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Purpose/background Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years. Methods/procedures We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT. Findings/results A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare. Implications/conclusions The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT.

Objective This study aims to investigate the clinical effects of benzodiazepines or anticonvulsant use during a course of electroconvulsive therapy (ECT). Method A case report study of a patient who received ECT with and without concomitant flurazepam and pregabalin is presented. The literature on the use of benzodiazepines and anticonvulsants during ECT is reviewed. Results A woman with treatment resistant depression received a course of ECT while taking flurazepam and pregabalin, but seizures were of short duration and symptomatic improvement was minimal. After discontinuation of flurazepam and pregabalin, a course of right unilateral ultrabrief ECT was associated with adequate seizures and remission of depression and suicidal ideation. Our literature review suggests that benzodiazepines decrease seizure duration, but most evidence shows no association with increased seizure threshold. One prospective RCT and 3 large retrospective studies found that benzodiazepines compromise the efficacy of unilateral but not bilateral ECT. Regarding anticonvulsants, several studies had varied and contradictory results on their effect on seizure duration and seizure threshold. Of the 2 large retrospective studies and 3 RCTs, only 1 retrospective study showed that anticonvulsants decrease the efficacy of ECT. Conclusions Judicious assessment of all medications used in combination with ECT is recommended. Overall, published studies suggest that benzodiazepines and anticonvulsants impact the clinical outcomes of ECT less than what would be expected given their pharmacologic effects. However, there are significant gaps in the literature, including a lack of study on suprathreshold stimulation of right unilateral ECT and the possibility of a greater effect with higher medication doses.

Tardive dyskinesia (TD) is a debilitating adverse effect associated with antipsychotic treatment. Older age and the presence of mood disorder have been identified as risk factors for the development of TD. Thus, we assessed the incidence of TD in younger and older patients with major depressive disorder with psychotic features who participated in a 12-week clinical trial comparing olanzapine plus sertraline versus olanzapine plus placebo. All subjects (n = 259) were assessed with the Abnormal Involuntary Movement Scale at baseline and after 4, 8, and 12 weeks of treatment (or at termination). We used 7 different published criteria to estimate the prevalence of TD at baseline and the incidence over the duration of the trial. We compared the incidence of TD in subjects 60 years or older and those younger than 60 years. The overall prevalence and incidence of TD varied almost 10-fold, depending on the criteria (prevalence range, 1.2%-8.9%; incidence range, 0.0%-5.9%). Tardive dyskinesia was observed as a clinical adverse event in only 1 subject (0.4%). Whereas older subjects had a higher prevalence of TD at baseline, the incidence in younger and older subjects did not differ significantly. The incidence of TD was relatively low in both younger and older patients with major depressive disorder with psychotic features treated acutely with olanzapine. However, the estimate of the risk of TD varies widely, depending on the criteria used to define TD.

Sensitivity to psychotropic medications presents a therapeutic challenge when treating neuropsychiatric symptoms in patients with dementia with Lewy bodies (DLB). We compared under randomized, double-blinded conditions the tolerability and efficacy of citalopram and risperidone in the treatment of behavioral and psychotic symptoms in patients with DLB and Alzheimer disease (AD). Thirty-one participants with DLB and 66 with AD hospitalized for behavioral disturbance were treated under randomized, double-blind conditions with citalopram or risperidone for up to 12 weeks. Neuropsychiatric symptoms were assessed with the nursing home version of the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). Side effects were measured using the UKU Side Effect Rating Scale. A significantly higher proportion of participants with DLB (68%) than with AD (50%) discontinued the study prematurely. Discontinuation rates were comparable in DLB participants treated with citalopram (71%) or risperidone (65%). However, participants with DLB randomized to risperidone experienced a higher overall burden of side effects. Scores on the NPI and the CGIC worsened in DLB participants and improved in those with AD. Most patients with behavioral disturbances or psychosis associated with DLB tolerate citalopram or risperidone poorly and do not seem to benefit from either medication.

Objective: Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite—N-desmethylclozapine (NDMC)—could explain these discrepancies. Methods: Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC. Results: Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/ NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model. Conclusions: After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.

The risk/benefit ratio of pharmacotherapy for behavioral symptoms of dementia is questionable: second-generation antipsychotics are poorly tolerated, and the efficacy of alternative treatments, for example, selective serotonin-reuptake inhibitors (SSRIs), is uncertain. Biomarkers of treatment response may improve this risk/benefit ratio. The length polymorphism of the serotonin transporter promoter gene (5-HTTLPR/SLC6A4) may moderate tolerability of SSRIs and expression of behavioral symptoms in dementia. We assessed the effect of 5-HTTLPR on tolerability and efficacy of citalopram and risperidone in a 12-week randomized controlled trial, which included nondepressed patients with dementia hospitalized for behavioral or psychotic symptoms. Genotypes including the A/G polymorphism of the L allele (rs25531) were determined in 92 of 103 participants. We used pattern-mixture models to account for dropout. Low-expression alleles (S and Lg) predicted greater early and overall side effects of citalopram and early treatment discontinuation. These results remained unchanged after excluding African-American participants and in covariate analyses. Unexpectedly, low-expression alleles seemed to predict greater early side effects of risperidone (but not early discontinuation) and poorer early response of psychosis symptoms to risperidone. In conclusion, 5-HTTLPR may be a useful biomarker of SSRI intolerance in dementia. Our findings of intolerance of a second-generation antipsychotics and persistence of psychosis in patients with low-expression alleles needs to be replicated.

PURPOSE OF REVIEW Biomarkers in clinical medicine are used to detect or diagnose specific illnesses, predict disease progression, and predict the response to treatment. As the proportion of adults over 65 years of age rises, there is a growing need to detect neurodegenerative disease at an earlier stage with the goal of improving treatment for highly prevalent illnesses such as late-life depression and dementia. RECENT FINDINGS The search for biomarkers of late-life mental disorders includes the exploration of structural neuroimaging, functional neuroimaging, genomics, proteomics, noninvasive neurophysiology, cerebrospinal fluid, and plasma analysis. Novel structural and functional neuroimaging techniques that have recently been developed show promise as biomarkers of both late-life depression and specific dementia syndromes. The fields of proteomics and genomics are advancing our ability to identify genes and aberrant proteins that detect preclinical dementia. As depression is often a harbinger of dementia in late life, recent studies are beginning to elucidate the relationship between different types of late-life depression and the subsequent emergence of dementia. SUMMARY Biomarker research in late-life mental disorders is progressing at a rapid pace. The application of current biomarkers to clinical practice may be on the horizon with further research that refines their sensitivity and specificity.

Weight gain has often been associated with olanzapine treatment, yet little is known about the influence of patient age or cumulative dose on olanzapine-associated weight gain. The first 118 participants in the National Institutes of Mental Health Study of the Pharmacotherapy of Psychotic Depression randomized clinical trial (Clinical Trials.gov Registration NCT00056472) completing at least 4 weeks of treatment with olanzapine were analyzed to determine the relationship between weight gain, age, and cumulative olanzapine dose. Younger (age 18-59 years) and older (age 60 + years) participants received open-label olanzapine and either sertraline or placebo for up to 12 weeks. Linear mixed effect regression modeling was used to determine the effects of age and cumulative olanzapine dose on weight gain, controlling for potential confounders. Age was observed to have a significant negative association with weight gain (P=0.01), even after controlling for differences in cumulative dose and baseline body mass index. Each 10-year increase in age was associated with a decrease in mean weight gain over 12 weeks of approximately 0.6 kg (95% confidence interval: 0.14-1.05 kg). Cumulative olanzapine dose was also significantly associated with weight gain (P< 0.0001). Approximately 60% of completers of the 12-week trial experienced clinically significant weight gain (≥ 7% of baseline weight).

OBJECTIVE: To determine if educating nursing home staff about pressure ulcer prevention reduces the differential risk of pressure ulcer development in black and white nursing home residents. DESIGN: Subanalysis of a study designed to monitor the emergence of all pressure ulcers in nursing home residents during 12-week baseline and intervention periods. PARTICIPANTS: All residents and staff of a not-for-profit, 136-bed nursing home in urban western Pennsylvania. MAIN OUTCOME MEASURE: The quality improvement intervention, featuring a computer-based interactive video education program on pressure ulcer prevention and early detection, consisted of 3 components: (1) staff ability enhancement, (2) staff financial incentives, and (3) real-time management feedback. Three specific outcome measures were monitored for differential risk of pressure ulcer development in black and white nursing home residents: (1) the rate of emergent Stage I-IV pressure ulcers identified, (2) the rate of emergent Stage II-IV pressure ulcers identified, and (3) the rate of individual residents developing at least 1 pressure ulcer (Stages II-IV). RESULTS: At baseline, black residents demonstrated a higher rate of Stage II-IV pressure ulcer emergence. Black residents with any pressure ulcer were also more likely to have multiple Stage II pressure ulcers compared with white residents. During the baseline period, 31.8% of the pressure ulcers detected in white residents were Stage I, whereas no Stage I pressure ulcers were detected in black residents. During the intervention period, the rate of emergence of all pressure ulcers declined for both groups in similar trends. CONCLUSION: Black residents were more likely to have multiple Stage II-IV pressure ulcers and were less likely to have Stage I pressure ulcers identified at baseline compared with white residents. The education intervention effectively reduced the rate of pressure ulcers for all residents and eliminated the racial disparity noted during the baseline period.

Background: To determine the optimal duration of an antidepressant trial in elderly patients, the authors examined the probability of eventually responding to treatment based on early improvement. Methods: Four hundred seventy-two elderly patients with major depression (nonpsychotic, nonbipolar) were treated under protocolized conditions for up to 12 weeks and assessed weekly with the Hamilton Rating Scale for Depression. The probability of full response after 12 weeks of treatment was calculated in patients who had not fully responded after periods of treatment that lasted for 4 to 10 weeks. Results: Most of the patients who had shown a partial improvement after 4 weeks of treatment became full responders after 4 or more additional weeks of treatment. By contrast, only a few of those who were nonresponders became full responders even after up to 8 additional weeks of treatment. Conclusions: After 4 weeks of treatment, it is possible to reliably identify a subgroup of elderly patients with depression who are more likely to benefit from a change in their treatment than from a few additional weeks of treatment with the same agent.

The electrical dosage of the ECT stimulus impacts on efficacy and cognitive side effects, yet seizure threshold (ST) may vary as much as 50-fold across patients. It would be desirable to predict ST on the basis of patient and treatment characteristics. In particular, concerns have been raised that benzodiazepine use and higher dosage of barbiturate anesthetics elevate ST. In a three-site study, ST was quantified at the first ECT session using an identical empirical titration procedure in 294 patients who met RDC and DSM-IIIR criteria for a major depressive episode. ST varied over a 35-fold range across patients treated with right unilateral (RUL) (n = 267) and bilateral (BL) (n = 27) ECT. Higher ST was associated with BL electrode placement (p = 0.001). Among patients treated with RUL ECT, univariate analyses indicated that higher ST was associated with advanced age (p < 0.001), male gender (p < 0.001), greater burden of medical illness (p < 0.001), weight (p < 0.01), duration of mood disorder (p < 0.01), and history of previous ECT (p < 0.05). Average lorazepam dose in the 48 hours prior to ECT was not associated with ST, but was associated with decreased seizure duration (p < 0.01). Absolute, but not weight-adjusted, methohexital dose was associated with ST (p < 0.01). Multivariate analyses in patients treated with unilateral ECT showed that only 27.6% of the variance in ST (p < 0.0001) could be predicted. In the multivariate analyses, only age (p = 0.0001), gender (p = 0.01), and methohexital dose (p = 0.0001) were independently related to ST. Low dosage of lorazepam and methohexital dosage below 1 mg/kg are unlikely to impact on ST. Given the limited capacity to predict ST, empirical titration remains the only accurate method to determine electrical dosage in RUL ECT.