Mental Health: A Report by the Surgeon General

The mechanism of action refers to how a pharmacotherapy interacts with its target in the body to produce therapeutic effects. Pharmacotherapies that act in similar ways are grouped together into broad categories (e.g., stimulants, antidepressants). Within each category are several chemical classes. The individual pharmacotherapies within a chemical class share similar chemical structures. Table 2-9 presents several common categories and classes, along with their indication, that is, their clinical use.

Many pharmacotherapies for mental disorders have as their initial action the alteration—either increase or decrease—in the amount of a neurotransmitter. Neurotransmitter levels can be altered by pharmacotherapies in myriad ways: pharmacotherapies can mimic the action of the neurotransmitter in cell-to-cell signaling; they can block the action of the neurotransmitter; or they can alter its synthesis, breakdown (degradation), release, or reuptake, among other possibilities (Cooper et al., 1996).

Neurotransmitters generally are concentrated in separate brain regions and circuits. Within the cells that form a circuit, each neurotransmitter has its own biochemical pathway for synthesis, degradation, and reuptake, as well as its own specialized molecules known as receptors. At the time of neurotransmission, when a traveling signal reaches the tip (terminal) of the presynaptic cell, the neurotransmitter is released from the cell into the synaptic cleft. It migrates across the synaptic cleft in less than a millisecond and then binds to receptors situated on the membrane of the postsynaptic cell. The neurotransmitter’s binding to the receptor alters the shape of the receptor in such a way that the neurotransmitter can either excite the postsynaptic cell, and thereby transmit the signal to this next cell, or inhibit the receptor, and thereby block signal transmission. The neurotransmitter’s action is terminated either by enzymes that degrade it right there, in the synaptic cleft, or by transporter proteins that return unused neurotransmitter back to the presynaptic neuron for reuse, a “recycling” process known as reuptake. The widely prescribed class of antidepressants referred to as the selective serotonin reuptake inhibitors primarily block the action of the transporter protein for serotonin, thus leaving more serotonin to remain at the synapse (Schloss & Williams, 1998). Depression is thought to be reflected in decreased serotonin transmission, so one rationale for this class of antidepressants is to boost the level of serotonin (see Chapter 4).

Table 2-9. Selected types of pharmacotherapies

* Also known as first-generation antipsychotics, they include these chemical classes: phenothiazines (e.g., chlorpromazine), butyrophenones (e.g., haloperidol), and thioxanthenes (Dixon et al., 1995).
** Also known as second-generation antipsychotics, they include these chemical classes: dibenzoxazepine (e.g., clozapine), thienobenzodiazepine (e.g., olanzapine), and benzisoxazole (e.g., risperidone).
*** Include imipramine and amitriptyline.

Source: Perry et al., 1997

Although the effects of reuptake inhibitors on neurotransmitter concentrations in the synapse occur with the first dose, therapeutic benefit typically lags behind by days or weeks. This observation has spurred considerable recent research on chronic and “downstream” actions of psychotropics, particularly antidepressants. For example, in animal models the repeated administration of nearly all antidepressants is associated with a reduction in the number of postsynaptic 12/7/99 receptors, so-called down-regulation that parallels the time course of clinical effect in patients (Schatzberg & Nemeroff, 1998). Some of the secondary effects of reuptake inhibitors may be mediated by the activation of intraneuronal “second messenger” proteins which result from the stimulation of postsynaptic receptors (Schatzberg & Nemeroff, 1998).

Receptors for each transmitter come in numerous varieties. Not only are there several types of receptor for each neurotransmitter, but there may be many subtypes. For serotonin, for example, there are seven types of receptors, designated 5-HT₁ –5-HT₇, and seven receptor subtypes, totaling 14 separate receptors (Schatzberg & Nemeroff, 1998). The pace at which receptors are identified has become so dizzying that these figures are likely to be obsolete by the time this paragraph is read.

A pharmacotherapy typically interacts with a receptor in either one of two ways—as an agonist or as an antagonist.¹⁴ When a pharmacotherapy acts as an agonist, it mimics the action of the natural neurotransmitter. When a pharmacotherapy acts as an antagonist, it inhibits, or blocks, the neuro-transmitter’s action, often by binding to the receptor and preventing the natural transmitter from binding there. An antagonist disrupts the action of the neurotransmitter.

The diversity of receptors presents vast opportunities for drug development. Through rational drug design, pharmacotherapies have become increasingly selective in their actions. Generally speaking, the more selective the pharmacotherapy’s action, the more targeted it is to one receptor rather than another, the narrower its spectrum of action, and the fewer the side effects. Conversely, the broader the pharmacotherapy’s action, the less targeted to a receptor type or subtype, the broader the effects, and the broader the side effects (Minneman, 1994). However, the interaction among neurotransmitter systems in the brain renders some of the apparent distinctions among medications more apparent than real. Thus, despite differential initial actions on neurotransmitters, both serotonin and norepinephrine reuptake blockers have similar biochemical effects after chronic dosing (Potter et al., 1985).

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