Stabilization treatment of remitted psychotic depression: the STOP-PD study.

OBJECTIVE: We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD). METHODS: Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination. RESULTS: The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change. CONCLUSION: Continuation of acute treatment was associated with stability of remission.

Rating scales measuring the severity of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD. METHOD: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed. RESULTS: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD. CONCLUSION: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice.

Measuring psychotic depression.

OBJECTIVE: Psychotic depression (PD) is a highly debilitating condition, which needs intensive monitoring. However, there is no established rating scale for evaluating the severity of PD. The aim of this analysis was to assess the psychometric properties of established depression rating scales and a number of new composite rating scales, covering both depressive and psychotic symptoms, in relation to PD. METHOD: The psychometric properties of the rating scales were evaluated based on data from the Study of Pharmacotherapy of Psychotic Depression. RESULTS: A rating scale consisting of the 6-item Hamilton melancholia subscale (HAM-D6 ) plus five items from the Brief Psychiatric Rating Scale (BPRS), named the HAMD-BPRS11 , displayed clinical validity (Spearman's correlation coefficient between HAMD-BPRS11 and Clinical Global Impression - Severity (CGI-S) scores = 0.79-0.84), responsiveness (Spearman's correlation coefficient between change in HAMD-BPRS11 and Clinical Global Impression - Improvement (CGI-I) scores = -0.74--0.78) and unidimensionality (Loevinger's coefficient of homogeneity = 0.41) in the evaluation of PD. The HAM-D6 fulfilled the same criteria, whereas the full 17-item Hamilton Depression Scale failed to meet criteria for unidimensionality. CONCLUSION: Our results suggest that the HAMD-BPRS11 is a more valid measure than pure depression scales for evaluating the severity of PD.

Persistent delusional theme over 13 episodes of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a highly debilitating condition, which needs intense monitoring and treatment. Among patients with recurrent PD, delusions tend to be very similar or identical over several separate episodes during the course of illness, but case-reports illustrating this clinical phenomenon in detail are lacking from the literature. METHODS: Case report describing the 45-year-old Ms. J, who has experienced multiple episodes of PD. The report is based on a review of her medical file. RESULTS: The delusional theme of Ms. J's initial episode of PD reappeared at several subsequent episodes. During the majority of admissions, Ms. J was treated with electroconvulsive therapy, which resulted in significant improvement in the depressive, psychotic and catatonic features. CONCLUSION: Ms. J's case illustrates that PD can be a stable phenotype over many episodes and that it is important to recognize psychotic symptoms in order to prescribe the best possible treatment.

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Depresión psicótica: la utilización del algoritmo aumenta las probabilidades de remisión / Psychotic depression: state-of-the-art algorithm improves odds for remision

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Sexual side effects of antidepressants.

Patients with depressive disorders frequently have concurrent sexual problems. The sexual dysfunction is often masked by the mood disorder, and many patients have difficulty discussing these problems openly. Thus, sexual dysfunction often is detectable only by careful inquiry. The relationship between sexual dysfunction and depressive disorders is further complicated by antidepressant therapy, which itself may cause sexual dysfunction, increasing the risk of noncompliance and relapse. This article reviews studies indicating that antidepressants may cause 30% to 40% of patients who take them to develop some degree of sexual dysfunction. Management strategies for alleviating sexual dysfunction as a complication of antidepressant treatment are discussed in terms of supporting research studies as well as practicality. Spontaneous resolution of antidepressant-induced sexual dysfunctions rarely occurs, and dose reductions may jeopardize the antidepressant effect. Antidotes, drug holidays, and timing sexual relations with respect to antidepressant dose are effective for some patients, but only a few of these strategies have been studied with double-blind paradigms. Switching to antidepressants that cause sexual dysfunction at lower rates and data comparing rates of sexual dysfunction among antidepressants are discussed.

Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness.

OBJECTIVE: At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions. METHOD: A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale. RESULTS: Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test). CONCLUSIONS: These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.

New directions in the treatment of antidepressant-induced sexual dysfunction.

OBJECTIVE: This article reviews options in the treatment of antidepressant-induced sexual dysfunction (SD). BACKGROUND: With adoption of structured interviews concerning sexual function, researchers have become increasingly aware that a substantial proportion of patients experience untoward sexual side effects from their antidepressants. As many as half of patients treated with selective serotonin reuptake inhibitors report delayed orgasm (ejaculation), and virtually all patients treated with clomipramine experience anorgasmia. Treatments proven to be effective include yohimbine, sildenafil citrate, buspirone, or other adjuncts, or a temporary drug holiday. SD is most effectively diagnosed and treated in the setting of an empathic physician-patient relationship, which includes frank discussions about sexuality. CONCLUSIONS: Although depressed patients do care about their sexual function, they may be reluctant, for fear of embarrassment, to report SD spontaneously to their physicians. SD is probably underreported and may result in covert noncompliance and attendant relapse into depression. Physicians thus need to assess sexual function during initial evaluation and throughout treatment. The importance of sexual function to sexually active patients with major depression should be weighed carefully when planning antidepressant therapy. A number of viable options exist to prevent or treat SD, including use of relatively new or novel antidepressants and appropriate adjunctive regimens.

Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients.

Several case reports have suggested that treatment with the benzodiazepine alprazolam can result in behavioral disinhibition. To address this question, the authors reviewed the medical records (blinded to all pharmacologic treatments the patients received) of 323 psychiatric inpatients treated with alprazolam (108 patients), clonazepam (111 patients), or no benzodiazepine (104 patients) between January 1989 and June 1990. During benzodiazepine treatment, there were no significant differences among the three groups on the following measures: (1) acts of self-injury (alprazolam, 1.9%; clonazepam, 1.8%; no benzodiazepine, 2.9%); (2) assaults on staff or other patients (alprazolam, 0%; clonazepam, 0.9%; no benzodiazepine, 1.0%); (3) need for seclusion or restraints (alprazolam, 3.7%; clonazepam, 6.3%; no benzodiazepine, 4.8%); (4) increased need for observation by hospital staff (alprazolam, 8.3%; clonazepam, 7.2%; no benzodiazepine, 6.7%); and (5) decrease in patient privileges (alprazolam, 11.1%; clonazepam, 12.6%; no benzodiazepine, 11.5%). The results indicate that in an inpatient psychiatric population, the frequency of behavioral disturbances with alprazolam, clonazepam, or no benzodiazepine does not differ. This suggests that alprazolam does not possess unique disinhibitory activity. Second, these data suggest that disinhibition may not be an important clinical problem associated with benzodiazepine use. The design of the study does not allow one to establish a relationship between the prescription of the benzodiazepine and worsening behaviors, and the findings need to be interpreted conservatively because it was a retrospective review of a heterogeneous population. However, it is noteworthy that the incidence of adverse events was low even in this high-risk population, and because the patients were in the hospital and under constant observation, the objective assessment of so-called paradoxical reactions was undertaken in a controlled setting.

Olanzapine response in psychotic depression.

BACKGROUND: Psychotic depression is more common than is generally realized, occurring in an estimated 16% to 54% of depressed patients. In controlled studies of patients with schizophrenia, the atypical antipsychotic olanzapine has been shown to be superior in efficacy to haloperidol at doses of 10 mg/day. Since olanzapine may have antidepressant effects in addition to its antipsychotic properties, the purpose of this study was to assess the safety and efficacy of olanzapine in the treatment of psychotic depression. METHOD: Hospitalized patients with the discharge diagnosis of DSM-IV psychotic depression (major depression with psychotic features or bipolar I disorder, depressed phase...with psychotic features) who had been treated with olanzapine during the first 9 months of its availability in the United States were identified. An age- and sex-matched sample of hospitalized patients with psychotic depression treated with other antipsychotics during the same time period was also identified. The medical records were expunged of all references to medication treatment and then reviewed and scored in a blind fashion for indications, doses, response, and side effects. RESULTS: Fifteen psychotic depression patients (10 women, 5 men), aged 36.9 +/- 10.1 years, who were treated with olanzapine were retrospectively compared with 15 psychotic depression patients (10 women, 5 men), aged 35.0 +/- 8.2 years, treated with other antipsychotics. Ten (67%) of 15 patients taking olanzapine were much or very much improved upon discharge compared with only 4 (27%) of 15 patients taking other antipsychotics (Fisher exact test, p = .037). Olanzapine was well tolerated: no patient discontinued the medication because of side effects. Twelve (80%) of 15 patients in each group were taking antidepressants in addition to the antipsychotic. Of the 3 patients taking olanzapine but not taking an antidepressant, 2 were much or very much improved (1 patient taking olanzapine alone, 1 taking olanzapine plus valproate sodium). CONCLUSION: Olanzapine appears to be effective and safe for patients with psychotic depression. Further prospective studies are warranted to ascertain whether olanzapine's unique pharmacologic profile may make it particularly useful for the treatment of psychotic depression either alone or in combination with antidepressants.

Treatment of antidepressant-induced sexual dysfunction.

Sexual dysfunction is a common side effect seen in patients taking selective serotonin reuptake inhibitors. Spontaneous resolution may occur in some patients, but modifications to therapy can be employed to eliminate undesirable side effects. These include reducing drug dosages, altering timing of drug dosages, taking drug holidays, adding an adjunctive drug, and switching to alternative antidepressants.

McLean Hospital depression research facility: early-onset phobic disorders and adult-onset major depression.

BACKGROUND: This study explores the temporal relationship between anxiety and major depressive disorders in a cohort of patients with current major depression. METHOD: Current prevalence and lifetime history of specific anxiety disorders were assessed using the Structured Clinical Interview for DSM-III-R Diagnosis (SCID-P) in 85 patients with DSM-III-R major depression. Consensus DSM-III-R diagnoses were assigned by at least two psychiatrists or psychologists. RESULTS: Twenty-nine per cent met criteria for at least one current anxiety disorder and 34% had at least one anxiety disorder at some point in their lives. The mean (s.d.) age of onset of anxiety disorder in the depressed patients with comorbid social or simple phobia (15 (9) years) was significantly younger than was that of their major depression (25 (9) years). In contrast, the mean (s.d.) age of onset of anxiety in patients with comorbid panic or OCD (20 (8) years) was similar to that seen for their major depression (21 (9) years). In patients with major depression with comorbid anxiety disorders, both the social phobia (10 of 13) and simple phobia (4 of 4) were more commonly reported to start at least two years prior to their major depression in contrast to depressives with comorbid panic (3 of 10 subjects)-Fisher's exact test, P = 0.01. CONCLUSIONS: Early-onset social and simple phobias appear to be risk factors for later onset of major depression.

Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments.

BACKGROUND: Many patients with unipolar depression experience a return of depressive symptoms while taking a constant maintenance dose of an antidepressant. METHOD: All cited studies were found using computerized literature searches of the MEDLINE database since 1966. RESULTS: The return of depressive symptoms during maintenance antidepressant treatment has occurred in 9% to 57% of patients in published trials. Possible explanations include loss of placebo effect, pharmacologic tolerance, increase in disease severity, change in disease pathogenesis, the accumulation of a detrimental metabolite, unrecognized rapid cycling, and prophylactic inefficacy. CONCLUSION: Although several strategies have been proposed to overcome the loss of antidepressant efficacy, double-blind controlled studies are needed to ascertain the optimal strategy for this perplexing clinical problem.

Psychiatrists' responses to failure of maintenance therapy with antidepressants.

Some patients being treated for recurrent major depression experience a return of depressive symptoms despite a constant maintenance dose of an antidepressant, a phenomenon known as breakthrough depression. A total of 145 psychiatrists who were members of the Massachusetts Psychiatric Society responded to a survey about intervention in hypothetical cases of breakthrough depression if the patient was taking either 20 mg of fluoxetine, 100 mg of sertraline, 100 mg of nortriptyline, or 40 mg of fluoxetine. For all drugs and dosages, the most popular choice was increasing the dosage, followed by augmenting with lithium or another antidepressant or changing to a different drug.

Basal ganglia choline levels in depression and response to fluoxetine treatment: an in vivo proton magnetic resonance spectroscopy study.

We have investigated proton magnetic resonance spectra of the basal ganglia in 41 medication-free outpatients with major depression, prior to starting an 8-week standardized trial of open-label fluoxetine, and 22 matched comparison subjects. Upon completing the trial, depressed subjects were classified as treatment responders (n = 18) or nonresponders (n = 23), based on changes in the Hamilton Depression Rating Scale. Depressed subjects had a lower area ratio of the choline resonance to the creatine resonance (Cho/Cr) than comparison subjects. This statistically significant difference between the depressed subjects and comparison subjects was more pronounced in the treatment responders than in the nonresponders. There were no differences in the relative volumes of gray matter or white matter in the voxel used for proton spectroscopy in depressed subjects relative to comparison subjects. These results are consistent with an alteration in the metabolism of cytosolic choline compounds in the basal ganglia of depressed subjects and, in particular, those who are responsive to fluoxetine.

Management of psychotic, treatment-resistant depression.

As there are no controlled studies on approaches to patients with treatment-resistant psychotic depression many questions remain to be answered. Those that seem worthy of high priority include (1) the efficacy of novel antipsychotic agents (e.g., clozapine, risperidone) for acute and maintenance treatment; (2) the efficacy of newer antidepressant agents such as the SSRIs and nefazodone plus neuroleptic medications; (3) decision trees to delineate the second and third lines of treatment when the first treatment is ineffective; (4) the comparative efficacy of bilateral versus unilateral ECT; (5) the length of time patients should be maintained on medications (which is of particular importance in the case of neuroleptic agents with their potential to cause tardive dyskinesia); (6) the optimal dose of neuroleptic agent for acute treatment; (7) the optimal length of time for medication trials; (8) the use of antidepressant medications during ECT treatments; (9) the importance of the sequence in which TCAs and neuroleptic agents are administered; (10) the delineation of the clinical characteristics of responders to medication versus ECT treatments; and (11) the role of antiglucocorticoid strategies. The answers to these questions would provide clinicians with important tools to treat patients with psychotic depression, an illness that all too frequently can become treatment-resistant.