Antidepressant Medications: Pharmacological Properties and Evidence for Acute-Phase Efficacy
Antidepressant Medications: Pharmacological Properties and Evidence for Acute-Phase Efficacy
Classification of Antidepressant Drugs and Overview of Their Mechanism of Action
Many strategies have been applied to the classification of antidepressant drugs, including systems based on the perceived behavioral effects of different drugs, the severity of depression (Paykel 1990), and the drugs’ chemical structures (Klein and Davis 1969). The traditional method involves the distinction between monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). This system has used pharmacological effects to define the former and chemical structure to define the latter. The advent of new medications that do not fall into either of these groups and increased knowledge regarding the pharmacological effects that are more important to the efficacy of current antidepressants have highlighted the inconsistencies in earlier approaches.
Most effective antidepressants potently increase synaptic levels of norepinephrine (NE) and/or serotonin (5-hydroxytryptamine [5-HT]) and in some cases dopamine (DA). Most accomplish this by inhibiting reuptake of monoamines (NE, DA, and serotonin) or inhibiting the enzyme monoamine oxidase (MAO). It has not been clear whether this increase in synaptic monoamine levels is the primary mechanism or even a necessary part of the mechanism of antidepressant action, because synaptic levels increase within hours of the first dose, but therapeutic response does not usually begin until 1-2 weeks later. This lack of temporal relationship between increased synaptic monoamine levels and clinical response led to a search for other effects that correlate more closely with therapeutic response.
Antidepressant and Antimanic Medications
Introduction
Diagnostic Indications and Contraindications
Indications for Use of Antidepressant and Antimanic Medications
Contraindications to Use of Antidepressant and Antimanic Medications
General Treatment Guidelines
Antidepressant Medications: Pharmacological Properties and Evidence for Acute-Phase Efficacy
Classification of Antidepressant Drugs and Overview of Their Mechanism of Action
Drugs With Mixed Pharmacological Properties
Antimanic Medications: Pharmacological Properties and Evidence for Acute-Phase Efficacy
Newer Anticonvulsants
Continuation- and Maintenance-Phase Efficacy
Antimanic Treatments
Pharmacological Effects Responsible for Common Side Effects of Antidepressant and Antimanic Medications
Withdrawal Reactions
Medication Treatment of Depression: Applications and Procedures
New evidence suggests that although increased synaptic monoamine levels are not temporally correlated with therapeutic response, they are an essential aspect of the mechanism of action of some medications. Selective partial depletion of serotonin or NE and DA (Delgado et al. 1993) causes a rapid relapse of depression in depressed patients having had therapeutic responses to and being maintained on antidepressant drugs. This relapse is qualitatively similar to the depression prior to treatment and correlates with the time course of monoamine depletion; the patients improve rapidly as monoamine content returns to baseline levels.
Depleting serotonin causes a rapid return of depression in depressed patients who have responded to fluoxetine, fluvoxamine, MAOIs, or imipramine but not in those who have responded to desipramine, nortriptyline, or bupropion. Depleting NE and DA causes a rapid return of depression in depressed patients who have improved with desipramine or mazindol but not with fluoxetine. These data strongly suggest that the monoamine reuptake-blocking properties are critical for the therapeutic action of these drugs and that more than one mechanism of action probably exists.
An important aspect of the neurotransmitter depletion studies that has to be taken into account when trying to understand antidepressant action is that neither serotonin depletion (Delgado et al. 1994) nor NE/DA depletion worsens mood in drug-free depressed patients. These findings suggest that the way in which monoamines are involved in the regulation of mood is nonlinear and that they are not directly modulating mood. Rapidly increasing levels of monoamines does not have an immediate antidepressant effect, and rapidly lowering monoamines does not lower mood unless a patient is being treated with a reuptake inhibitor. This suggests that monoamine reuptake inhibition is only the first step in a process that eventually leads to an antidepressant response and that important changes associated with successful antidepressant response take place downstream from and postsynaptic to the monoamine systems (
Figure 39-2
).A variety of secondary effects occur as a consequence of monoamine reuptake inhibition. These effects include presynaptic and postsynaptic changes in receptor number, G-protein coupling, second-messenger function, and gene transcription, as well as changes in the critical balance between neurotransmitter systems. Given this, the mechanism of antidepressant action should be seen as a cascade of biological effects that is most often triggered by an increase in synaptic levels of monoamines.
When the basic mechanisms underlying antidepressant action are better understood, these drugs will be categorized by that mechanism rather than by chemical structure or side-effect profile. Most antidepressant drugs are metabolized into pharmacologically active compounds that frequently have effect profiles that are different from those of the parent compound. For example, clomipramine primarily blocks serotonin reuptake, whereas its primary active metabolite, desmethylclomipramine, primarily blocks NE reuptake. Thus, the in vivo effects of some antidepressant drugs will include the effects of both the parent compound and the active metabolites. In
Table 39-5
, available drugs reported to have antidepressant properties are listed and grouped based on pharmacological effects of the parent compound that are likely to underlie the therapeutic effects.In the following subsections we describe the specific pharmacological properties and evidence for efficacy of each group of antidepressant drugs. Common side effects of each individual drug are described; a comparison of the side effects of these drugs is presented later in this chapter.
Check also:
Antidepressant and Antimanic Medications
Depression-Focused Psychotherapies
Psychodynamic Psychotherapies
Combined Medication and Psychotherapy
Electroconvulsive Therapy
Light Therapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: July 5, 2011
Last revised: by Amalia K. Gagarina, M.S., R.D.