Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.1 General Principles of Psychopharmacology

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

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. 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- Drug Factors Pharmacodynamics