Acute Major Depression

In patients receiving antidepressants for acute major depression, the initial therapeutic response is often delayed by several weeks. Patients with severe anxiety or insomnia may benefit from the concurrent, time-limited use of a benzodiazepine or short-acting hypnotic (Chapter 3). A patient may initially experience a return of energy and motivation while still having feelings of hopelessness and excessive guilt. Such patients may be at an increased risk for suicide because a return of energy in an extremely dysphoric individual may provide the impetus and means for an act of self-destruction. 

It is a clinical challenge to distinguish symptoms of the illness from medication side effects. Many symptoms that patients attribute to antidepressant treatment—such as constipation, poor memory or concentration, nausea or vomiting, diarrhea, difficulty 

An adequate trial of antidepressant medication is defined as treatment with therapeutic doses of a drug for a total of 4 weeks. After 4 weeks of antidepressant treatment, patients can be divided into three groups those who have achieved a full response, those who have achieved a partial response, and those who have not responded. In the case of patients who achieve full remission, treatment should continue for a minimum of 4-6 months, or longer if the patient has a history of recurrent depression (see Maintenance Treatment of Major Depression later in this chapter). If a partial response has been achieved by 4 weeks, a full response may be evident within an additional 2 weeks without further intervention. If the symptoms do not respond at all, the dose should be increased, a different antidepressant should be used, or the therapy should be augmented with another medication (see Treatment-Resistant Depression later in this chapter). 

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Paroxetine in the Treatment of Acute Major Depression in Adults A Systematic Re-Examination of Published and Unpublished Data from Randomized Trials , Canadian Medical Association Journal 178, no. 3 (2008) 296-305... 

TREATMENT OF SPECIFIC DISORDERS Acute Major Depression... 

Discontinuation of antidepressant medication should be concordant with the guidelines for treatment duration (see Acute Major Depression subsection in the preceding section). It is advisable to taper the dose while monitoring for signs and symptoms of relapse. Abrupt discontinuation is also more likely to lead to antidepressant discontinuation symptoms, often referred to as withdrawal symptoms. The occurrence of these symptoms after medication discontinuation does not imply that antidepressants are addictive. 

Levkovitz. Y., Caftori, R., Avital, A., Richter-Levin. G. The SSRI drug fluoxetine, but not the noradrenergic tricyclic drug desipramine, improves memory performance during acute major depression. Brain Res. Bull. 58, 345-350, 2002. 

A 35-year-old man was recently started on an antidepressant medication to treat his acute major depressive episode. Which of the following medications is most likely the antidepressant medication that is contributing to his insomnia ... 

LF sometimes is used as an alternative or adjunct to antidepressants in severe, especially melancholic, recurrent depression, as a supplement to antidepressant treatment in acute major depression, including in patients who present clinically with only mild mood elevations or hypomania (bipolar II disorder), or as an adjunct when later response to an antidepressant alone is unsatisfactory. In major affective disorders, LT has stronger evidence of reduction of suicide risk than any other treatment. Clinical experience also suggests the utility of IF in the management of childhood disorders that are marked by adult-like manic depression or by severe changes in mood and behavior, which are probable precursors to bipolar disorder in adults. Evidence of efficacy of Li in many additional episodic disorders (e.g., premenstrual dysphoria, episodic alcohol abuse, and episodic violence) is unconvincing. 

There is little evidence to support the addition of lithium to ongoing APD and/or antidepressant treatment for the emergence of acute major depressive disorder. 

Since the typical major depressive episode lasts 6 months or longer, if antidepressant therapy is interrupted for any reason following the acute phase, the patient may relapse into the depressive episode. When treating the first depressive episode, antidepressants must be given for an additional 4 to 9 months in the continuation phase for the purpose of preventing relapse. 

Bauer M et al. (2002). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. Part 1 Acute and continuation treatment of major depressive disorder. World Journal of Biological Psychiatry, 3, 5-43. 

The efficacy of psychotherapy and antidepressants is considered to be additive. Psychotherapy alone is not recommended for the acute treatment of patients with severe and/or psychotic major depressive disorders. For uncomplicated nonchronic major depressive disorder, combined treatment may provide no unique advantage. Cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear to be equal in efficacy. 

Maintenance/Continuation/Extended treatment - Acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Periodically reassess patients to determine the need for maintenance treatment and the appropriate dose for such treatment. 

The first report on cortisol levels in PTSD was that of Mason et al. who found that the mean 24-h urinary excretion of cortisol was significantly lower in combat Vietnam veterans with PTSD compared to psychiatric patients in four other diagnostic groups (Mason et al. 1986). The authors noted surprise at the fact that cortisol levels were low, since certain clinical features such as depression and anxiety [in PTSD] might have been expected to be associated with increased activity of the pituitary-adrenal cortical system. Since this initial observation, the majority of the evidence supports the conclusion that cortisol alterations in PTSD are different from those observed in acute and chronic stress, and major depression, but more importantly, that the HPA axis appears to be regulated differently. 

Studies at the National Institutes of Health (NIH) have detailed the clinical characteristics of patients in the PANDAS subgroup (Swedo et al., 1998). The rate of neuropsychiatric comorbidity in this population is quite striking. Twenty of the 50 children (40%) met DSM-IV criteria for ADHD and/or oppositional defiant disorder (ODD), 18 (36%) for major depressive disorder, 14 (28%) for overanxious disorder, and 10 (20%) for separation anxiety disorder. Six children (12%) were enuretic, often episodically and closely correlated with periods of OCD and tic exacerbations. Depressive symptoms, ADHD, and separation anxiety disorder also waxed and waned in concert with the OCD/ tic symptoms. In addition, exacerbations of OCD and tics were accompanied frequently by the acute onset of choreiform movements (clinically distinct from chorea), emotional lability and irritability, tactile/sensory defensiveness, motoric hyperactivity, messy handwriting, and symptoms of separation anxiety (Perlmutter et al., 1998 Becker et al., 2000). 

It is important to note that specific psychotherapies (CBT or IPT) (Brent et ah, 1997 Mufson et ah, 1999) are also reasonable initial choices for the acute treatment of a youth with the first noncomplicated episode of major depression. Nevertheless, if patients are treated with psychotherapy alone, pharmacotherapy... 

FIGURE 36.1 Major depressive disorder—acute treatment phase. 

There are several controlled trials of young outpatients with bipolar and bipolar spectrum conditions. Geller et al. (1998) studied 25 adolescents in a 6-week, doubleblind, placebo-controlled study. Twelve received lithium, of whom 4 had BP-I (presumably acute mania), 4 had BP-II (presumably hypomania), and 4 had major depression with bipolar predictors. All had concurrent substance abuse. There were no significant differences in outcome between active and placebo groups, except in... 

Keller MB, Hanks DL Course and outcome in panic disorder and depression. J Clin Psychopharmacol Biol Psychiatry 17 551-570, 1993 Keller MB, Shapiro RW Double depression superimposition of acute depressive episodes on chronic depressive disorders. Am J Psychiatry 139 438-442, 1982 Keller MB, Shapiro RW, Lavori PW, et al Recovery in major depressive disorder analysis with the life table and regression models. Arch Gen Psychiatry 39 905-910, 1982a... 

Furthermore, most psychiatric disorders are chronic, although some may go through intervals of apparent remission (e.g., major depressive disorder), whereas others are persistent but relatively asymptomatic (e.g., schizophrenia) with effective treatment. Flence, treatment with psychotropics is best considered in terms of months or years of continuous or intermittent therapy, rather than a few days or weeks. By contrast, the vast majority of the clinical trials involve short-term use. Thus, a typical database for the approval of a new antidepressant is usually based on experience with 2,000 to 8,000 patients (carefully selected as described earlier), with the majority exposed to the medication for less than 2 months. Often less than 25% will have received medication for more than 4 months, and less than 10% for more than 6 months. When a drug is marketed, most patients will be exposed to it for a minimum of 4 to 6 months. Yet, when treatment goes beyond 2 months, the database on the safety and continued efficacy of a medication is modest at best. Thus, although clinicians commonly use psychotropics for both maintenance and prophylactic purposes, an approved drug only has to be shown effective in the acute phase. 

Patients with SAD have been found to be resistant to exacerbation of depressive symptoms following acute tryptophan depletion ( 32), suggesting that dysfunction of central serotonin mechanisms may be less relevant to the pathophysiology of SAD than other forms of major depression. 

Our approach to both acute and maintenance therapy is consistent with the American Psychiatric Association guidelines for the treatment of major depressive disorder in adults (292). 

In addition, a number of studies have compared the efficacy of specific forms of psychotherapy, particularly cognitive-behavioral therapy (CBT), and antidepressants in the treatment of patients with an acute episode of major depression (388, 389, 390, 391, 392, 393, 394 and 395). Most studies have reported these forms of psychotherapy and antidepressants to be equally effective. As a result of disparate findings, spirited debate has arisen with regard to this issue. Issues raised in this debate have included relative efficacy in patients with mild versus more severe episodes of major depression and the adequacy of antidepressant treatment in these studies. A summary of these issues is presented in the following paragraphs. 

Another source of evidence supporting the neurotrophic hypothesis of depression comes from studies of the direct effects of BDNF on emotional regulation. Direct infusion of BDNF into the midbrain, hippocampus, and lateral ventricles of rodents has an antidepressant-like effect in animal models. Moreover, all known classes of antidepressants are associated with an increase in BDNF levels in animal models with chronic (but not acute) administration. This increase in BDNF levels is consistently associated with increased neurogenesis in the hippocampus in these animal models. Other interventions thought to be effective in the treatment of major depression, including electroconvulsive therapy, also appear to robustly stimulate BDNF levels and hippocampus neurogenesis in animal models. 

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. 

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