Major Depressive Disorder


Phillip W. Long, M.D.
Updated: Feb. 9, 1998


The Pain of Depression Can Be Treated

"Every week a doctor commits suicide in North America, and each one knew that depression is potentially treatable or self-limiting; insight goes faster in depression than in any other illness. Depression is psychological pain, and a severe depressive illness is arguably the most unpleasant disease in the Western world bar rabies. Samuel Johnson once said he'd suffer a limb to be amputated to recover his spirits. An old clergyman who had recovered from a severe depression later badly scalded his genitals, thighs, and abdomen. When asked which type of pain was worse, he said, 'I would suffer the scalding a hundred times rather than have a depression again. Every night I pray to God to let me die before the depression returns. When I was scaled I prayed for relief and I was heard, but during the depression I lost my faith. There is no comparison between those two kinds of pain.'" [1]

A recent World Health Organization report predicts that depression will be the leading cause of disability and premature death in the industrial world by the year 2020. Without treatment, ten to fifteen percent of people suffering from severe Major Depressive Disorder commit suicide. With treatment, the majority of patients with this illness recover.

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What Therapy Is Best?

In 1990, 11 million people in the United States suffered from major depression, which annually cost the nation $44 billion. [2]

Thus, the treatment of major depression is literally a billion dollar industry. Surprisingly, little research has been done on the effectiveness of the different treatments for depression.

The best way to scientifically evaluate the effectiveness of therapy is to conduct a randomized controlled clinical trial. In these trials, patients are randomly assigned to treatment and control groups. Both the patient and the investigators are kept "blind" as to whether the patient is in the treatment or control group. Usually the control group receives a placebo (inactive) therapy. The clinical trial then waits to see if the treatment group does better than the control (placebo) group.

Here are the results of the few randomized controlled clinical trails that have been done:

Therapies for Severe Major Depression

Treatment Effectiveness Reference
Antidepressant medication Good [3]
Electroconvulsive therapy Good [4]
Lithium (for prevention) Good [5]
Anticonvulsant medication (for prevention) Good [6]
Interpersonal psychotherapy Fair [3]
Antianxiety medication Poor [7]
Cognitive therapy Poor [3]
Antipsychotic medication Unknown  
Stimulant medication Unknown  
Psychoanalytic psychotherapy Unknown  
Family therapy Unknown  
Group therapy Unknown  
Self-help groups Unknown  


Rating Scale for Treatment Effectiveness

Rating Definition
Unknown No randomized controlled clinical trials to support any claims
Poor 0-24% improvement No better than placebo therapy
Fair 25-49% improvement Mildly better than placebo therapy
Good 50-74% improvement Moderately better than placebo therapy
Excellent 75-100% improvement Markedly better than placebo therapy

Psychotherapy or Pharmacotherapy?

In 1989, the National Institute of Mental Health (NIMH) completed the most careful study ever done comparing the success rates of psychotherapy vs. antidepressant drug therapy in the treatment of major depression.

Patients with major depression were assigned at random for 16 weeks to one of four treatments: an antidepressant drug (imipramine), a placebo pill (monitored by brief, supportive, weekly visits to a physician), interpersonal therapy, or cognitive behavioral therapy.

The interpersonal therapy focused on the immediate social context of the depression and the depressed person's relations with other people. The cognitive therapy focused on correcting the patient's negative thinking, irrational guilt and pessimism.

Most patients in all four groups improved during treatment. The major findings were surprising:[3]

What are the important implications of this National Institute of Mental Health study?

Psychological or Biological?

The dramatic success of antidepressant drug therapy for severe major depression has made many scientists question if depression has a strong biological, rather than psychological, basis.

Thus many are questioning whether genetics or stress plays the major role in causing major depression. Recent research has shown that both play a major role in major depression. [9]

Surprisingly, stress has been shown to play a major role in the patient's first two episodes of major depression, but not in later episodes. [10]

So what causes major depression?

It appears that major depression often requires stress to "get the ball rolling", but after a few episodes, the illness develops its own momentum and no longer needs stress to "keep rolling". This is a familiar pattern seen in many medical illnesses.

Thus, the treatment of major depression must address the major contribution that stress, genetics and temperament play in this disorder. Unfortunately, most current therapies lack this well-rounded approach.

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Psychosocial Therapies

Interpersonal Therapy

The National Institute of Mental Health studied interpersonal therapy as one of the most promising types of psychotherapy. Interpersonal therapy (IPT) is a short-term psychotherapy, normally consisting of 12 to 16 weekly sessions. It was developed specifically for the treatment of major depression, and focuses on correcting current social dysfunction. Unlike psychoanalytic psychotherapy, it does not address unconscious phenomena, such as defense mechanisms or internal conflicts. Instead, interpersonal therapy focuses primarily on the "here-and-now" factors that directly interfere with social relationships. [11]

Cognitive Behavioral Therapy

The National Institute of Mental Health studied cognitive behavioral therapy as the other most promising type of psychotherapy. The cognitive behavioral theory of depression states that the patient's excessive self-rejection and self-criticism causes major depression. This therapy seeks to correct these negative thoughts or dysfunctional attitudes in order to overcome the patient's pessimism and hopelessness. Homework assignments are given to break through the depressed patient's vicious cycle of increased negative thinking leading to increased social isolation which further increases the negative thinking.

A recent review of the scientific literature concluded that cognitive behavioral therapy for depression was promising, but not yet adequately tested. [12]

Recent research suggests that, for moderately to severely depressed patients, pharmacotherapy is superior to cognitive behavioral therapy (at 8 and 12 weeks). [13]

Critics of pharmacotherapy have argued that antidepressant medication only removes the symptoms of depression, but doesn't treat the patient's underlying dysfunctional attitudes.

Critics of cognitive behavioral therapy have argued that the depressed patient's pessimistic, negative thoughts are a result of their major depression, not its cause. Recent research has shown that pharmacotherapy of major depression removes these negative dysfunctional attitudes. [14]

Psychoanalytically Oriented Therapy

The psychoanalytic approach to treating major depression, unlike other psychotherapies, focuses on hypothesized unconscious phenomena, such as defense mechanisms or internal conflicts. This approach to psychotherapy analyzes the historical reasons why the patient has "turned anger inwards against the self" in becoming depressed. This focus on the patient's past is in direct contrast to the "here-and-now" focus of interpersonal therapy and cognitive behavioral therapy.

Psychoanalytic psychotherapy for major depression usually continues with one or more weekly visits for several years. Hence this form of psychotherapy is the most time-intensive and expensive of all the psychotherapies.

There is a surprising lack of any scientific research done on the effectiveness of psychoanalytic psychotherapy for major depression. A modified form of this technique, short-term psychodynamic psychotherapy, has yet to be scientifically proven effective. [15]

Family Therapy

Family therapy is not generally viewed as a primary therapy for the treatment of depression, but it is indicated for cases in which (1) the depression appears to be seriously jeopardizing the patient's marriage and family functioning or (2) a patient's depression appears to be promoted and maintained by marital and family interaction patterns. Family therapy examines the role of the depressed member in the overall psychological well-being of the whole family; it also examines the role of the entire family in the maintenance of the depression.

Patients with mood disorders have a very high rate of divorce, and approximately 50 percent of spouses report they would not have married the patient or had children had they known that the patient was going to have a mood disorder. Family therapy, therefore, can be a crucial and effective modality in the treatment of mood disorders. [16]

Medical Therapies

Major depression is as crippling as chronic heart disease, yet many severely ill depressed patients receive little or no antidepressant therapy. This needless suffering is tragic in this age of newer, highly effective, antidepressant medications. [17]


The first and most critical decision the therapist must make is whether to hospitalize a patient with major depression, or to attempt outpatient treatment.

Clear indications for hospitalization are: (1) risk of suicide or homicide, (2) grossly reduced ability to care for food, shelter, and clothing, and (3) the need for medical diagnostic procedures.

A patient with mild to moderate depression may be safely treated in the office if the therapist evaluates the patient frequently. The patient's support system should be strengthened and involved in treatment whenever possible.

Antidepressant Therapy

Antidepressant therapy for major depression can dramatically reduce suicide rates and hospitalization rates. [18]

Unfortunately, very few suicide victims receive antidepressants in adequate doses, and - even worse - most receive no treatment for depression whatsoever. [19] [20]

Most patients don't stay on their antidepressant medication long enough for it to be effective. A recent study found that only 25% of patients started on antidepressants by their family physician stayed on it longer than one month. [21]

General Guidelines For Prescribing Antidepressant Drugs (For Physicians)

Strategy For Initial Antidepressant Therapy (For Physicians)

Failure Of A Drug Trial (For Physicians)

If an antidepressant has been used for four weeks at maximal dosages without a therapeutic effect, the clinician should consider either: (1) trying another antidepressant, (2) supplementing the current antidepressant with lithium or liothyronine (T3 or L-triiodothyronine) (Cytomel), (3) supplementing the SSRI antidepressant with a tricyclic antidepressant, (4) supplementing or replacing the current antidepressant with carbamazepine (Tegretol), (5) supplementing the current antidepressant with d-amphetamine (Dexedrine) or methylphenidate (Ritalin), (6) supplementing the antidepressant with phototherapy if the patient has seasonal major depression, (7) supplementing the antidepressant with an antipsychotic medication if the patient has a psychotic major depression, (8) trying electroconvulsive therapy (ECT), or (9) stopping pharmacotherapy and proceeding only with psychotherapy.

Research has shown that adding lithium or liothyronine (T3 or L-triiodothyronine) (Cytomel) to an antidepressant often is successful in overcoming nonresponse. The addition of 25-50 mcg/day of liothyronine (T3 or L-triiodothyronine) (Cytomel) to an antidepressant regimen for 7 to 14 days may convert antidepressant nonresponders into responders. The adverse effects of T3 are minor but may include a headache and feeling warm. If T3 augmentation is successful, the T3 should be continued for two months and then tapered at the rate of 12.5 mcg a day every three to seven days. [36] [37]

Recently, research is showing that combination of a SSRI antidepressant with a tricyclic antidepressant markedly improves the outcome. [38]

More recently, the anticonvulsants carbamazepine (Tegretol) and valproate (Epival, Depakote, Depakene) have been found effective in preventing the return of major depression [6] [39]. Two psychostimulants, d-amphetamine (Dexedrine) and methylphenidate (Ritalin), have also been found to be effective in the treatment of major depression when used to augment antidepressant medication [40].

Patients with seasonal (winter) major depression often benefit from bright light phototherapy. [41]

Patients with psychotic depression usually require an antipsychotic medication in addition to their antidepressant regimen. The antipsychotic medication can be tapered and stopped when the psychosis has subsided. [42]

When rapid lifting of the depression is deemed necessary to prevent suicide, electroconvulsive therapy may be a treatment of choice. Research, however, has yet to show that ECT is superior to antidepressant medication. [4]

Ordinary ECT treatment should be unilateral, on the nondominant side, and should be given for several sessions beyond remission of the depressive symptoms. Stopping the treatments as soon as remission occurs is associated with a higher incidence of relapse. The total number of treatments is usually between eight and 12, given at a rate of about three per week. ECT may be given in combination with antidepressant or antipsychotic drugs. ECT may cause severe confusion (delirium) when used in combination with lithium. [43]

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  1. Morrant JCA: Depression And Some Newer Antidepressants. BC Medical Journal 1997; 39(12):636-640. Depression is the commonest medical illness and is probably a syndrome with different causes. It can be difficult to diagnose because it can masquerade as physical pain affecting various systems. Many diseases can also masquerade as a depressive illness, and depression can be a side effect of many drugs. The treatment of depression is evolving, and antidepressant medicines are a major part of the therapeutic armamentarium. The newer antidepressants are no more powerful than older types, but they have fewer side effects and are better tolerated and safer. Interactions with other drugs can cause the serotonin syndrome and other potentially fatal pharmacological responses, so physicians should prescribe cautiously and start with lower doses.

  2. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER: Depression: A Neglected Major Illness. Journal of Clinical Psychiatry 1993; 54(11):419-24. BACKGROUND: To illustrate the burden depression imposes on society, the present estimates of the annual costs of depression--$44 billion--as well as the number of individuals it affects per year--almost 11 million. Although these estimates point to depression as a major illness, this study examines why it is not generally considered as such by the medical and public health communities or by society at large. METHOD: We develop a framework that compares depression with major illnesses such as coronary heart disease, cancer, and AIDS by highlighting salient characteristics of each illness. This comparative illness framework considers the costs, prevalence, distribution of sufferers, mortality, recognition, and treatability of each disease. This comparison underscores many of the similarities and differences among the illnesses examined. RESULTS: Because depression often is not properly recognized and begins to affect many people at a relatively early age, it exacts costs over a longer period of time and in a more subtle manner than other major illnesses. It also imposes a particularly heavy burden on employers in the form of higher workplace costs. CONCLUSION: We conclude that, because of the potential for successful treatment, increased attempts to reach untreated sufferers of depression appear to be warranted. Employers as a group have a particular incentive to invest in the recognition and treatment of this widespread problem, in order to reduce the substantial costs it imposes upon them each year.

  3. Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass DR, Pilkonis PA, Leber WR, Docherty JP, et al: National Institute Of Mental Health Treatment Of Depression Collaborative Research Program. General Effectiveness Of Treatments. Arch Gen Psychiatry 1989; 46(11):971-82. Summary: We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depression disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed significant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on initial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.

  4. Piper A Jr: Tricyclic Antidepressants Versus Electroconvulsive Therapy: A Review Of The Evidence For Efficacy In Depression. [Review]. Annals of Clinical Psychiatry 1993; 5(1):13-23. Summary: The author examines the thesis that electroconvulsive therapy is superior to tricyclic antidepressants in treating nonpsychotic major depression. Every study published in English since 1960 comparing electroconvulsive therapy against tricyclics in treating this condition was reviewed. Because of numerous methodological weaknesses in the studies, the data is inadequate to support the claim that one treatment is superior to the other. [References: 70]

  5. Souza FG, Goodwin GM: Lithium Treatment And Prophylaxis In Unipolar Depression: A Meta-Analysis. Br J Psychiatry 1991; 158:666-75. Summary: Meta-analysis was used to establish the efficacy of lithium in acute treatment and prophylaxis of depressive illness from existing published clinical trials. Effect sizes were measured by the odds ratio using the Mantel-Haenszel method and the Pearson product-moment correlation coefficient. Some benefit from lithium, compared with other treatments, emerged from trials of acute treatment. Lithium was clearly superior to placebo in the acute treatment of bipolar depressed patients. In controlled studies of lithium prophylaxis over five months to three years, an impressive effect was found for lithium when compared with placebo. For uncontrolled studies there was a similar-sized effect, corresponding to an improvement in the rate of favourable outcome from 35% for placebo to 70% with lithium treatment. The comparison of lithium with other antidepressants in prophylaxis showed no conclusive advantage for lithium in unipolar illness. There is no reason to doubt the efficacy of lithium in the prophylaxis of unipolar depressive illness.

  6. Stuppaeck CH, Barnas C, Schwitzer J, Fleischhacker WW: Carbamazepine In The Prophylaxis Of Major Depression: A 5-Year Follow-Up. Journal of Clinical Psychiatry 1994; 55(4):146-50. BACKGROUND: The prophylaxis of unipolar depression is still controversial. Some physicians prefer lithium, others maintenance treatment with antidepressants. The role of carbamazepine remains unclear. Only a few patients have been described in the literature; most are lithium nonresponders or rapid cyclers. METHODS: In an open-label naturalistic study, 15 patients suffering from major depression with melancholia (DSM-III, 296.2, 296.3) and receiving long-term prophylaxis with carbamazepine were followed for 5 years. Four had been pretreated with lithium without satisfactory effects, 11 were prophylaxis naive. We compared the number of depressive episodes before and during carbamazepine treatment. RESULTS: The mean time span patients received carbamazepine was 49.5 months. Seventy-three percent (11 of 15) of the patients gained substantial benefit from carbamazepine. Side effects were infrequent. CONCLUSION: Our results encourage further controlled and prospective studies using carbamazepine for maintenance treatment of patients with unipolar major mood disorder.

  7. Hubain PP, Castro P, Mesters P, De Maertelaer V, Mendlewicz J: Alprazolam And Amitriptyline In The Treatment Of Major Depressive Disorder: A Double-Blind Clinical And Sleep EEG Study. J Affective Diss 1990; 18(1):67-73. Summary: This study was designed to compare the antidepressant effects of alprazolam and amitriptyline in a group of 30 inpatients suffering from a severe major endogenous depression, diagnosed by Research Diagnostic Criteria and the Newcastle Rating scale, and to examine the effects of alprazolam and amitriptyline on two biological markers of depression, the dexamethasone suppression test and sleep EEG parameters. The 6-week study was double-blind with a random allocation of treatment. Patients were treated with flexible doses of 4-9 mg of alprazolam and 100-225 mg of amitriptyline. After 4 weeks of treatment the antidepressant effects of amitriptyline significantly exceeded those of alprazolam, as measured on the Hamilton Rating Scale for Depression. There was a high drop-out rate in the alprazolam group because of ineffectiveness of treatment. Alprazolam showed similar effects on sleep parameters as amitriptyline: lengthening of the REM latency and a tendency to shorten stages 3 and 4 and stage REM. These negative clinical results should be interpreted with caution, because of the severity of our selection criteria, and should not be extended to all depressive disorders.

  8. Shea MT, Elkin I, Imber SD, Sotsky SM, Watkins JT, Collins JF, Pilkonis PA, Beckham E, Glass DR, Dolan RT, et al: Course Of Depressive Symptoms Over Follow-Up. Findings From The National Institute Of Mental Health Treatment Of Depression Collaborative Research Program. Archives of General Psychiatry 1992; 49(10):782-7. Summary: We studied the course of depressive symptoms during an 18-month naturalistic follow-up period for outpatients with Major Depressive Disorder treated in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. The treatment phase consisted of 16 weeks of randomly assigned treatment with the following: cognitive behavior therapy, interpersonal therapy, imipramine hydrochloride plus clinical management (CM), or placebo plus CM. Follow-up assessments were conducted at 6, 12, and 18 months after treatment. Of all patients entering treatment and having follow-up data, the percent who recovered (8 weeks of minimal or no symptoms following the end of treatment) and remained well during follow-up (no Major Depressive Disorder relapse) did not differ significantly among the four treatments: 30% (14/46) for those in the cognitive behavior therapy group, 26% (14/53) for those in the interpersonal therapy group, 19% (9/48) for those in the imipramine plus CM group, and 20% (10/51) for those in the placebo plus CM group. Among patients who had recovered, rates of Major Depressive Disorder relapse were 36% (8/22) for those in the cognitive behavior therapy group, 33% (7/21) for those in the interpersonal therapy group, 50% (9/18) for those in the imipramine plus CM group, and 33% (5/15) for those in the placebo plus CM group. The major finding of this study is that 16 weeks of these specific forms of treatment is insufficient for most patients to achieve full recovery and lasting remission. Future research should be directed at improving success rates of initial and maintenance treatments for depression.

  9. Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ: The Prediction Of Major Depression In Women: Toward An Integrated Etiologic Model. American Journal of Psychiatry 1993; 150(8):1139-48. OBJECTIVE: The authors develop an exploratory, integrated etiologic model for the prediction of episodes of major depression in an epidemiologic sample of women. METHOD: Both members of 680 female-female twin pairs of known zygosity from a population-based register were assessed three times at greater than 1-year intervals. The last two assessments included a structured interview evaluation for presence of episodes of major depression, defined by DSM-III-R, in the preceding year. The final structural equation model contained nine predictor variables: genetic factors, parental warmth, childhood parental loss, lifetime traumas, neuroticism, social support, past depressive episodes, recent difficulties, and recent stressful life events. RESULTS: The best-fitting model predicted 50.1% of the variance in the liability to major depression. The strongest predictors of this liability were, in descending order, 1) stressful life events, 2) genetic factors, 3) previous history of major depression, and 4) neuroticism. While 60% of the effect of genetic factors on the liability to major depression was direct, the remaining 40% was indirect and mediated largely by a history of prior depressive episodes, stressful life events, lifetime traumas, and neuroticism. The model suggested that at least four major and interacting risk factor domains are needed to understand the etiology of major depression: traumatic experiences, genetic factors, temperament, and interpersonal relations. CONCLUSION: Major depression is a multifactorial disorder, and understanding its etiology will require the rigorous integration of genetic, temperamental, and environmental risk factors.

  10. Ezquiaga E, Ayuso Gutierrez JL, Garcia Lopez A: Psychosocial Factors And Episode Number In Depression. J Affective Dis 1987; 12(2):135-8. Summary: We studied the relationship between 2 types of psychosocial factors, life events and chronic stress, and the numerical order of the depressive episodes. The population studied consisted of 97 subjects suffering from major depressive disorder and 65 controls. Life events occurred with the first 2 depressive episodes with significantly higher frequency than with later episodes or with the control group. Patients in the third or later episode had no more life events than controls. No significant differences were apparent in the incidence of chronic stress in the different depressive episodes of the patient group or in the comparison of this group with controls. No second order interaction between life events and chronic stress was found.

  11. Weissman MM, Markowitz JC: Interpersonal Psychotherapy. Current Status. Archives of General Psychiatry 1994; 51(8):599-606. Summary: Interpersonal psychotherapy (IPT), a time-limited treatment for major depression, was developed, defined in a manual, and tested in randomized clinical trials by the late Gerald L. Klerman, MD, and collaborators. It has subsequently been modified for different age groups and types of mood and nonmood disorders and for use as a long-term treatment. Having begun as a research intervention, IPT has yet to be well disseminated among clinicians or in residency training programs. The publication of efficacy data, the recent appearance of two practice guidelines that include IPT among treatments for depression, and the interest in defined treatments for managed care have led to increasing requests for information and training. [References: 53]

  12. Hollon SD, Shelton RC, Davis DD: Cognitive Therapy For Depression: Conceptual Issues And Clinical Efficacy. Journal of Consulting & Clinical Psychology 1993; 61(2):270-5. [REVIEW] Summary: Cognitive therapy has emerged as 1 of the most promising psychosocial interventions for the treatment of depression. It appears to be at least the equal of alternative interventions (including pharmacotherapy) with respect to acute treatment. In addition, there are indications that it may reduce risk of symptom return after treatment termination. Nonetheless, design limitations reduce the certainty with which such conclusions can be drawn. Furthermore, tests of its efficacy have largely been limited to nonbipolar outpatient (or subclinical) samples. At this time, cognitive therapy is best considered a promising, but as yet not adequately tested, intervention for the treatment of depression. [References: 60]

  13. Watkins JT, Leber WR, Imber SD, Collins JF, Elkin I, Pilkonis PA, Sotsky SM, Shea MT, Glass DR: Temporal Course Of Change Of Depression. Journal of Consulting & Clinical Psychology 1993; 61(5):858-64. Summary: Two hundred fifty moderately to severely depressed outpatients were randomly assigned to 16 weeks of cognitive-behavioral therapy, interpersonal psychotherapy, imipramine plus clinical management, or pill placebo plus clinical management. Two hundred thirty-nine patients actually began treatment. The most rapid change in depressive symptoms occurred in the imipramine plus clinical management condition, which achieved significantly better results than the other treatments at 8 and 12 weeks on 1 or more variables. Change over the course of treatment on variables hypothesized to be most specifically affected by the respective treatments was found only in the case of pharmacotherapy, in which imipramine produced significantly greater changes on the endogenous measure at 8 and 12 weeks.

  14. Fava M, Bless E, Otto MW, Pava JA, Rosenbaum JF: Dysfunctional Attitudes In Major Depression. Changes With Pharmacotherapy. Journal of Nervous & Mental Disease 1994; 182(1):45-9. Summary: High levels of dysfunctional attitudes have been associated with greater severity of depression and poorer response to pharmacological treatment. The goal of our study was to examine this relationship and the changes in dysfunctional attitudes after treatment with fluoxetine, a relatively selective serotonin uptake inhibitor. Dysfunctional attitudes were evaluated with both the Cognitions Questionnaire (CQ) and the Dysfunctional Attitudes Scale (DAS) in 115 outpatients diagnosed as having major depressive disorder. After 8 weeks of treatment with fluoxetine, 67 of these patients again completed the DAS and the CQ. Dysfunctional attitudes were associated with depression severity both before and after treatment and decreased linearly with treatment of the depression. Negative thinking and dysfunctional attitudes, as measured by both DAS and CQ, were not predictive of the degree of improvement in depressive symptoms. These findings partly support a state-dependent interpretation of dysfunctional attitudes, and provide evidence of significant reductions in these attitudes after treatment with a serotonin uptake inhibitor.

  15. Svartberg M, Stiles TC: Comparative Effects Of Short-Term Psychodynamic Psychotherapy: A Meta-Analysis. Journal of Consulting & Clinical Psychology 1991; 59(5):704-14. Summary: In a review of 19 clinically relevant comparative outcome studies published 1978-1988, short-term psychodynamic psychotherapy was evaluated as to overall effects, differential effects, and moderating effects vis-a-vis no-treatment controls and alternative psychotherapies, respectively. Overall, short-term psychodynamic psychotherapy was superior to no-treatment controls at posttreatment, inferior to alternative psychotherapies at posttreatment, and even more so at 1-year follow-up. Short-term psychodynamic psychotherapy was inferior to alternative psychotherapies in treating depression and, in particular, to cognitive-behavioral therapy for major depression. Short-term psychodynamic psychotherapy was equally successful with mixed neurotics. As research quality increased, short-term psychodynamic psychotherapy grew less superior to no-treatment controls. Furthermore, short-term psychodynamic psychotherapy decreased its overall superiority over no-treatment controls and increased its overall inferiority to AT on a series of clinically relevant variables. Improvement in research quality from 1978 to 1988 was noted. Evidence, although limited, supported the view that short-term psychodynamic psychotherapy approaches do seem to differ along a few major dimensions.

  16. Beardslee WR, Hoke L, Wheelock I, Rothberg PC, van de Velde P, Swatling S: Initial Findings On Preventive Intervention For Families With Parental Affective Disorders. American Journal of Psychiatry 1992; 149(10):1335-40. OBJECTIVE: The purpose of this study was to develop a clinician-based cognitive, psychoeducational, preventive intervention for families with parental affective disorder that would be suitable to widespread use, test its feasibility and safety, and define the areas affected by the intervention. The intervention was designed to increase understanding of parental illness and resilience in the children. METHOD: The authors studied the first seven families (14 parents) to receive the intervention. Enrollment criteria included affective disorder during the preceding year in at least one parent, presence of at least one child between the ages of 8 and 14 years who was not psychiatrically ill at the time of participation, and willingness to participate in the research study. The intervention consisted of parent, child, and family sessions. Assessment included semistructured interviews with parents about affective disorders, standard ratings of marital satisfaction and therapeutic alliance, and a recently developed semistructured interview to assess response to the intervention. RESULTS: Overall satisfaction with the intervention was rated moderate to high by parents. No harm was reported. Ten of 14 parent subjects reported five or more behavior and attitude changes that they attributed to the intervention. The most frequent behavior and attitudinal changes reported were increased discussion of the illness and related issues and increased understanding of information about affective illness. CONCLUSION: The authors conclude that the intervention is safe and feasible in families with parental affective disorder.

  17. Stokes PE: Current Issues In The Treatment Of Major Depression. [Review]. Journal of Clinical Psychopharmacology 1993; 13(6 Suppl 2):2S-9S. Summary: Major depression is a common psychiatric disorder associated with considerable suffering for individuals and their families. Indeed, the Medical Outcomes Study reported that the degree of physical and social impairment and the use of health care resources among patients with diagnosable depressive disorders is comparable only to that with chronic cardiac disease. In addition, recent studies in the United States and by the Cross-National Collaborative Group suggest that the cumulative lifetime incidence of major depression is increasing, with the more recent birth cohorts at increased risk. Unfortunately, major depression remains an underdiagnosed and undertreated condition. Evidence from the National Institute of Mental Health (NIMH) Collaborative Depression Study suggests that significant numbers of depressed patients receive little or no antidepressant therapy, despite the availability of effective treatments. Data from the NIMH Collaborative Depression Study further indicate that depression is a chronic and recurrent disorder. The diagnosis and treatment of depression in the elderly remain a significant challenge. Concomitant medical illness frequently obscures the diagnosis, and as a result, large numbers of depressed elderly go untreated. Although there is evidence that pharmacotherapy generally is as effective in the elderly as in younger adults, problems with side effects and compliance may limit the usefulness of some agents. Further investigation is needed to evaluate the effectiveness of antidepressant drugs in the very old and in those with concomitant medical illness. [References: 30]

  18. Rutz W, von Knorring L, Walinder J: Long-term Effects of an Educational Program For General Practitioners Given By The Swedish Committee For The Prevention And Treatment Of Depression. Acta Psychiatrica Scandinavica 1992; 85(1):83-8. Summary: In 1983-1984 the Swedish Committee for the Prevention and Treatment of Depression offered an educational program on diagnosis and treatment of depressive disorders to all general practitioners on the island of Gotland. The program has been carefully evaluated; 1982 was used as the baseline and the main evaluation was carried out in 1985. After the educational programs, the frequency of sick leave for depressive disorders decreased, the frequency of inpatient care for depressive disorders decreased to 30% of that at the baseline; the prescription of antidepressants increased, but prescription of major tranquilizers, sedatives and hypnotics decreased. The frequency of suicide on the island decreased significantly. This study describes the long-term effects. In 1988, 3 years after the project ended, the inpatient care for depressive disorders increased, the suicidal rate returned almost to baseline values and the prescription of antidepressants stabilized. Thus, the effects were strictly related in time to the educational programs, indicating that the effects were real and not only a coincidence with local trends on Gotland. Furthermore, the results indicate that educational programs that can have pronounced effects on the health care system have to be repeated approximately every 2 years if long-term effects are to be expected.

  19. Isacsson G, Boethius G, Bergman U: Low Level Of Antidepressant Prescription For People Who Later Commit Suicide: 15 Years Of Experience From A Population-Based Drug Database In Sweden. Acta Psychiatrica Scandinavica 1992; 85(6):444-8. Summary: The use of antidepressants has been low in Jamtland County for many years, while the suicide rate has been among the highest in Sweden. A continuous outpatient prescription recording system has been in operation in Jamtland since 1970. Through this system we traced the prescription pattern of 80 individuals who committed suicide from 1970 to 1984. Suicide patients obtained 1.5 times more prescription drugs than 80 matched controls, mainly psychotropics and vitamins. During the 3 months prior to the suicide, half of the patients had received medical attention and 73% of the women and 40% of the men had obtained prescription drugs, in one-third from the psychiatric department. While 53% and 29%, respectively, obtained psychotropic drugs, only 13% and 9% respectively were prescribed antidepressants, often in low doses. People who will commit suicide often seek medical help. The low rate of antidepressant prescription in patients committing suicide probably reflects insufficient diagnosis and treatment of depressive disorders. It is urgent--for the individual as well as for society--that diagnostic and pharmacotherapeutic routines be improved.

  20. Isometsa ET, Henriksson MM, Aro HM, Heikkinen ME, Kuoppasalmi KI, Lonnqvist JK: Suicide In Major Depression. American Journal of Psychiatry 1994; 151(4):530-6. OBJECTIVE: The purpose of this study was to examine a sample representing all suicide victims with current DSM-III-R major depression in Finland within 1 year in aspects relevant to suicide prevention, including comorbidity, clinical history, current treatment, suicide methods, and communication of suicide intent. METHOD: Using the psychological autopsy method, the authors examined all 71 suicide victims with current unipolar DSM-III-R major depression, taken from a random sample of 229 subjects representing 16.4% of all suicide victims in Finland in 1 year. RESULTS: The majority (85%) were complicated cases with comorbid diagnoses, and comorbidity varied according to the subjects' sex and age. Three-quarters had a history of psychiatric treatment, but only 45% were receiving psychiatric treatment at the time of death. Most suicide victims had received no treatment for depression. Only 3% had received antidepressants in adequate doses, 7% weekly psychotherapy, and 3% ECT. None of the 24 psychotic subjects had received adequate psychopharmacological treatment. Few (8%) had used an antidepressant overdose as a suicide method. Men had received less treatment for depression and had more commonly used violent suicide methods. CONCLUSION: Although about half of the suicide victims with major depression were receiving psychiatric care at the time of death, few were receiving adequate treatment for depression. There were significant sex differences in current and previous treatment and suicide methods. For suicide prevention in major depression, it would seem crucial to improve treatment and follow-up, for males with major depression, in particular.

  21. Simon GE, VonKorff M, Wagner EH, Barlow W: Patterns Of Antidepressant Use In Community Practice. General Hospital Psychiatry 1993; 15(6):399-408. Summary: Computerized pharmacy records from a large staff-model health maintenance organization were used to examine patterns of antidepressant use by primary care physicians and psychiatrists. Based on timing of prescription refills, patients treated by psychiatrists were more likely than those treated in primary care to continue medication for more than 30 days (35% vs 25%, p < 0.00001)

  22. Kapur S, Mieczkowski T, Mann JJ: Antidepressant Medications And The Relative Risk Of Suicide Attempt And Suicide .. JAMA 1992; 268(24):3441-5. BACKGROUND: Suicide by drug overdose is a major public health problem, and antidepressant medications are the most common agent involved. European studies suggest differences in the rates of suicide by overdose among antidepressants, but no reports have been published for the United States. We estimated the comparative risks of suicide attempts and suicides, and the relative risk of fatality in the event of an overdose for the major antidepressants currently marketed in the United States. METHOD: Information regarding suicide attempts and suicides by antidepressant overdose was obtained from the published reports of the Drug Abuse and Warning Network and the annual report of the American Association of Poison Control Centers, and corrected for differences in total annual prescriptions using data from the National Prescription Audit. RESULTS: The risk of a suicide attempt did not appear to differ among antidepressants. The tricyclic antidepressants were associated with a higher rate of death in the event of an overdose than the newer nontricyclic antidepressants in both the annual report of the American Association of Poison Control Centers and the Drug Abuse and Warning Network data. The chance of death after an overdose was greater for desipramine hydrochloride than for other tricyclics. CONCLUSION: The higher risk of suicide with tricyclics vs nontricyclics may be explained by a higher rate of death from overdose rather than more suicide attempts. Tricyclics carry the risk of greater cardiotoxicity. The basis for the even higher rate of death/overdose of desipramine is not known and requires further research. If these findings are replicated in a case-control study design, they have important implications for the choice of an antidepressant for the depressed patient at risk for suicidal behavior.

  23. Nemeroff CB: Evolutionary Trends In The Pharmacotherapeutic Management Of Depression. [Review]. Journal of Clinical Psychiatry 1994; 55 Suppl:3-15; discussion 16-7. Summary: The past decade has brought an exponential increase in our knowledge of the pharmacotherapeutic management of depression. Much has been learned about the prevalence, risks, and course of depression in the general population, the elderly, and patients with comorbid medical illnesses and about the biological basis of depression. This article reviews evolving trends in the diagnosis and management of depression and evaluates the main classes of antidepressants. Although depression carries a high risk of morbidity and mortality, it is very treatable, and early diagnosis and early treatment are now emphasized. Antidepressant medication is continued after the patients' acute depressive symptoms resolve, sometimes for as long as 1 to 5 years to prevent relapse and recurrence of depression; in addition, full doses, rather than lower doses of antidepressant are prescribed for maintenance therapy. The armamentarium of antidepressants too has changed. In addition to monoamine oxidase inhibitors and tricyclic and tetracyclic antidepressants, the serotonin reuptake inhibitors fluoxetine, sertraline, and paroxetine are now available, as well as a group of antidepressants with atypical mechanisms of action that includes bupropion, trazodone, venlafaxin, and nefazodone. Although comparable in efficacy to the tricyclic antidepressants, these new drugs are safer and better tolerated because they are believed to act selectively on specific neurotransmitter systems. [References: 78]

  24. Piccinelli M, Wilkinson G: Outcome Of Depression In Psychiatric Settings. [Review]. British Journal of Psychiatry 1994; 164(3):297-304. Summary: We reviewed follow-up studies of adults with depressive disorders seen in psychiatric settings, and noted outcomes in terms of recovery, recurrence, and persistent depression, at six months, one year, two to five years, and ten or more years after an index episode of depression. Recovery increased with time: about half recovered at least briefly by six months, and a large majority did so in the long term. Only about a quarter recovered from an index episode and remained well more than ten years thereafter. A quarter of patients suffered recurrence of depression within a year of an index episode, and three-quarters did so at least once during follow-up periods lasting more than ten years. For more than one in ten patients, the depression proved persistent, the proportion affected remaining relatively stable over time. The review highlighted a relative paucity of conclusive investigations on the outcome of the commonest psychiatric disorder in clinical settings. [References: 73]

  25. Greden JF: Antidepressant Maintenance Medications: When To Discontinue And How To Stop. [Review]. Journal of Clinical Psychiatry 1993; 54 Suppl:39-45; discussion 46-7. Summary: Most depressive disorders, once developed, have a lifetime course. For the majority of patients, the risk for future episodes increases as the number of past episodes increases. The length of the well interval between episodes becomes progressively shorter with each new episode. Those who are older at onset often have higher probabilities of relapse during future years if not maintained on treatment. As the number of episodes grows larger and the patient becomes older, severity often intensifies, treatment responsivity to conventional antidepressants may diminish or even disappear, and the destructive consequences of the disorder progressively worsen. This destructive lifetime pattern can be prevented in many if not most patients since antidepressant and other maintenance medications are being shown to be efficacious in preventing most future episodes of depression, and preserving quality of life. On the basis of these and other still-developing findings (and with the recognition that maintenance strategies have been inadequately tested in depressed children and adolescents), reasonable clinical wisdom might suggest that lifetime pharmacologic maintenance may be indicated for patients 50 years or older at first episode, 40 years or older with two or more prior episodes, or for those with three or more prior episodes. "Maintenance" dosages need to be comparable to established "treatment" dosages until it is proven that lower doses are efficacious; such data now are lacking. When medication is selected for long-term treatment, strong considerations should be given to the agent's side effect profile, since compliance is essential for success. [References: 29]

  26. Lonnqvist J, Sintonen H, Syvalahti E, Appelberg B, Koskinen T, Mannikko T, Mehtonen OP, Naarala M, Sihvo S, Auvinen J, et al: Antidepressant Efficacy And Quality Of Life In Depression: A Double-Blind Study With Moclobemide And Fluoxetine. Acta Psychiatrica Scandinavica 1994; 89(6):363-9. Summary: The efficacy of moclobemide (300-450 mg/day) was compared with fluoxetine (20-40 mg/day) in a double-blind, multicentre study in 209 patients with new episodes of depression selected from 612 consecutive depressed patients representative of those consulting psychiatric services in Finland. Antidepressant efficacy was assessed with the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale and Clinical Global Impression (CGI). The Medical Outcome Study Short-form General Health Survey (SF-20) and 15D Measure of Quality of Life were used to measure effectiveness in terms of health-related quality of life. Efficacy was evident with both drug treatments, with 67% in the moclobemide group and 57% in the fluoxetine group having a reduction in HDRS of more than 50%. Similarly, 77% of the patients in the moclobemide group and 67% in the fluoxetine group were assessed on the CGI as much better or very much better after 6 weeks of treatment. The most commonly reported adverse events were nausea, other gastrointestinal symptoms, nervousness, dizziness and sleep disorders. Nausea was significantly more common in the fluoxetine group and was found especially in women. Premature terminations of treatment were 18% in the moclobemide and 21% in the fluoxetine group. A significant change for the better in quality of life was found in both treatment groups, even at week 2 but especially after 6 weeks of treatment. Improvement was not only seen in dimensions measuring depression or mental health but also in other dimensions.

  27. Peet M: Induction Of Mania With Selective Serotonin Re-Uptake Inhibitors And Tricyclic Antidepressants. British Journal of Psychiatry 1994; 164(4):549-50. Summary: The rate of treatment-emergent switch into mania has been calculated from all available clinical trial data on the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine, fluvoxamine, paroxetine, and sertraline, relative to comparative groups treated with tricyclic antidepressants (TCAs) or placebo. In predominantly unipolar depressives, the rate of manic switch is less than 1% and differences between drugs and placebo are statistically but not clinically significant. In bipolar depressives, manic switch occurs substantially more often with TCAs (11.2%) than with SSRIs (3.7%) or placebo (4.2%).

  28. Tignol J: A Double-Blind, Randomized, Fluoxetine-Controlled, Multicenter Study Of Paroxetine In The Treatment Of Depression. Journal of Clinical Psychopharmacology 1993; 13(6 Suppl 2):18S-22S. Summary: Paroxetine is a novel phenylpiperidine antidepressant agent that acts as a potent and selective inhibitor of serotonin reuptake. We report results of a 6-week, randomized, double-blind, multicenter study comparing paroxetine and fluoxetine in the treatment of major depression. One hundred seventy-eight inpatients, who met DSM-III-R criteria for a major depressive episode and had a Montgomery Asberg Depression Rating Scale (MADRS) score of 24 or more, were included in the study. Their ages ranged from 18 to 65 years. Subjects were randomized to receive either paroxetine or fluoxetine for 6 weeks. A 20-mg fixed dose, given once daily in the morning, was used for both drugs. After baseline, regular assessments were made at the end of weeks 1, 2, 3, 4, and 6. Efficacy measures included the MADRS, the Clinical Global Impression severity of illness scale, the Hamilton Rating Scale for Anxiety, the Hospital Anxiety and Depression scale, and the Visual Analogue Scale for anxiety. Safety and tolerability were assessed by adverse event reports, clinical examinations, vital signs, and laboratory data. A marked antidepressant response and good tolerability were seen with both drugs. These results further support the usefulness of paroxetine in the treatment of depressive illness.

  29. Stokes PE: Fluoxetine: A Five-Year Review. [Review]. Clinical Therapeutics 1993; 15(2):216-43; discussion 215. Summary: Depression is associated with significant morbidity, mortality, and economic cost. Although effective pharmacologic therapy has been available for nearly 40 years, most patients have been treated inadequately. The side effects associated with available antidepressants usually led to subtherapeutic dosing, premature discontinuation of therapy, or lack of patient compliance. The introduction in 1988 of fluoxetine hydrochloride, the first selective serotonin uptake inhibitor (SSUI) or selective serotonin reuptake inhibitor (SSRI) available in the United States, represented a major advance in the pharmacologic management of depression. Large-scale trials showed fluoxetine to be as effective as existing agents, but because of its selectivity, the side effects of fluoxetine treatment are generally mild and transient and rarely cause premature discontinuation of therapy. In clinical trials approximately twice as many patients discontinue treatment because of side effects with tricyclic antidepressants (TCAs) as with fluoxetine. In contrast to older agents fluoxetine requires no titration and can be dosed once daily. It is also safer in overdose than TCAs. Numerous clinical trials and widespread postintroduction clinical experience have demonstrated the advantages of fluoxetine compared with older antidepressants. It may also have some advantages over the two SSUIs that have followed thus far, sertraline and paroxetine, although comparative trials will be required to resolve this issue. [References: 109]

  30. Nemeroff CB: Paroxetine: An Overview Of The Efficacy And Safety Of A New Selective Serotonin Reuptake Inhibitor In The Treatment Of Depression. [Review]. Journal of Clinical Psychopharmacology 1993; 13(6 Suppl 2):10S-17S. Summary: Paroxetine is a novel phenylpiperidine compound that is a potent and selective serotonin reuptake inhibitor. It has little affinity for alpha-adrenergic, dopamine, histamine, and cholinergic receptors. The pharmacokinetic properties of paroxetine are well suited to clinical use. Its bioavailability is not affected by food or antacids; its mean half-life of about 24 hours is consistent with once-a-day dosing; also, it has no pharmacologically active metabolites. In clinical studies involving over 6,700 patients worldwide, the efficacy of paroxetine has been shown consistently to be superior to placebo and comparable to tricyclic antidepressant agents in the treatment of depression. During these trials, paroxetine was used in a broad range of depressed patients, including the moderately to severely depressed, the elderly, and patients whose depressions were accompanied by symptoms of anxiety. In addition, it has been shown to be effective for the prevention of depressive relapse during long-term treatment. Side effects associated with paroxetine tend to be relatively mild, transient, and easily managed. As with other selective serotonin reuptake inhibitors, the most common side effect associated with paroxetine treatment is nausea, although this effect rarely leads to dose reduction or drug discontinuation. Paroxetine should not be coadministered with monoamine oxidase inhibitors or L-tryptophan. Animal data and limited clinical experience suggest that paroxetine is considerably safer in overdose than are tricyclic antidepressant drugs. [References: 42]

  31. Kishimoto A, Kamata K, Sugihara T, Ishiguro S, Hazama H, Mizukawa R, Kunimoto N: Treatment Of Depression With Clonazepam. Acta Psychiatr Scand 1988; 77(1):81-6. Summary: The antidepressive effect of an anticonvulsant clonazepam was studied with maximum daily dose of 1.5 to 6.0 mg (mean 3.4 mg) in 27 patients with major depression (n = 18) or bipolar disorder (n = 9). Two of them dropped out at an early stage of the treatment, and the antidepressive effect of clonazepam was evaluated for the remaining 25 patients. A marked to moderate improvement was obtained for 21 patients (84%), and the onset of the antidepressive effect of clonazepam appeared within 1 week in most of the cases who responded to the therapy. The total scores on the Hamilton Depression Rating Scale and the Beck Self-Rating Scale were significantly reduced after the clonazepam treatment. Side effects occurred in 14 patients, but most of them were not severe. From these results, it is thought that clonazepam might be useful as an antidepressant for patients in whom conventional antidepressant treatment are contraindicated.

  32. Fava M, Rosenbaum JF, McGrath PJ, Stewart JW, Amsterdam JD, Quitkin FM: Lithium And Tricyclic Augmentation Of Fluoxetine Treatment For Resistant Major Depression: A Double-Blind, Controlled Study. American Journal of Psychiatry 1994; 151(9):1372-4. Summary: Forty-one patients who had failed to respond to 8 weeks of treatment with 20 mg of fluoxetine were randomly assigned to one of three treatments for 4 weeks: 40-60 mg/day of fluoxetine, 20 mg/day of fluoxetine plus 25-50 mg/day of desipramine, and 20 mg/day of fluoxetine plus 300-600 mg/day of lithium. Patients treated with high-dose fluoxetine (N = 15) did significantly better than patients treated with fluoxetine plus lithium (N = 14) and those treated with fluoxetine plus desipramine (N = 12). High-dose fluoxetine was the most effective treatment among partial responders to previous treatment, but high-dose fluoxetine and fluoxetine plus lithium were the most effective treatments among nonresponders.

  33. Brown WA, Harrison W: Are Patients Who Are Intolerant To One Serotonin Selective Reuptake Inhibitor Intolerant To Another?. Journal of Clinical Psychiatry 1995; 56(1):30-4. BACKGROUND: The question was asked whether patients who discontinue one serotonin selective reuptake inhibitor (SSRI) because of side effects can be treated successfully with another SSRI. METHOD: 113 patients with major depression who had discontinued fluoxetine because of side effects were enrolled in an open, multicenter, 8-week study designed to evaluate the tolerability and efficacy of sertraline. After a washout period of at least 3 weeks following fluoxetine discontinuation and an additional 1-week, single-blind, placebo washout period, patients began treatment with 50 mg of sertraline once daily. Doses were titrated upward as necessary to a maximum daily dose of 200 mg. Depressive symptoms and adverse events were evaluated weekly. RESULTS: Based on the Clinical Global Impressions Scale, 79 (71.8%) of 110 patients evaluated for efficacy were "much" or "very much" improved relative to baseline. Only 11 (9.8%) of 112 patients discontinued sertraline because of adverse reactions. CONCLUSION: These results suggest that patients who discontinue one SSRI because of side effects can be treated successfully with another.

  34. Delgado PL, Price LH, Charney DS, Heninger GR: Efficacy Of Fluvoxamine In Treatment-Refractory Depression. J Affective Dis 1988; 15(1):55-60. Summary: The efficacy of the potent and selective unicyclic serotonin reuptake inhibitor, fluvoxamine, was evaluated in 38 consecutively admitted depressed patients judged refractory to standard antidepressants using operationalized criteria. Twenty-eight patients completed a single-blind protocol involving greater than or equal to 2 weeks of placebo and 4-6 weeks of active fluvoxamine. Eight (29%) were judged responders to fluvoxamine alone, eight (29%) responded to lithium augmentation of fluvoxamine and two (7%) responded to fluvoxamine, lithium and perphenazine. These data suggest that selective and potent serotonin reuptake inhibitors may be effective in patients refractory to generally available antidepressant medications.

  35. Feighner JP: The Role Of Venlafaxine In Rational Antidepressant Therapy. [Review]. Journal of Clinical Psychiatry 1994; 55 Suppl A:62-8; discussion 69-70, 98-100. Summary: The antidepressant venlafaxine has a unique chemical structure and neuropharmacologic profile. It significantly inhibits reuptake of both serotonin and norepinephrine and lacks notable muscarinic-cholinergic or alpha-adrenergic effects. Premarketing studies involving more than 2000 patients showed the efficacy of venlafaxine to be significantly greater than placebo at dosages between 75 and 375 mg/day in both outpatients and inpatients. The medication may be administered twice or three times daily. Venlafaxine was found equally effective for patients older and younger than 60 years and in those with psychomotor retardation or agitation; it proved slightly more efficacious than fluoxetine in a comparison study with melancholic inpatients. A promising finding of these studies is the suggestion of a rapid onset of clinical effect for venlafaxine. In some studies, venlafaxine showed a consistent and robust clinical superiority over placebo by Week 1, and in the inpatient study involving melancholic patients, the superiority of venlafaxine was demonstrated as early as Day 4. In general, early responses are seen at the higher dosages. Venlafaxine has also shown promise in treating rigorously defined treatment-refractory depression. The adverse effects of venlafaxine that most often led to discontinuation from a clinical study were nausea (6%), somnolence (3%), insomnia (3%), and dizziness (3%). Although nausea was the most common adverse effect overall, it resolved rapidly--within the first 1 to 3 weeks of therapy. Other adverse events with incidences significantly higher than with placebo were dizziness, constipation, sweating, nervousness, and abnormal ejaculation. The seizure rate and potential for cardiac conduction changes or orthostatic hypotension with venlafaxine were comparable with rates seen with the serotonin selective reuptake inhibitors. A small number of patients experienced dose-dependent blood pressure elevation with venlafaxine in premarketing studies (3% to 5% of those receiving < or = 200 mg/day; 7% of those receiving 201-300 13% 300 mg/day vs. 2% receiving placebo). In general, venlafaxine is well tolerated, and its treatment discontinuation rate is similar to those of the newer antidepressants and superior to discontinuation rates with the first-generation agents. [References: 19]

  36. Joffe RT, Singer W, Levitt AJ, MacDonald C: A Placebo-Controlled Comparison Of Lithium And Triiodothyronine Augmentation Of Tricyclic Antidepressants In Unipolar Refractory Depression. Archives of General Psychiatry 1993; 50(5):387-93. OBJECTIVE: To directly compare the efficacy of lithium carbonate and liothyronine sodium (triiodothyronine) in the augmentation of therapeutic response in antidepressant nonresponders. DESIGN: A randomized, double-blind, placebo-controlled study of 2 weeks' duration. SETTING: The Mood Disorders Program, Clarke Institute of Psychiatry and the University of Toronto, Ontario. PATIENTS: Fifty outpatients, males and females, with unipolar, nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride. RESULTS: Both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression. However, the antidepressant augmenting effect of these two compounds did not differ from each other. When response was defined as a 50% or more reduction in the Hamilton Rating Scale for Depression scores and a final score less than 10, we found that 10 of 17 (58%) subjects responded to liothyronine, nine of 17 (53%) responded to lithium and three of 16 (19%) responded to placebo. CONCLUSION: Our study suggests that both lithium and liothyronine may be considered as alternatives in augmenting antidepressant response in patients who do not respond to treatment with a tricyclic antidepressant.

  37. Howland RH: Thyroid Dysfunction In Refractory Depression: Implications For Pathophysiology And Treatment. [Review]. Journal of Clinical Psychiatry 1993; 54(2):47-54. BACKGROUND: Many studies of thyroid augmentation in refractory depression are methodologically weak, have had mixed results, and often do not include biological measures of hormonal effects. In this paper, recent clinical and preclinical research on thyroid dysfunction in refractory depression is reviewed. METHOD: A search of MEDLINE for articles published from 1970 to the present was conducted, in addition to a search of the bibliographies of published papers in this area. The clinical studies chosen for review included those in which the patient population was identified as having refractory depression and where a specific measure of thyroid function was used, such as thyroid indices, thyroid-releasing hormone stimulation, or basal metabolic rate. Animal studies of depression using the learned helplessness experimental paradigm were also reviewed and included if they examined the factors involved in antidepressant treatment response. RESULTS: Fifty-two percent of patients with refractory depression in six clinical studies evidenced subclinical hypothyroidism (range, 29%-100%), which can be contrasted with a prevalence of approximately 8% to 17% in unselected populations of depressed patients. Four studies investigating an animal model of refractory depression strongly implicate a pathophysiologic role for hypothyroidism, perhaps mediated by altered beta-adrenergic function. CONCLUSION: These findings indicate that hypothyroidism is significantly associated with refractory depression, suggesting that this characterizes one biological subtype of refractory depression. Failure to rigorously investigate the effects of thyroid augmentation, including measures of thyroid and beta-adrenergic function, may partly explain the ambiguous results from many treatment studies, and future research should incorporate these measures in the study of refractory depression. [References: 86]

  38. Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI: A Preliminary, Open Study Of The Combination Of Fluoxetine And Desipramine For Rapid Treatment Of Major Depression. Arch Gen Psychiatry 1991; 48(4):303-7. Summary: Prompted by a recent study suggesting that the combination of desipramine hydrochloride and fluoxetine down-regulates beta-adrenergic receptors more rapidly than either drug alone, we administered both desipramine and fluoxetine to 14 inpatients with major depression in an open, 4-week trial. Desipramine plasma levels drawn 24 hours after an initial standardized dose were used to rapidly adjust desipramine dosage and compensate for the interactive effects of fluoxetine on desipramine levels in the blood. Responses were retrospectively compared with those of 52 inpatients who were descriptively similar and previously treated in the same setting with desipramine alone. Response was significantly more rapid in the group that received both drugs. One week after treatment began, the mean change in Hamilton Depression Rating Scale scores was 42% in the group that received both drugs and 20% in the group that received desipramine alone (Mann-Whitney U test, P = .007). Two weeks after administration of the drugs, the mean change in scores of the group that received both drugs was 60%, while a 30% change was noted in the patients treated with desipramine alone (P = .001). Ten (71%) of the 14 patients in the group that received both drugs completely remitted (change in Hamilton Depression Rating Scale score of greater than 75%, and final score of less than 7) within 4 weeks, while few patients treated with desipramine alone met these criteria within 4 weeks. This preliminary study suggests that treatment with both desipramine and fluoxetine is a rapid and effective strategy for treatment of major depression, and supports recent hypotheses of noradrenergic-serotonergic synergism.

  39. Schaff MR, Fawcett J, Zajecka JM: Divalproex Sodium In The Treatment Of Refractory Affective Disorders. Journal of Clinical Psychiatry 1993; 54(10):380-4. Summary: BACKGROUND: Anticonvulsants have been shown to be effective in many patients with psychiatric disorders, especially those with bipolar affective disorder. We present our clinical experience with divalproex sodium in the treatment of 63 patients with a variety of affective disorders that had proved refractory to conventional pharmacotherapy. METHOD: We reviewed the charts of 63 patients diagnosed as bipolar I (35 patients), bipolar II (23 patients), or schizoaffective, bipolar type (5 patients). Twelve patients who appeared to have recurrent unipolar depression had a retrospectively recognized history of "covert cycling," with brief periods of socially acceptable hypomania occurring between depressive episodes. Prior to treatment with divalproex, 45 patients had been classified as treatment failures with lithium, 29 patients had been classified as treatment failures with carbamazepine, and 35 patients had also failed on a combination of lithium and carbamazepine. Divalproex was given to these patients and titrated to achieve blood levels in the range of 50 to 100 mg/L. RESULTS: Forty-seven (75%) of the 63 patients responded positively to the addition of divalproex to their regimens. Of 45 patients who had failed to respond to lithium, 38 (84%) responded when divalproex was added. Of 29 patients who had failed to respond to carbamazepine, 20 (69%) responded when divalproex was added. Of 26 rapid-cycling patients, 21 (81%) responded to the addition of divalproex. Side effects required drug withdrawal in 9 patients (14%). CONCLUSION: The results confirm previous findings that both mania and rapid mood cycling may respond to a pharmacologic regimen that includes divalproex. Many patients who appear to have recurrent, major unipolar depression may actually be convert cyclers who will respond to divalproex, sometimes in combination with an antidepressant medication.

  40. Warneke L: Psychostimulants In Psychiatry. Can J Psychiatry 1990; 35(1):3-10. Summary: The use of the psychostimulants in psychiatry is reviewed. A brief historical perspective on dextroamphetamine is presented, and a brief review of the psychopharmacology of dextroamphetamine, methylphenidate and magnesium pemoline is given. The literature on the use of stimulants in the treatment of resistant depression, apathetic geriatric patients and patients medically ill with a secondary depression is summarized and two case histories given to illustrate the clinical usefulness of the stimulants. The literature on the use of stimulants as an adjunct to antidepressant therapy and as a diagnostic test is also discussed. Finally the use of stimulants in obsessional illness and adult attention deficit disorder is summarized. The writer concludes by commenting that the stimulants have a very useful role in the treatment of certain categories of depression as well as other psychiatric syndromes and such patients should not be deprived of symptom relief by these drugs. The approach to therapy should be much the same as the use of analgesics for chronic pain sufferers.

  41. Partonen T, Partinen M: Light Treatment For Seasonal Affective Disorder: Theoretical Considerations And Clinical Implications. [Review]. Acta Psychiatrica Scandinavica, Supplementum 1994; 377:41-5. Summary: The concept of seasonal affective disorder (SAD) includes any depression whose onset is related to a certain season. Reduced environmental light is hypothesized to be the main precipitating factor of winter depression. Light treatment is used to prevent the onset of depressive episodes and to reduce depressive symptoms in patients with depression during winter months. The mechanisms of action which lead to the well-documented antidepressant response are still unknown. Several hypotheses of the pathogenesis of SAD are discussed, and the clinical practice of light treatment is reviewed. [References: 48]

  42. Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT: Efficacy Of The Combination Of Fluoxetine And Perphenazine In The Treatment Of Psychotic Depression. Journal of Clinical Psychiatry 1993; 54(9):338-42. BACKGROUND: The aim of this study was to examine the efficacy of the combination of fluoxetine plus perphenazine in the treatment of psychotic depression. METHOD: Thirty patients who met DSM-III-R criteria for major depression with psychotic features were treated with fluoxetine plus perphenazine for 5 weeks. Patients were assessed at baseline and weekly using the Hamilton Rating Scale for Depression (HAM-D), Brief Psychiatric Rating Scale (BPRS), and a side-effect checklist that included specific extrapyramidal and anticholinergic side effects. RESULTS: Twenty-two (73%) of the 30 patients had a 50% or greater reduction in total HAM-D by Week 5. There was a significant improvement in HAM-D and BPRS scores at each week compared with baseline scores. Side effects reported by the patients included dry mouth (40%), blurry vision (40%), constipation (40%), tremor or rigidity (40%), and orthostatic hypotension or dizziness (27%). CONCLUSION: Fluoxetine when used in combination with perphenazine for the treatment of patients with psychotic depression has a response rate similar to the reported rates of response for tricyclic antidepressants (TCAs) plus antipsychotics, amoxapine, and electroconvulsive therapy. The side effects produced by the fluoxetine plus perphenazine combination were less than what has been reported for TCA plus antipsychotic treatment of psychotic depression and similar to the side effects reported with amoxapine. These data suggest that the combination of fluoxetine and perphenazine is effective for the treatment of psychotic depression and may be easier for patients to tolerate than a TCA plus antipsychotic.

  43. el-Mallakh RS: Complications Of Concurrent Lithium And Electroconvulsive Therapy: A Review Of Clinical Material And Theoretical Considerations. Biol Psychiatry 1988; 23(6):595-601. Summary: Several anecdotal reports and two retrospective chart reviews have examined complications of concurrent lithium and electroconvulsive treatment. Discussions have generally been contradictory or confusing. This article reviews the literature and particularly emphasizes theoretical considerations and mechanisms, concluding (A) that lithium may act synergistically with neuromuscular blockers, but the effect is not clinically significant, and (B) that repeated electroconvulsive seizures may cause a toxic delirium in patients concurrently taking lithium.

  44. Laws D, Ashford JJ, Anstee JA: A Multicentre Double-blind Comparative Trial Of Fluvoxamine Versus Lorazepam In Mixed Anxiety And Depression Treated In General Practice. Acta Psychiatr Scand 1990; 81(2):185-9. Summary: Fluvoxamine, a selective serotonin reuptake inhibitor, was compared with lorazepam in a multicentre double-blind, parallel group study in 112 general practice patients with mixed anxiety and depression. For inclusion, patients were required to have minimum baseline scores of 21 on the Montgomery-Asberg Depression Rating Scale (MADRS) and 11 on the Clinical Anxiety Scale (CAS). Treatment was for 6 weeks. There were no significant differences between treatments at any point except in an elderly subgroup in whom anxiety improved more rapidly with lorazepam. There were significant improvements in MADRS, CAS and global ratings compared with baseline at all subsequent assessments. Improvement continued during the whole treatment period. Lorazepam produced more sedation, whilst fluvoxamine produced significantly more nausea and vomiting; this was usually early in onset and, if tolerated, resolved during the course of the study. As it is now widely recognized that benzodiazepines should only be given in short courses of 2-4 weeks, the continued improvement up to 6 weeks has implications regarding choice of treatment.

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