Some of the growth in antidepressant use may be related to the broad application of these agents for conditions other than major depression. For example, antidepressants have received FDA approvals for the treatment of panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). In addition, antidepressants are commonly used to treat pain disorders such as neuropathic pain and the pain associated with fibromyalgia. Some antidepressants are used for treating premenstrual dysphoric disorder (PMDD), mitigating the vasomotor symptoms of menopause, and treating stress urinary incontinence. Thus, antidepressants have a broad spectrum of use in medical practice. However, their primary use remains the treatment for MDD
SSRI
Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and 
adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants, SSRIs are highly lipophilic. The popularity of SSRIs stems largely from their ease of use, safety in overdose, relative tolerability, cost (all except escitalopram are generically available), and broad spectrum of uses.
Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).
The SNRIs include venlafaxine, its metabolite desvenlafaxine, and duloxetine. Another SNRI, milnacipran, is in late clinical trials in the USA but has been available in Europe for several years. In addition to their use in major depression, other applications of the SNRIs include the treatment of pain disorders including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause.
Venlafaxine's in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors
Tricyclic Antidepressants
The TCAs were the dominant class of antidepressants until the introduction of SSRIs in the 1980s and 1990s. Nine TCAs are available in the USA, and they all have an iminodibenzyl (tricyclic) core (Figure 30–4). The chemical differences between the TCAs are relatively subtle. For example, the prototype TCA imipramine and its metabolite, desipramine, differ by only a methyl group in the propylamine side chain. However, this minor difference results in a substantial change in their pharmacologic profiles. Imipramine is highly anticholinergic and is a relatively strong serotonin as well as norepinephrine reuptake inhibitor. In contrast, desipramine is much less anticholinergic and is a more potent and somewhat more selective norepinephrine reuptake inhibitor than is imipramine
At the present time, the TCAs are used primarily in depression that is unresponsive to more commonly used antidepressants such as the SSRIs or SNRIs. Their loss of popularity stems in large part from relatively poorer tolerability compared with newer agents, to difficulty of use, and to lethality in overdose. Other uses for TCAs include the treatment of pain conditions, enuresis, and insomnia
5-HT2 Antagonists
Two antidepressants are thought to act primarily as antagonists at the 5-HT2 receptor: trazodone and nefazodone.
The most common use of trazodone in current practice is as an unlabeled hypnotic, since it is highly sedating and not associated with tolerance or dependence. The primary indications for both nefazodone and trazodone are major depression, although both have also been used in the treatment of anxiety disorders.
Tetracyclic and untetracyclic agents
Mirtazapine was introduced in 1994 and, like bupropion, is one of the few antidepressants not commonly associated with sexual side effects. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds.
Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the N-methylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents
MAOI: Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder
Selective Serotonin Reuptake Inhibitors
The prototype SSRI, fluoxetine, differs from other SSRIs in some important respects (Table 30–1). Fluoxetine is metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs. As a result, fluoxetine has to be discontinued 4 weeks or longer before an MAOI can be administered to mitigate the risk of serotonin syndrome.
Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this contributes to potential drug interactions (see drug interactions). In contrast, fluvoxamine is an inhibitor of CYP3A4, whereas citalopram, escitalopram, and sertraline have more modest CYP interactions
SNRI: Both have similar half-lives of about 11 hours. Despite the relatively short half-lives, both drugs are available in formulations that allow once-daily dosing. Venlafaxine and desvenlafaxine have the lowest protein binding of all antidepressants (27–30%). Unlike most antidepressants, desvenlafaxine is conjugated and does not undergo extensive oxidative metabolism. At least 45% of desvenlafaxine is excreted unchanged in the urine compared with 4–8% of venlafaxine
TCA: As a result, most are dosed once daily at night because of their sedating effects. TCAs undergo extensive metabolism via demethylation, aromatic hydroxylation, and glucuronide conjugation. Only about 5% of TCAs are excreted unchanged in the urine. The TCAs are substrates of the CYP2D6 system, and the serum levels of these agents tend to be substantially influenced by concurrent administration of drugs such as fluoxetine
Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT2 antagonists and mirtazapine). Ultimately, the increased availability of monoamines for binding in the synaptic cleft results in a cascade of events that enhance the transcription of some proteins and the inhibition of others. It is the net production of these proteins, including BDNF, glucocorticoid receptors, 
adrenoceptors, and other proteins that appears to determine the benefits as well as the toxicity of a given agent.
When extracellular serotonin binds to receptors on the transporter, conformational changes occur in the transporter and serotonin, Na+, and Cl– are moved into the cell. Binding of intracellular K+ then results in return of the transporter to its original conformation and the release of serotonin inside the cell. SSRIs allosterically inhibit the transporter by binding the receptor at a site other than active binding site for serotonin. At therapeutic doses, about 80% of the activity of the transporter is inhibited. Functional polymorphisms exist for SERT that determine the activity of the transporter.
SSRIs have modest effects on other neurotransmitters. Unlike TCAs and SNRIs, there is little evidence that SSRIs have prominent effects on adrenoceptors or the norepinephrine transporter, NET. Binding to the serotonin transporter is associated with tonic inhibition of the dopamine system, although there is substantial interindividual variability in this effect. The SSRIs do not bind aggressively to histamine, muscarinic, or other receptors
Venlafaxine is a weak inhibitor of NET, whereas desvenlafaxine, duloxetine, and milnacipran are more balanced inhibitors of both SERT and NET. Nonetheless, the affinity of most SNRIs tends to be much greater for SERT than for NET. The SNRIs differ from the TCAs in that they lack the potent antihistamine, -adrenergic blocking, and anticholinergic effects of the TCAs. As a result, the SNRIs tend to be favored over the TCAs in the treatment of MDD and pain syndromes because of their better tolerability
Tricyclic Antidepressants
The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine's known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition.
Common adverse effects of the TCAs, including dry mouth and constipation, are attributable to the potent antimuscarinic effects of many of these drugs. The TCAs also tend to be potent antagonists of the histamine H1 receptor. TCAs such as doxepin are sometimes prescribed as hypnotics and used in treatments for pruritus because of their antihistamine properties. The blockade of adrenoceptors can result in substantial orthostatic effects, particularly in older patients.
5-HT2 Antagonists
The principle action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor. Inhibition of this receptor in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects. Conversely, agonists of the 5-HT2A receptor, eg, lysergic acid (LSD) and mescaline, are often hallucinogenic and anxiogenic. The 5-HT2A receptor is a G protein-coupled receptor and is distributed throughout the neocortex.
Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone's benefits as an antidepressant might be attributed to this effect. Trazodone also has weak-to-moderate presynaptic -adrenergic blocking properties and is a modest antagonist of the H1 receptor
Mirtazapine has a complex pharmacology. It is an antagonist of the presynaptic 2 autoreceptor and enhances the release of both norepinephrine and 5-HT. In addition, mirtazapine is an antagonist of 5-HT2 and 5-HT3 receptors. Finally, mirtazapine is a potent H1 antagonist, which is associated with the drug's sedative effects.
The actions of amoxapine and maprotiline resemble those of TCAs such as desipramine. Both are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Unlike the TCAs or other antidepressants, amoxapine is a moderate inhibitor of the postsynaptic D2 receptor. As such, amoxapine possesses some antipsychotic properties
Monoamine Oxidase Inhibitors
MAOIs act by mitigating the actions of monoamine oxidase in the neuron and increasing monoamine content. There are two forms of monoamine oxidase. MAO-A is present in both dopamine and norepinephrine neurons and is found primarily in the brain, gut, placenta, and liver; its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on tyramine, phenylethylamine, and benzylamine. Both MAO-A and -B metabolize tryptamine and dopamine.
MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible. Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs. Moclobemide is a reversible and selective inhibitor of MAO-A but is not available in the USA. Moclobemide can be displaced from MAO-A by tyramine, and this mitigates the risk of food interactions. In contrast, selegiline is an irreversible MAO-B–specific agent at low doses. Selegiline is useful in the treatment of Parkinson's disease at these low doses, but at higher doses it becomes a nonselective MAOI similar to other agents
Clinical indications The FDA indication for the use of the antidepressants in the treatment of major depression is fairly broad. Most antidepressants are approved for both acute and long-term treatment of major depression. Acute episodes of MDD tend to last about 6–14 months untreated but at least 20% of episodes last 2 years or longer.
The goal of acute treatment of MDD is remission of all symptoms. Since antidepressants may not achieve their maximum benefit for 1–2 months or longer, it is not unusual for a trial of therapy to last 8–12 weeks at therapeutic doses. The antidepressants are successful in achieving remission in about 30–40% of patients within a single trial of 8–12 weeks. If an inadequate response is obtained, therapy is often switched to another agent or augmented by addition of another drug. For example, bupropion, an atypical antipsychotic, or mirtazapine might be added to an SSRI or SNRI to augment antidepressant benefit if monotherapy is unsuccessful. Seventy to eighty percent of patients are able to achieve remission with sequenced augmentation or switching strategies. Once an adequate response is achieved, continuation therapy is recommended for a minimum of 6–12 months to reduce the substantial risk of relapse.
Approximately 85% of patients who have a single episode of MDD will have at least one recurrence in a lifetime. Many patients have multiple recurrences, and these recurrences may progress to more serious, chronic, and treatment-resistant episodes. Thus, it is not unusual for patients to require maintenance treatment to prevent recurrences. Although maintenance treatment studies of more than 5 years are uncommon, long-term studies with TCAs, SNRIs, and SSRIs suggest a significant protective benefit when given chronically. Thus, it is commonly recommended that patients be considered for long-term maintenance treatment if they have had two or more serious MDD episodes in the previous 5 years or three or more serious episodes in a lifetime.
Anxiety: The benzodiazepines (see Chapter 22) provide much more rapid relief of both generalized anxiety and panic than do any of the antidepressants. However, the antidepressants appear to be at least as effective and perhaps more effective than benzodiazepines in the long-term treatment of these anxiety disorders. Furthermore, antidepressants do not carry the risks of dependence and tolerance that may occur with the benzodiazepines.
OCD is known to respond to serotonergic antidepressants. It is characterized by repetitive anxiety-provoking thoughts (obsessions) or repetitive behaviors aimed at reducing anxiety (compulsions). Clomipramine and several of the SSRIs are approved for the treatment of OCD, and they are moderately effective. Behavior therapy is usually combined with the antidepressant for additional benefits.
Social anxiety disorder is an uncommonly diagnosed but a fairly common condition in which the patient experiences severe anxiety in social interactions. This anxiety may limit their ability to function adequately in their jobs or interpersonal relationships. Several SSRIs and venlafaxine are approved for the treatment of social anxiety. The efficacy of the SSRIs in the treatment of social anxiety is greater in some studies than their efficacy in the treatment of MDD.
Antidepressants appear to be helpful in the treatment of bulimia but not anorexia. Fluoxetine was approved for the treatment of bulimia in 1996, and other antidepressants have shown benefit in reducing the binge-purge cycle. The primary treatment for anorexia at this time is refeeding, family therapy, and cognitive behavioral therapy
At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as the therapeutic dose for most patients, and so titration may not be required. In addition, most SSRIs are now generically available and inexpensive. Other agents, including the SNRIs, bupropion, and mirtazapine, are also reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason. However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients. The primary indication for bupropion is in the treatment of major depression, including seasonal (winter) depression. Off-label uses of bupropion include the treatment of attention deficit hyperkinetic disorder (ADHD), and bupropion is commonly combined with other antidepressants to augment therapeutic response. The primary indication for mirtazapine is in the treatment of major depression. However, its strong antihistamine properties have contributed to its occasional use as a hypnotic and as an adjunctive treatment to more activating antidepressants.
SSRIs enhance serotonergic tone, not just in the brain but throughout the body. Increased serotonergic activity in the gut is commonly associated with nausea, gastrointestinal upset, diarrhea, and other gastrointestinal symptoms. Gastrointestinal adverse effects usually emerge early in the course of treatment and tend to improve after the first week. Increasing serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest. As a result, at least 30–40% of patients treated with SSRIs report loss of libido, delayed orgasm, or diminished arousal. Other adverse effects related to the serotonergic effects of SSRIs include an increase in headaches and insomnia or hypersomnia. Some patients gain weight while taking SSRIs, particularly paroxetine
SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation.
The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects result in dry mouth, constipation, urinary retention, blurred vision, and confusion. They are more common with tertiary amine TCAs such as amitriptyline and imipramine than with the secondary amine TCAs desipramine and nortriptyline. The potent -blocking property of TCAs often results in orthostatic hypotension. H1 antagonism by the TCAs is associated with weight gain and sedation. The TCAs are class 1A antiarrhythmic agents (see Chapter 14) and are arrhythmogenic at higher doses. Sexual effects are common, particularly with highly serotonergic TCAs such as clomipramine. The TCAs have a prominent discontinuation syndrome characterized by cholinergic rebound and flulike symptoms.
The most common adverse effects associated with the 5-HT2 antagonists are sedation and gastrointestinal disturbances. Sedative effects, particularly with trazodone, can be quite pronounced.
Tetracyclics and Unicyclics
Amoxapine is sometimes associated with a parkinsonian syndrome due to its D2-blocking action. Mirtazapine has significant sedative effect. Maprotiline has a high affinity for NET, may cause TCA-like adverse effects and, rarely, seizures. Bupropion is occasionally associated with agitation, insomnia, and anorexia.
The most common adverse effects of the MAOIs leading to discontinuation of these drugs are orthostatic hypotension and weight gain. In addition, the irreversible nonselective MAOIs are associated with the highest rates of sexual effects of all the antidepressants. Anorgasmia is fairly common with therapeutic doses of some MAOIs. The amphetamine-like properties of some MAOIs contributes to activation, insomnia, and restlessness in some patients
Principles of Treatment and Management
Treatment is divided into three phases (acute, continuation, and maintenance), each of which has specific objectives. Acute treatment aims at full symptom remission and restoration of full function. Continuation treatment aims to sustain those gains, thereby preventing the return of the index episode. Maintenance treatment is designed to prevent a new episode (recurrence). Typically, maintenance phase treatment is indicated if there have been at least two and certainly three or more episodes, especially if there has been incomplete interepisode recovery or if the index episode has been chronic (>2 years).
When initiating acute treatment, clinicians must elect the best setting (e.g., inpatient, outpatient, or day hospital) guided by (1) an estimate of imminent suicidal risk, (2) the capacity of patients to recognize and adhere to recommendations, (3) the level of psychosocial support, and (4) psychosocial stress and functional impairment.
Next, the type of treatment (the strategy) must be chosen. For most, the choices are medication, psychotherapy, the combination, or electroconvulsive therapy (ECT) or, for some, light therapy alone or in combination with medication or therapy. Factors affecting this choice include acceptability, severity, acuity (e.g., for ECT), seasonal pattern (for light therapy), and chronicity. Chronic depressions appear to do best with a combination of medication and psychotherapy
Continuation treatment typically lasts 4 to 9 months. In theory, the duration depends on an estimate of when the episode would have spontaneously remitted. Thus, patients with longer prior episodes (e.g., 9 to 15 months) who have had only 2 months of a current depression, for example, would be candidates for 5 to 11 months of continuation treatment, assuming that acute treatment lasted 2 months. For those with psychotic depressions, follow-up studies 1 year after acute phase treatment indicate a poorer prognosis than for nonpsychotic depression. Thus, continuation phase treatment for psychotic depressions should be longer.
Psychotherapy may be added to continuation phase medication if psychosocial residua do not remit with medication alone. Whether to continue psychotherapy after response to acute phase combined treatment is unclear and is left entirely up to clinical judgment. On the basis of a recent randomized trial of continuation phase cognitive therapy, after response to acute phase cognitive therapy alone, continuation phase therapy is recommended for those who do not achieve remission with acute phase treatment and for those with longer-standing courses of illness (e.g., earlier age at onset of the first major depressive episode).
Patients with chronic depression may continue to improve during the medication continuation phase. Of those who respond during 12 weeks of acute phase treatment but still have residual symptoms, about 40 percent will achieve remission after 4 more months of medication alone. Conversely, a substantial number relapse during continuation phase medication. Thus, careful monitoring of symptom status during continuation phase treatment is recommended to facilitate early intervention, if needed.
Maintenance treatment aims at preventing new episodes (recurrences). It is appropriate for recurrent or chronic depressions but not for single-episode major depressive disorder
When to discontinue maintenance medication treatment is unclear. As noted previously, RCT evidence indicates that those with highly recurrent depressions (e.g., more than three episodes) continue to be benefited by maintenance treatment for at least 5 years. Some patients may require prolonged periods (e.g., a decade) or even lifetime maintenance medication treatment. When discontinuation occurs, careful monitoring is needed, as the first 6 months after discontinuation appear to be a particular risk period for recurrences.
Tactical issues in acute treatment: Thus, at least a 6-week trial is often useful, especially for those with more severe, chronic, or complicated (i.e., more Axis I or III comorbidities) depressions to ensure that the treatment (given at a vigorous but tolerable dose) has sufficient time to work. The specific decision point will likely vary across patients. A suggested rule of thumb is that the treatment should continue if at least a 25 percent reduction in initial symptom severity is found at 4 to 6 weeks
Failure to tolerate or to respond to one medication does not imply that other medications will also fail. In fact, with a shift from one medication class to another, there is a 50 percent chance of response to the initial medication and to the next medication, should the first be ineffective (these estimates are largely based on open trial data). Consistent with this notion, in terms of remission, the recent STAR*D trial found a 33 percent remission rate in the first step and a 30 percent rate in the second step.
Meta-analyses of studies comparing venlafaxine (Effexor) to selective serotonin reuptake inhibitors (SSRIs) suggested a 5 to 6 percent higher response rate with venlafaxine in 8-week trials. But since these trials were brief, the certainty of these findings is limited. In addition, other studies comparing dual action agents (e.g., imipramine [Tofranil]) have not revealed greater efficacy than a comparator SSRI (e.g., sertraline [Zoloft]). Finally, in the second step in the STAR*D trial, a dual action agent was not more effective than either a second SSRI or an out-of-class switch following failure of the first step SSRI. Thus, dual action agents may be minimally more effective than more selective agents
Two issues are confronted when two or more acute treatment steps are needed: When to decide to change the initial or subsequent treatments and the choice of the second or subsequent treatments. When to decide that an acute treatment is inadequate is straightforward when intolerance is present (assuming dose reduction does not solve the problem). But when the agent is tolerated, at what point can one decide that the treatment is ineffective? The recent STAR*D trial found that one-half of those who remitted over a 14-week acute treatment period did so after 6 weeks, and one in three responded after 6 weeks. Patients slowest to respond or remit were more likely to have more severe depression or to have more comorbid anxiety or Axis III disorders. Thus, the decision point may vary depending on the patient. Clearly, a trial should not be declared as a failure until at least 6 weeks, and preferably 8 to 10 weeks, to ensure that those who can respond will have the opportunity to do so. As for augmentation, because remissions occur with monotherapy for up to 12 to 14 weeks, augmentation may be premature before 14 weeks.
The objectives of formal psychotherapy, when used alone to treat mood disorders, are identical to those for medication: (1) symptom remission, (2) psychosocial restoration, and (3) prevention of relapse and recurrence. When used in combination with medication, psychotherapies can also achieve additional objectives, such as reducing the secondary psychosocial consequences of the disorder (e.g., marital discord and occupational difficulties) or increasing medication adherence. Formal psychotherapy to address the psychosocial consequences of the disorder may include individual, family, couples, or occupational approaches. These types of therapy, when used in combination with medication, result in improvement of the targeted difficulty (e.g., marital counseling improves interpersonal conflicts).
Four forms of time-limited therapy have demonstrated efficacy in reducing or eliminating depressive symptoms (IPT, cognitive therapy, behavioral therapy, and cognitive-behavioral analytic system of psychotherapy [CBASP]). The latter is designed for the treatment of chronic depression, with efficacy demonstrated to be equivalent to medication in a 12-week, randomized, controlled acute phase trial.
There are no established clinical predictors by which to select from among these psychotherapies. Cognitive therapy may be somewhat less effective in those with more dysfunctional attitudes, and IPT may be somewhat less effective in those with more interpersonal problems. These predictors, however, lack the power to be clinically useful. Time-limited therapies are usually preferred over time-unlimited therapies for depressive symptom reduction, because time-limited therapies have established efficacy in RCTs, whereas time-unlimited therapies do not, and because medication is an effective alternative if psychotherapy alone fails.
Some believe that reconstructive (time-unlimited) psychotherapies are more useful in the treatment of Axis II disorders, whereas re-educative therapies may be more useful with Axis I conditions. There is no evidence, however, that psychotherapy alone is preferred over medication when there is a concurrent Axis II disorder. On the other hand, different psychotherapeutic tactics may be called for in the medication management of depressed patients with Axis II conditions to ensure adherence. Logically, psychotherapy, if used alone, should be tried for a finite time period, and symptomatic outcomes should be evaluated, just as with any medication trial.
The combination of medication and formal psychotherapy at the outset of acute phase treatment would be called for if (1) there is a chronic course to the depressive illness; (2) formal psychotherapy is used to increase adherence, while medications are used for symptom control; or (3) if the targets of each treatment were defined as somewhat distinct, and both were in need of early remediation (e.g., medication for depressive symptoms and psychotherapy for marital problems). In addition, clinical impression suggests that combination treatment may be preferable to treatment alone (1) when there is a coexisting Axis II disorder; (2) when the patient is discouraged and demoralized, as well as clinically depressed; or (3) when the depression is treatment resistant to medications alone based on prior history.
For those with atypical symptom features, there is strong evidence that tricyclic antidepressant agents are less effective than the monoamine oxidase inhibitors (MAOIs). There is some suggestive evidence for the efficacy of the SSRIs or bupropion (Wellbutrin) in atypical depression. Thus, in general, the nonmood disorder dictates the choice of treatment. Recent evidence from STAR*D found that when concurrent, comorbid anxiety disorders are present, remission rates may be lower, no matter what medication is selected.
About 45 to 60 percent of outpatients with nonpsychotic major depressive disorder who have minimal psychiatric and general medical comorbidity and a nonchronic and non-treatment-resistant prior history who begin treatment with medication or psychotherapy, or a combination of the two, respond (i.e., achieve at least a 50 percent reduction in baseline symptoms). Only 35 to 50 percent achieve remission (i.e., the virtual absence of depressive symptoms). Consequently, at least one-half of patients should anticipate a second treatment trial (i.e., if the initial treatment is poorly tolerated or ineffective
Extending the initial trial further is indicated if (1) the initial trial is less than 6 weeks, (2) there is a partial response (≥25 percent reduction in pretreatment depressive symptom severity) by 6 weeks, or (3) prior medication trials have been unsuccessful and shorter than 6 weeks
The choice between switching from the initial single treatment to a new single treatment (as opposed to adding a second treatment to the first one) rests on the philosophy guiding the clinician, the patient's prior treatment history, the degree of benefit and side-effect burden with the initial treatment, other clinical issues, and patient preference. The best documented augmentation strategies involve inexpensive medicines (e.g., lithium [Eskalith] or thyroid hormone), and response, if it occurs, is often within 2 to 4 weeks. Conversely, a switching strategy, in some cases, involves a washout period (e.g., switching from fluoxetine [Prozac] to an MAOI) for safety reasons, as well as the need to wait longer than 2 weeks to attain a full effect. Alternatively, how long to continue augmentation is not clear, and lithium augmentation entails some expense and inconvenience
If the initial trial is the patient's first treatment and if other clinical or economic reasons favor a single treatment, then switching rather than augmenting is preferred. On the other hand, augmentation strategies seem to be preferred with patients who have gained some benefit with the initial treatment but who have not achieved remission. Thus, switching might be preferable for those with only one or two prior treatment attempts or no meaningful benefit from the initial treatment, whereas augmentation may be preferable for those who have not benefited sufficiently from several single treatment trials. Recent reviews indicate that, if the initial medication is ineffective or cannot be tolerated, a reasonable step in primary care is to switch medication classes. In psychiatric settings, augmentation may be more likely to be called for, because more psychiatric patients have not benefited from several adequate prior single treatments.
Choosing more sedating antidepressants (e.g., amitriptyline [Elavil, Endep]) for more anxious depressed patients or more activating agents (e.g., desipramine) for more psychomotor-retarded patients is not based on evidence of differential efficacy. Some clinicians believe, however, that such choices, based on side-effect profile, increase adherence in the initial weeks of treatment. That is, patients with marked insomnia and anxiety feel some immediate relief from these associated symptoms before the full antidepressant effect of the drug appears, and they therefore are thought to be more likely to comply with acute phase treatment. These clinical observations are not supported by empirical data, however. In fact, attrition associated with paroxetine (Paxil) or fluoxetine (less sedating drugs) is lower in acute phase treatment than attrition with imipramine or amitriptyline (more sedating drugs)
