Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.

BACKGROUND: Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established. AIM: To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication. METHODS: Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate. CONCLUSION: This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.

Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients.

BACKGROUND: There is a clear need for effective, well-tolerated intramuscular (i.m.) agents for the acute control of agitated psychotic patients. Currently used agents, including conventional antipsychotics and/or benzodiazepines, may be associated with distressing side effects such as extrapyramidal side effects and excessive sedation. OBJECTIVE: The objective of this study was to evaluate the efficacy and tolerability of the rapid-acting i.m. formulation of the novel antipsychotic ziprasidone in the treatment of inpatients with psychosis and acute agitation (DSM-IV diagnoses). METHOD: In a 24-hour, double-blind, fixed-dose clinical trial, patients were randomly assigned to receive up to 4 injections (every 2 hours p.r.n.) of 2 mg (N = 54) or 10 mg (N = 63) of ziprasidone i.m. The Behavioral Activity Rating Scale measured behavioral symptoms at baseline and the response to treatment up to 4 hours after the first i.m. injection. RESULTS: Ziprasidone i.m., 10 mg, rapidly reduced symptoms of acute agitation and was significantly more effective (p < .01) than the 2-mg dose up to 4 hours after the first injection. Patients were calmed but not excessively sedated, and over half were classed as responders 2 hours after the 10-mg dose. No acute dystonia or behavioral disinhibition was reported. One patient who received the 10-mg dose experienced the extrapyramidal side effect akathisia. CONCLUSION: Ziprasidone i.m., 10 mg, is rapidly effective and well tolerated in the short-term management of the agitated psychotic patient. Comparison with a study of identical design comparing 2-mg with 20-mg doses in patients with similar levels of psychopathology suggests that efficacy with 10 mg or 20 mg of ziprasidone i.m. is significant and dose related.

Clinical issues in long-term treatment with antidepressants.

Historically, the emphasis in treating depression has been focused on the acute phase of treatment, with few published data on the continuation and maintenance phases of treatment. Yet the risk of depression increases with each episode, with a 50% to 90% chance of developing another episode after 1 or 2 prior episodes of depression. Moreover, subsequent episodes of depression are often of longer duration, more severe, and less responsive to treatment. Most patients with major depression require some form of long-term antidepressant treatment, and many need lifelong treatment. Optimizing efficacy and minimizing side effects are essential during both the acute and long-term phases of antidepressant treatment. Antidepressant side effects, including insomnia or somnolence, weight gain, asthenia, and sexual dysfunction, can significantly decrease patient compliance with long-term treatment for depression. Identification and management of side effects, combined with early and ongoing educational messages to the patient about treatment issues and the importance of sustaining illness remission, help improve compliance and reduce the potential for premature discontinuation of an otherwise optimal antidepressant.

A systematized approach to the management of the depressed and anxious patient.

The coexistence of depression and anxiety is a common occurrence that frequently poses diagnostic and treatment challenges in the clinical setting. As epidemiological studies continue to confirm the enormous prevalence of this comorbid condition, the separation in diagnosis and treatment between depression and anxiety has become increasingly less pronounced. Additionally, the discovery that pharmacotherapeutic modalities have a broader range of efficacy, often overlapping both depression and anxiety, has led to an evolving reclassification of treatment, away from 'antidepressants' and 'anxiolytics' toward one based on mechanism of action. A rational approach to the systematized management of the various comorbidities of depressive and anxiety disorders is discussed.

The effect of nefazodone on comorbid anxiety symptoms associated with depression: experience in family practice and psychiatric outpatient settings.

Retrospective analysis of two randomized, placebo-controlled trials evaluated the effectiveness of nefazodone in relieving depression-associated anxiety symptoms of patients with major depression in two practice settings. One study involved depressed patients (N = 138) treated in a family practice setting, the other, psychiatric clinic outpatients (N = 180). Nefazodone treatment was broadly effective across several measures of anxiety symptoms (HAM-D, HAM-A and SCL rating scales) in relieving depression-associated anxiety. The comparison drug, imipramine, was also found to be more effective than placebo treatment, although the treatment effect on depression-associated anxiety, as measured by several factors, was less than that seen with nefazodone. A subgroup of psychiatric clinic outpatients with comorbid major depression and panic disorder (N = 55) was identified by blinded record review. During nefazodone treatment, patients with panic disorder experienced marked global improvement compared with placebo-treated patients, including relief of panic and phobic anxiety symptoms. Imipramine treatment was not significantly better than placebo for improvement in depression and anxiety ratings in this patient group. These results extend previous findings indicating that the new antidepressant nefazodone effectively relieves anxiety and depressive symptoms of patients with major depression.

The efficacy of fluoxetine combined with a heterocyclic antidepressant in treatment-resistant depression: a retrospective analysis.

BACKGROUND: Treatment-resistant depression is a common clinical challenge that often requires the use of innovative pharmacologic treatments. Recent reports suggest the efficacy of the combination of a serotonin selective reuptake inhibitor and a heterocyclic antidepressant (HCA) in depressed patients who fail monotherapy with either agent alone. We present our clinical experience with the use of fluoxetine combined with an HCA in a group of 25 treatment-resistant depressed subjects. METHOD: Twenty-five depressed subjects who failed to adequately respond to at least 4 weeks of open-label fluoxetine treatment (mean dose = 73 mg/day) had an HCA added to their fluoxetine. The dose of the HCA was increased to maximize efficacy and minimize side effects. Efficacy was measured using the 21-item Hamilton Rating Scale for Depression (HAM-D-21) score and the Clinical Global Impressions-Global Improvement (CGI) scale. RESULTS: Response to treatment was defined as a 50% or greater drop in the HAM-D-21 score and a CGI of either very much improved or moderately improved from the start of the HCA. Seven (35%) of 20 subjects who demonstrated a poor or partial response to fluoxetine responded when an HCA was added to the fluoxetine. Five (71%) of the responders had previously failed to respond to monotherapy with the HCA that they responded to when used with fluoxetine. Additionally, 5 subjects who demonstrated significant improvement with fluoxetine but who had mild, residual depressive symptoms experienced at least partial further improvement with the addition of an HCA. CONCLUSION: The results suggest that the addition of an HCA to fluoxetine may be an effective treatment in treatment-resistant depressed patients who have failed to adequately respond to monotherapy with fluoxetine. Additional controlled trials are warranted to further explore the efficacy of this treatment combination in patients who demonstrate a poor or partial response to monotherapy. When using this drug combination, the clinician is cautioned to prescribe low doses of the HCA and monitor serum levels closely since fluoxetine can raise serum HCA levels.

Mood disturbance versus other symptoms of depression in multiple sclerosis.

We administered the Multiscale Depression Inventory (MDI) and the Beck Depression Inventory (BDI) to 84 multiple sclerosis (MS) patients, 101 patients diagnosed with major depression and 87 nonmedical, nonpsychiatric controls. The MDI consists of three separate depression scales measuring mood, vegetative, and evaluative symptoms. We found that: (a) MS patients did not significantly differ from the controls in mood symptoms, (b) the depression prevalence rate in MS patients was significantly lower when measured by the mood scale (17.7%) than by the BDI (30.5%) or MDI total score (26.6%), and (c) MS patients showed significantly less mood disturbance than a non-MS comparison group matched on BDI measured depression severity. We suggest that the inclusion of nonmood symptoms in self-report depression scales may artificially raise both prevalence rates and severity ratings of MS related depression and that the most valid measure of depression in MS is mood disturbance.

Management of comorbid anxiety and depression.

The coexistence of anxiety and depression is common and frequently poses diagnostic and treatment challenges in the clinical setting. Although precise diagnosis is important for treatment selection, it is often complicated by the shortcomings of the current classification system. Whereas some patients present with symptoms that meet the diagnostic criteria for both an anxiety disorder and major depression, others may present with "subsyndromal" symptoms of depression and/or anxiety. Epidemiologic data and a rational treatment approach to the patient with mixed anxiety and depression, depressive symptoms coexistent with "syndromal" and "subsyndromal" symptoms of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social phobia are discussed, as well as areas of future research to examine coexisting anxiety and depression.

Divalproex sodium in the treatment of refractory affective disorders.

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.

CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression.

We report on our clinical experience with a combination of a CNS stimulant (either pemoline or dextroamphetamine) and a monoamine oxidase inhibitor (MAOI) for treating 32 depressed patients (mainly outpatients) refractory to standard antidepressant pharmacotherapy. This combination, though not approved by the FDA, appears to be safe and effective. Twenty-five (78%) of these patients experienced at least 6 months of symptom remission with a stimulant + MAOI combination. Many patients required adjunctive antidepressant treatment, including tricyclics and lithium. Side effects were not excessive, though 6 patients (3 unipolar and 3 bipolar) cycled to mania (N = 1) or hypomania (N = 5). None developed hypertensive crises. With properly motivated and complaint patients and careful clinical monitoring by the prescribing psychiatrist, stimulant potentiation of MAOIs may be a viable option for treatment-resistant depressed patients.

Antidepressant combination and potentiation.

This chapter will describe the clinical indications and safety/efficacy factors of antidepressant potentiation. Examples include TCA/MAOI combinations, MAOI/stimulant combination, antidepressant potentiation with thyroid, lithium or l-tryptophan.

Innovative somatic treatments for depression.

This chapter will briefly review the current theories on the biochemical etiology of depression that are contributing toward the development of innovative somatic treatments. A description of clinically approved pharmacological treatments will be described in detail. Investigational pharmacological treatments that have demonstrated a high probability for general clinical use will also be discussed. Finally, a description of sleep deprivation will be included.