Ahsan Y. Khan

Factors associated with chronic depressive episodes: A preliminary report from the STAR-D project

Objective:  To identify baseline sociodemographic and clinical factors associated with a current chronic major depressive episode (MDE).

Substance use in persons with schizophrenia: Baseline prevalence and correlates from the NIMH CATIE study

This study examined baseline correlates of substance use in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness project. Approximately 60% of the sample was found to use substances, including 37% with current evidence of substance use disorders. Users (with and without substance use disorders), compared with nonusers, were significantly more likely to be male, be African-American, have lower educational attainment, have a recent period of homelessness, report more childhood conduct problems, have a history of major depression, have lower negative symptom and higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. Individuals with comorbid substance use disorders were significantly more likely to be male, report more childhood conduct problems, have higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. These analyses suggest that substance use disorders in schizophrenia are especially common among men with a history of childhood conduct disorder problems and that childhood conduct disorder problems are potent risk factors for substance use disorders in schizophrenia.

Clinical and Demographic Factors Associated With DSM-IV Melancholic Depression

BACKGROUND The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression. METHODS Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants. RESULTS Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance. CONCLUSIONS Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.

Examining Concentration-dependent Toxicity of Clozapine: Role of Therapeutic Drug Monitoring

Highly variable plasma concentrations are found in patients receiving the same dose of clozapine. Therefore, rational dose adjustment of clozapine that is guided by therapeutic drug monitoring (TDM) can improve efficacy while reducing risk of toxicity. As a background to the discussion of the use of TDM for clozapine, the pharmacodynamics and pathways of clozapine biotransformation are first reviewed, in particular the role of the primary enzymes involved. These are CYP1A2, the primary enzyme involved in converting clozapine to norclozapine, and CYP3A4, the primary enzyme involved in converting clozapine to clozapine-N-oxide. The factors that can influence plasma levels of clozapine are next reviewed; these include dose, gender, smoking, age, body weight, caffeine intake, and drug-drug interactions. The authors then examine the concentration-dependent toxicity of clozapine based on a review of published data. Finally, the authors present four cases illustrating the issues involved and how TMD can be used to improve clinical care of patients being treated with clozapine, both in terms of improving efficacy and minimizing potential toxicity.

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

OBJECTIVE The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

The effectiveness of antipsychotic medications in patients who use or avoid illicit substances: Results from the CATIE study

OBJECTIVE This double-blind study compared a second generation (atypical) antipsychotic drugs compared to a representative older agent for patients with schizophrenia who use or avoid illicit substances. METHODS Schizophrenic subjects were recruited at 57 U.S. sites and randomly assigned to olanzapine, perphenazine, quetiapine, risperidone or ziprasidone for up to 18 months. The primary aim of this analysis was to delineate differences between the overall effectiveness of these five treatments among patients who used or did not use illicit substances. RESULTS There were no significant differences between treatment groups in time to all-cause treatment discontinuation among patients who use illicit drugs (median 3.3 to 6.8 months). Among non-users time to treatment discontinuation was significantly longer for patients treated with olanzapine (median 13.0 months) than perphenazine ( 5.9 months), risperidone (5.6 months), or quetiapine (5.0 months); time to discontinuation for ziprasidone (4.3 months) was even shorter, although the latter difference was not significant. The difference between risperidone and quetiapine, although small, was significant. All remaining differences were non-significant. Similar results were found for discontinuation due to inefficacy. There were no differences between illicit users and non-users in symptom reduction and global improvement, after adjustment for differential duration of treatment. Differences in discontinuation results were attenuated by non-compliance, but the trends persisted after controlling for treatment compliance. CONCLUSIONS Among patients with chronic schizophrenia who avoid use of illicit drugs, olanzapine was more effective than other antipsychotics as reflected by longer time to all-cause discontinuation, but illicit substance abuse attenuated this advantage, reinforcing the need for concurrent substance abuse treatment.

Effect of study criteria on recruitment and generalizability of the results.

Objective: Clinical trials are indispensable to drug approval process. This research examined the effect of a specific study criteria on recruitment and generalizability of the results. Methods: The following were reviewed: (a) the usual inclusion and exclusion criteria for the antipsychotic trials performed at the Institute; (b) epidemiologic data, to determine the effect of study criteria on the target population; and (c) the recruitment procedures/strategies used to identify potential candidates. A survey was conducted to determine the percentage of schizophrenic patients in a conventional outpatient psychiatric clinic conforming to the usual enrollment criteria for antipsychotic trials. Results: Intensive recruitment efforts in a general population of 3.6 million would have been expected to yield only 632 eligible subjects out of 36,000 suffering from schizophrenia. Out of 632, only 50 contacted the research site after an intensive recruitment effort. From those 50, 30 were excluded during a telephone interview. Of the 20 remaining, 6 were excluded for a variety of reasons during a face-to-face interview. Thus, only 14 subjects out of a population of 3.6 million met the study criteria. Conclusions: These results emphasize the rarified nature of patients-volunteers who enter a clinical trial. Inclusion and exclusion study criteria can severely restrict the number of eligible subjects, dictate recruitment strategies, and in turn affect generalizability of the results.

Effects of Race and Ethnicity on Depression Treatment Outcomes: The CO-MED Trial

OBJECTIVE The investigators examined whether outcomes differ by race-ethnicity for patients with major depressive disorder in acute- (12 weeks) and continuation-phase (weeks 12-28) treatment with one of two antidepressant combinations or one selective serotonin reuptake inhibitor. METHODS This single-blind, seven-month prospective, randomized trial enrolled 352 non-Hispanic white (59%), 169 black (28%), and 79 white Hispanic (13%) participants from six primary and nine psychiatric care U.S. sites. Patients had nonpsychotic chronic or recurrent major depressive disorder (or both) of at least moderate severity. Escitalopram plus placebo, bupropion sustained-release plus escitalopram, or venlafaxine extended-release plus mirtazapine were delivered according to measurement-based care. The primary outcome was remission (last two consecutive 16-item Quick Inventory of Depressive Symptomatology-Self-Report ratings <8 and <6); secondary outcomes included side effects, adverse events, quality of life, function, and attrition. RESULTS Black participants had greater baseline psychiatric and medical comorbidity. Baseline depression severity did not significantly differ between groups. In both phases more blacks than those in other groups exited the trial early. There were only minor differences in side effects, no significant differences in remission rates, and no significant differences between groups in other outcomes for each treatment. CONCLUSIONS Despite differences in sociodemographic characteristics and comorbidities, when measurement-based care was used, members of different minority groups had similar outcomes when treated with one antidepressant or a combination of two antidepressants. Black participants had the highest attrition rate, an important issue to address in clinical care.

Diurnal mood variation in outpatients with major depressive disorder

Background: Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features of major depressive disorder (MDD) according to the Diagnostic and Statistical Manual. This report used data from the sequenced treatment alternatives to relieve depression study to determine whether DMV was associated with treatment outcome to citalopram. Methods: Two thousand eight hundred and seventy‐five outpatients with nonpsychotic MDD were evaluated during a 14‐week trial of the selective serotonin reuptake inhibitor citalopram. Participants were divided into three groups: those with “classic” DMV (early morning worsening), those with any form of DMV (morning, afternoon, or evening worsening), and those with no DMV. Participants with classic DMV and those with any form of DMV were compared to those with no DMV in terms of baseline sociodemographic and clinical characteristics, treatment outcomes, and treatment features. Results: Minor baseline clinical characteristics and treatment feature differences were found between participants with and without DMV. Participants with classic morning DMV had slightly higher response rates than those without DMV. However, no differences were found in response or remission between either group of participants with DMV and those with no DMV. Conclusion: DMV does not appear to be associated with a unique prominent pattern of response to selective serotonin reuptake inhibitor treatment in patients with depression, and does not appear to be a serotonergically modulated process. Further evaluation is necessary to determine if this relationship holds true for dopaminergic and noradrenergic antidepressant agents, such as dual‐acting agents or antidepressant medication combinations. Depression and Anxiety, 2009.

Can hypnosis differentiate epileptic from nonepileptic events in the video/EEG monitoring unit? Data from a pilot study

OBJECTIVE An estimated 24% of patients referred to epilepsy clinics actually have nonepileptic seizures. Various procedures have been used to precipitate nonepileptic events. The goal of this study was to use hypnosis in seizure provocation and differentiation between epileptic and nonepileptic seizure events. METHODS Fifty study participants were enrolled from the Via Christi Comprehensive Epilepsy Centers video/electroencephalography unit. Patients underwent the Hypnotic Induction Profile (HIP) to assess susceptibility to hypnosis. After completion of the HIP, participants underwent hypnosis by a physician trained to do so. They received a hypnotic suggestion to have a seizure. All seizure-like events were classified as either an epileptic, nonepileptic, or undetermined event based on whether or not the patient had abnormal EEG activity during the event. RESULTS Of the 50 participants enrolled, 3 withdrew consent, resulting in 47 participants. Seven (15%) participants failed to have an event of any type and were classified as undetermined. Sixteen (34%) participants were classified as having epileptic seizure events, and 24 (51%) participants had nonepileptic events. Most participants were Caucasian (87%), female (57%), and unemployed (55%). HIP scores ranged from 0 to 10. Participants classified with nonepileptic scores had higher mean HIP scores (8.08, SD 2.483) than those diagnosed with epileptic seizures [5.94, SD 3.492, t(25)=2.126, P=0.044]. The sensitivity of eliciting a nonepileptic event during hypnosis was only 0.46, but the specificity was 0.88. CONCLUSION Hypnosis may be considered as a method of seizure provocation. Events provoked by hypnotic suggestion were more likely than not to be nonepileptic events. However, the current study has moderate specificity and poor sensitivity. Seizures could not be induced in patients who did not also have spontaneous seizures. Additional methodologies for seizure provocation need to be explored.