drug, then all drugs that cause
these changes should produce equivalent benefits. This is not
the case. Multiple obscure actions, several steps removed from
events at neuronal receptor sites, are probably responsible for
the therapeutic effects of psychotropic drugs. These
downstream
elements are postulated to represent the actual reasons that these
drugs produce clinical improvement. A glossary of terms related
to receptor drug interactions is given in Table 29.1-1.
Side Effects
Side effects are an unavoidable risk of medication treatment.
Although it is impossible to have an encyclopedic knowledge of
all possible adverse drug effects, prescribing clinicians should
be familiar with the more common adverse effects, as well as
those with serious medical consequences. No single text or doc-
ument, including the product information, contains a complete
list of possible treatment-emergent events.
Side effect considerations include the probability of its
occurrence, its impact on a patient’s quality of life, its time
course, and its cause. Just as no one drug is certain to produce
clinical improvement in all patients, no side effect, no matter
how common, occurs in every patient. When concurrent medi-
cal disorders or a history of a similar adverse reaction puts a
patient at increased risk for a side effect, it is logical to con-
sider prescribing a compound not typically associated with that
adverse reaction.
Side effects can result from the same pharmacological
action that is responsible for a drug’s therapeutic activity or
from an unrelated property. In examples of the latter, some of
the most common adverse effects of the TCAs are caused by
blockade of muscarinic acetylcholine receptors or histamine 2
receptors. If a patient is sensitive to these effects, alternative
agents without these properties should be prescribed. When
side effects are manifestations of the drug’s presumed mecha-
nism of action, side effects may be unavoidable. Thus, blockade
of serotonin reuptake by SSRIs can cause nausea and sexual
dysfunction. The D
2
blockade of drugs used to treat psychosis
can cause extrapyramidal side effects. Agonist action of benzo-
diazepine receptors can cause ataxia and daytime sleepiness. In
these cases, additional medications are frequently used to make
the primary agent better tolerated.
Time Course
Adverse effects differ in terms of their onset and duration. Some
side effects appear at the outset of treatment and then rapidly
diminish. Nausea occurring with SSRIs or venlafaxine (Effexor)
and sedation occurring with mirtazapine (Remeron) are good
examples of early, time-limited side effects. Early-onset, but
