Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.

OBJECTIVE: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. METHOD: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. RESULTS: Six studies were identified. All were conducted with triiodothyronine (T(3)) and a tricyclic antidepressant. Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(3) in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention.

Treatment-resistant bipolar disorder.

Over the last few years, the number of potential pharmacotherapies for bipolar disorder has greatly expanded. Yet the database for virtually all these newer treatments consists of case reports and case series. Among these newer treatments, recently released anticonvulsants are most promising. Lamotrigine has already shown efficacy for treating bipolar depression, while gabapentin's efficacy has yet to be documented in a controlled study. Alone among its medication class, topiramate, another anticonvulsant, is associated with weight loss. Novel antipsychotics are effective in treating acute mania. With the exception of clozapine, their efficacy as true mood stabilizers is still unknown. Utilizing combinations of mood stabilizers is common and appropriate but demands knowledge of potential pharmacokinetic interactions. Other approaches for treatment resistant bipolar disorder include high-dose thyroid hormones, calcium channel blockers, electroconvulsive therapy, and omega-3 fatty acids. Finally, the efficacy of adjunctive psychosocial strategies is a topic of active investigation.

Fluphenazine levels during maintenance treatment of recent-onset schizophrenia: relation to side effects, psychosocial function and depression.

RATIONALE: The utility of fluphenazine levels during maintenance treatment of schizophrenia is still unclear. OBJECTIVES: This study investigated the relationship between fluphenazine levels and a variety of clinical measures during maintenance treatment of schizophrenia. METHODS: Fluphenazine levels, side effects, depression and psychosocial outcome were measured at five time points over approximately 1 year in 59 recent onset schizophrenic patients treated with a maintenance dose of injectable fluphenazine decanoate. Negative symptoms were evaluated at the 1-year endpoint. RESULTS: Fluphenazine levels showed marked intraindividual variability even when measurements were restricted to the second 6 months of treatment, by which time steady state levels should have been achieved. No consistent relationship was found between fluphenazine levels and any of the outcome measures. CONCLUSIONS: The results of this study suggest that fluphenazine plasma levels do not routinely add relevant clinical information beyond that of dose in evaluating potential side effects or negative consequences during maintenance treatment with the decanoate form of the medication.

Gender and bipolar illness.

BACKGROUND: For major depression and schizophrenia, gender differences have been reported in symptom expression and course of illness. Gender differences in bipolar disorder are becoming increasingly apparent, but have been less studied. Research data on these differences will help determine whether gender is important in influencing illness variables such as course, symptom expression, and likelihood of comorbidity. METHOD: Charts of 131 patients (63 women and 68 men) with a DSM-IV diagnosis of bipolar disorder admitted to the University of California Los Angeles Mood Disorders Program over a 3-year period were reviewed to gather data on demographic variables and course of illness and to assess differences in the illness across genders. RESULTS: No significant gender differences were found in the rate of bipolar I or bipolar II diagnoses, although women were overrepresented in the latter category. Also, no significant gender differences emerged in age at onset, number of depressive or manic episodes, and number of hospitalizations for depression. Women, however, had been hospitalized significantly more often than men for mania. Further, whereas bipolar men were significantly more likely than bipolar women to have a comorbid substance use disorder, women with bipolar disorder had 4 times the rate of alcohol use disorders and 7 times the rate of other substance use disorders than reported in women from community-derived samples. CONCLUSION: For bipolar disorder, course of illness variables such as age at onset and number of affective episodes of each polarity do not seem to differ across genders. Women, however, may be more likely than men to be hospitalized for manic episodes. While both men and women with the illness have high rates of comorbidity with alcohol and other substance use disorders, women with bipolar disorder are at a particularly high risk for comorbidity with these conditions.

Efficacy and response time to sertraline versus fluoxetine in the treatment of unipolar major depressive disorder.

BACKGROUND: Few studies have compared the treatment efficacy of the 2 selective serotonin reuptake inhibitors sertraline and fluoxetine. METHOD: A randomized, single-blind, parallel-group study of 10 weeks' duration comparing the efficacy of sertraline, 50 mg/day; sertraline, 100 mg/day; and fluoxetine, 20 mg/day, was conducted in 44 psychiatric outpatients with DSM-IV unipolar major depressive disorder. Antidepressant dosages were doubled at 6 weeks for subjects who had not achieved remission. Primary outcome measurements included the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions-Improvement scale (CGI-I), with scores of < or = 7 on the HAM-D and < or = 2 on the CGI-I representing a positive treatment response, i.e., remission. RESULTS: At 4 weeks, significant differences in rate of positive treatment response were noted, with 0% for sertraline, 50 mg; 46% for sertraline, 100 mg; and 31% for fluoxetine, 20 mg (p = .023). At 6 weeks, positive treatment response rates were 21%, 43%, and 31% for subjects taking 50 mg of sertraline, those taking 100 mg of sertraline, and those taking 20 mg of fluoxetine, respectively, with treatment groups no longer differing significantly from each other. In subjects for whom antidepressant dose was doubled at week 6, response rates at week 10 (4 weeks on increased dose) were 40% for sertraline, 100 mg; 43% for sertraline, 200 mg; and 55% for fluoxetine, 40 mg. CONCLUSION: Subjects taking sertraline, 100 mg, and fluoxetine, 20 mg, demonstrated an earlier treatment response compared with subjects taking sertraline, 50 mg. For patients without a positive response at 6 weeks, an increased antidepressant dose resulted in remission for a substantial proportion of patients when assessed 4 weeks later.

Bipolar depression and antidepressant-induced mania: a naturalistic study.

BACKGROUND: The likelihood and character of antidepressant-induced mania remain important but poorly understood factors in the treatment of bipolar depression. METHOD: We examined the response to naturalistic treatment of 29 bipolar I patients who experienced a total of 79 depressive episodes. Treatment consisted primarily of mood stabilizers used alone (N = 31) or in combination with antidepressants (N = 48). Intensity of baseline mood stabilizer therapy, adequacy of added antidepressant therapy, intensity of ensuing mania or hypomania, and course of illness prior to study were measured, and selected comparisons were made between treatment groups. RESULTS: Postdepressive mood elevations (i.e., switches) that occurred during or up to 2 months after each depressive episode were present in 28% (22/79) and judged to be severely disruptive in only 10% (8/79) of episodes. Examining only the first episode per patient, a history of a greater number of past manic episodes was associated with a higher risk of switching (p < .023). Antidepressant treatment combined with mood stabilizer therapy was not associated with higher rates of postdepressive mood elevation than mood stabilizer therapy alone. At a descriptive level, subjects treated with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were associated with a higher switch rate than those treated with fluoxetine; TCAs were also associated with more intense switches. CONCLUSION: The frequency and severity of postdepressive mood elevation associated with acute or continuation antidepressant therapy may be reduced by mood stabilizers. Such elevations may be more likely in patients with a strong history of mania.

Relapse and impairment in bipolar disorder.

OBJECTIVE: The purpose of this study was to evaluate the outcome of bipolar disorder in the context of maintenance pharmacotherapy. METHOD: Eighty-two bipolar outpatients were followed prospectively for a mean of 4.3 years (minimum of 2 years); symptom rating and psychosocial outcome scales were used, and pharmacotherapy was rated on a 5-point scale. RESULTS: Despite continual maintenance treatment, survival analysis indicated a 5-year risk of relapse into mania or depression of 73%. Of those who relapsed, two-thirds had multiple relapses. Relapse could not be attributed to inadequate medication. Even for those who did not relapse, considerable affective morbidity was observed. A measure of cumulative affective morbidity appeared to be a more sensitive correlate of psychosocial functioning than was the number of relapses. Poor psychosocial outcome paralleled poor syndromal course. Poor psychosocial functioning, especially occupational disruption, predicted a shorter time to relapse. Depressions were most strongly related to social and family dysfunction. CONCLUSIONS: Even aggressive pharmacological maintenance treatment does not prevent relatively poor outcome in a significant number of bipolar patients.

Effects of depression and antidepressants on sexual functioning.

With serotonergic antidepressants dominating the treatment of depressive disorders, antidepressant-induced sexual side effects have emerged as a major clinical issue. Surprisingly, the effects of depression on sexuality are less well established and more variable than previously thought. It is likely that antidepressants with strong serotonergic effects--selective serotonin reuptake inhibitors, clomipramine, and monoamine oxidase inhibitors--are associated with higher rates of sexual side effects, compared to other antidepressant classes. Orgasmic and ejaculation difficulties are prominent with these medications, although alterations in libido, arousal, and erectile function are also common. Treatment of these side effects includes both general strategies and specific antidotes, such as cyproheptadine, yohimbine, dopamine agonists, and buspirone.

Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches.

BACKGROUND: The recognition and treatment of sexual side effects caused by psychotropic agents have become topics of increasing clinical concern. Gaps in our understanding of the biology of sex and in our knowledge of the effect of Axis I disorders on sexual functioning have made both recognition of sexual side effects and a coherent treatment approach to these side effects difficult. METHOD: The author reviews case reports, case series, and animal studies derived from a MEDLINE search for English language articles on the topics of the effects of psychiatric disorders on sexual functioning, the biology of sex, rates of sexual dysfunction associated with each medication class, and treatment approaches when these side effects occur. RESULTS: In evaluating sexual function in patients taking psychotropic medications, clinicians should first consider other potential causes of sexual dysfunction. In general, dopamine increases sexual behavior, serotonin inhibits it, while norepinephrine has conflicting effects. Sexual side effects have been described in association with all the major classes of psychotropic medications. Neuroleptics are often associated with sexual side effects. Priapism, seen with neuroleptics and trazodone, should be treated as a urological emergency. Anxiolytics cause mild, nonspecific sexual side effects as do the mood stabilizers. Among the antidepressants, the more powerful serotonergic medications--e.g., the serotonin selective reuptake inhibitors (SSRIs), clomipramine, and MAO inhibitors--may cause more sexual side effects than the tricyclics. Potential strategies to treat antidepressant-induced sexual side effects include lowering the dose, waiting, and switching to another agent. A number of specific antidotes, such as cyproheptadine and yohimbine, have been reported to reverse these side effects in a limited number of cases. CONCLUSION: Clinicians must be aware of and specifically ask about medication-induced sexual side effects. More effective treatments of these side effects must await much needed double-blind studies of various approaches, especially those to treat SSRI-induced sexual dysfunction.

Pharmacotherapy of personality disorders: conceptual framework and clinical strategies.

This article delineates the conceptual models used when medications are prescribed for patients with personality disorders and reviews the data on the efficacy of these medications. Studies before 1980 are difficult to interpret because of changes in diagnostic criteria. Nonetheless, early studies on non-DSM-III disorders such as pseudoneurotic schizophrenia, emotionally unstable character disorder, hysteroid dysphoria, and subaffective disorders indicated the potential utility of pharmacotherapy for treating personality disorders. Models to consider in evaluating the possible use of medications for treating personality disorders are: (1) treating the disorder itself; (2) treating symptom clusters within and across disorders; and (3) treating associated axis I disorders. Among the current personality disorders, borderline personality disorder has been the most extensively studied, with antipsychotic agents being the most well-documented treatment. Monoamine oxidase inhibitors, fluoxetine, and carbamazepine show promise. Schizotypal disorders may respond to low-dose antipsychotic drugs. Although heuristically valuable, the symptom cluster approach to treatment has not yet been validated. Axis I disorders, especially depression, are frequently associated with all personality disorders. Dependent personality disorder is linked to panic disorder with agoraphobia, whereas avoidant personality disorder is associated with social phobia and panic. In general, pharmacotherapy for axis I disorders is less effective in the presence of a comorbid personality disorder. Despite the modest benefits seen in many studies, pharmacotherapy can add significantly to the overall treatment of those with personality disorders. Future research must carefully assess the effect of comorbid axis I disorders on responses. The symptom cluster/psychobiologic dimension approach should be investigated in clinical studies.

Lithium-induced renal insufficiency.

Recent reviews of the effects of lithium on renal function have generally concluded that no clinically significant effect on glomerular function is apparent even after many years. Yet, a handful of studies over the last 3 years indicate that a small percentage of lithium-treated patients may develop rising levels of creatinine in serum after a decade or more of treatment. In the current sample of 82 bipolar patients treated in an affective disorders clinic, 3 (3.7%) were found to have developed creatinine levels in serum greater than 2.0 mg/100 ml from baseline levels that were within normal limits. One of these patients has progressed to chronic renal failure and hemodialysis, making him the second probable reported case of lithium-induced chronic renal failure. No common risk factor for renal disease among these patients was apparent. As increasing numbers of patients are treated with lithium for a decade or more, previous conclusions as to the benign effects of long-term lithium treatment on renal function may need to be revised. Regular monitoring of creatinine levels in serum and medical consultation if the level rises and remains above 1.6 mg/100 ml are recommended.

Lithium: serum levels, renal effects, and dosing strategies.

Lithium prescribing practices have changed over the course of its forty years of use in psychiatric patients. Currently there are controversies as to clinically effective serum levels, dosing strategies, and effects of lithium on renal functioning. These issues are discussed, and recommendations are offered for effective management of the patient taking lithium.

Clinical aspects of depression in chronic pain patients.

It has been widely recognized that an appreciable proportion of chronic pain patients have depressive disorders. Although numerous studies and several literature reviews have examined the relationship between chronic pain and depression, disorders of mood come in many forms, and little attention has been paid to the different types of depressive disorders found among patients with chronic pain. In this article, the different ways in which a chronic pain patient may manifest depression are discussed. Diagnostic criteria for major depression, dysthymia, and atypical depression are described, and the relevance of these disorders and of masked depression to chronic pain is discussed. The medical illnesses and medications that can cause symptoms of depressive disorders are also briefly described. Depressive disorders and their concomitants are an integral part of the experience of chronic pain and are important in developing an optimal treatment plan. For these reasons, they should be carefully evaluated in all patients with chronic pain.