The time course and intensity of a drug’s effects are referred to as its pharmacodynamics. Major pharmacodynamic considerations include receptor mechanisms, the dose-response curve, the therapeutic index, and the development of tolerance, dependence, 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.

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, histamine, γ-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 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 receptor. Similarly, benzodiazepine agonists bind a receptor complex that contains benzodiazepine and GABA receptors.

Accounts of so-called mechanisms of action should nevertheless 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 associated 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.

Therapeutic index is a relative measure of the toxicity or safety of a drug and is defined as the ratio of the median toxic dose to the median effective dose. The median toxic dose is the dose at which 50 percent of patients experience a specific toxic effect, and the median effective dose is the dose at which 50 percent of patients have a specified therapeutic effect. When the therapeutic index is high, as it is for haloperidol, it is reflected by the wide range of doses in which that drug is prescribed. Conversely, the therapeutic index for lithium is quite low, thus requiring careful monitoring of serum lithium levels in patients for whom the drug is prescribed.

Safety in overdose is always a consideration in drug selection. Almost all of the newer agents, however, have a wide margin of safety when taken in overdose. By contrast, a 1-month supply of tricyclic antidepressants could be fatal. The depressed patients they were used to treat were the group most at risk to attempt suicide. Because even the safest drugs can sometimes produce severe medical complications, especially when combined with other agents, clinicians must recognize that the prescribed medication can be used in an attempt to commit suicide. Although it is prudent to write nonrefillable prescriptions for small quantities, this practice passes along increased copay costs to the patient. In fact, many pharmacy benefit management programs encourage the prescribing of a 3-month supply of medication.