Roman M. Dale

Valproate-induced hyperammonemic encephalopathy: a brief review

Abstract Background: This brief review presents a comprehensive evaluation of valproate-induced encephalopathy (VHE) and also discusses potential mechanisms of the condition. Scope: Sodium valproate (VPA) is an effective antiepileptic drug used in neurology as well as in psychiatry, in adults and children. VHE requires early diagnosis and management. Focused research efforts in understanding the condition will help decrease its incidence. Delay in recognition of VHE can result in the development of potentially life-threatening complications. Findings: Management options are described. Since VPA frequently causes a modest rise in plasma ammonia levels which is asymptomatic, it is important to recognize the symptoms of VHE promptly and to correlate them with the plasma ammonia levels. Conclusions: Although there are several case reports on VHE, this review is a comprehensive evaluation of its causes and potential mechanisms. Rapid diagnosis and management will help in reducing VHE-related morbidity.

Effects of electroconvulsive therapy on brain functional activation and connectivity in depression.

Objective Past neuroimaging work has suggested that increased activation to cognitive and emotional tasks and decreased connectivity in frontal regions are related to cognitive inefficiency in depression; normalization of these relationships has been associated with successful treatment. The present study investigated brain function before and after electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD) and demonstrated the effect of treatment on cortical activation patterns. Methods Six ECT-naive patients with depression (mean ± SD age, 39.0 ± 5.4 years) were treated with ECT. Within 1 week before and 1 to 3 weeks after ECT, the patients underwent a magnetic resonance imaging session with functional magnetic resonance image scanning during working memory and affective tasks and during rest. Changes in voxelwise statistical maps of brain response to each task in regions identified to be relevant from past studies of depression were compared with changes in depression severity as measured by the Hamilton Depression Rating Score. Changes in functional connectivity between brain regions were also compared with changes in depression severity. Results Activation during both tasks was generally found to be decreased after ECT. Remission of depression was significantly associated with reduced affective deactivation after ECT in the orbitofrontal cortex (P = 0.03). Whole-brain functional connectivity of the anterior cingulate cortex showed a consistent increase in connectivity to the right dorsolateral prefrontal cortex and posterior cingulate cortex after ECT. Conclusions These results suggest that successful ECT for MDD is associated with decreased activation to cognitive and emotional tasks and an increase in resting connectivity.

A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression.

BACKGROUND Acute administration of subanesthestic doses of intravenous ketamine have been shown to elicit a rapid antidepressant response in patients with treatment-resistant depression. However, it remains to be seen if repeated doses over a longer period of time will have the same effects. Here, we assess the long-term efficacy of repeated intravenous ketamine infusions in three patients with high treatment-resistant depression via a naturalistic observation study. METHOD Three patients consented to intravenous ketamine infusions as a therapy for their treatment-resistant depression. Patients were administered ketamine at 0.5mg/kg of ideal body weight over 40 min followed by a saline flush until discharge. Severity of depressive symptoms was rated with the Montgomery-Asberg Depression Rating Scale. RESULTS All three patients responded to the ketamine infusions, but each went through an individualized course of treatment based on their own response. LIMITATIONS This was an open-label naturalistic observation without blinding, randomization, or a placebo control. CONCLUSIONS These cases add to the literature supporting the therapeutic effect of low-dose repeated intravenous ketamine for patients with treatment-resistant depression. Further study is needed to define the risks, benefits, indications, and contraindications of this potential treatment.

A Critical Examination of Bifrontal Electroconvulsive Therapy : Clinical Efficacy, Cognitive Side Effects, and Directions for Future Research

Bifrontal (BF) electroconvulsive therapy (ECT), although researched less extensively than bitemporal (BT) or right unilateral (RUL) ECT, has been suggested to be comparable to the other 2 electrode placements with respect to clinical efficacy while resulting in less cognitive impairment than BT ECT. Imaging studies have indicated that seizures induced by BF ECT affect the brain differently than BT or RUL ECT, in that BF ECT increases cerebral blood flow in the frontal lobes more intensely than either of the other 2 placements. Therefore, it is possible that the cognitive impairment manifested after a course of BF ECT could also be different than the impairment seen with BT and RUL ECT. Research conducted on cognitive impairment from BF ECT to date has been inadequate due to the use of nonspecific cognitive measures (such as the Mini-Mental Status Examination) or an inordinate focus on memory functioning (which is believed to be mostly subsumed in the temporal lobes). Because BF ECT increases cerebral blood flow in the frontal lobes more intensely than either of the other placements, research must instead focus on investigating the possible effects of BF ECT on executive functioning, which is believed to be subsumed in the frontal lobes. This is especially important because of the established relationship between executive dysfunction and depression and also because of the increasing popularity of BF ECT.

Failed response to repeat intravenous ketamine infusions in geriatric patients with Major Depressive Disorder

Geriatric depression has reported prevalence rates of 1.6 to 15% of the population1. New effective fast-acting treatment modalities in this population would be cost saving and alleviate suffering and disability for the patients and their families. The rapid onset of antidepressant effect produced by subanesthetic intravenous (IV) ketamine provides such a promise. Single2, 3 and repeat 4-7 ketamine infusions have been shown to produce an antidepressant effect within hours with a sustained effect lasting days to weeks. But not all depressed patients who are administered ketamine have a response. Using a 50% reduction in baseline symptoms as the response criteria, response rates of 43-90% are reported within 40 minutes, 24 hours, and 72 hours post-infusion8. Although a large number of patients do respond, studies to accurately predict who responds are at an early stage. Here, we report a case series where IV ketamine infusions in geriatric patients with Treatment Resistant Depression (TRD) did not prove beneficial. Four patients (mean (± SD) age, 72.25 (± 5.38) years) admitted to an inpatient psychiatric unit due to a relapse in their Major Depressive Disorder (MDD), with histories of multiple failed medication trials and failed electroconvulsive therapy (ECT), were offered IV ketamine treatments, as described elsewhere9. An Institutional Review Board approved retrospective chart review was conducted for this case series. After the initial inpatient infusion demonstrated no physiological concerns, the infusions were continued on an outpatient basis. Prescribed medications were continued throughout the infusions.

Binge eating in adults with mood disorders: Results from the International Mood Disorders Collaborative Project

A post hoc analysis was conducted using data from participants (N=631) with a DSM-IV-TR defined diagnosis of major depressive disorder (MDD) or bipolar disorder (BD) who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. It was determined that 20.6% of adults with mood disorders as part of the IMDCP fulfilled criteria for binge eating behaviour (BE). A higher percentage of individuals with BD met criteria for BE when compared to MDD (25.4% vs. 16%; p=0.004) Univariate analyses indicated that individuals with a mood disorder (i.e., MDD or BD) and BE had greater scores on measures of anxiety severity (p=0.013) and higher rates of lifetime and current substance dependence, lifetime alcohol abuse (p=0.007, p=0.006, and p=0.015, respectively), Attention Deficit Hyperactivity Disorder (ADHD) (p=0.018) and measures of neuroticism (p=0.019). Individuals with a mood disorder and concurrent BE had lower scores on measures of conscientiousness (p=0.019). Individuals meeting criteria for BE were also significantly more likely to be obese (i.e., BMI≥30kg/m2) (50% vs. 25.5%; p<0.001). Binge eating is common amongst adults utilising tertiary care services principally for a mood disorder. The presence of BE identifies a subset of adults with mood disorders who have greater illness complexity as evidenced by course of illness variables and comorbidity. Screening for BE amongst individuals with mood disorders is warranted; parsing neurobiological substrates subserving non-homeostatic eating behaviour amongst individuals with mood disorders is a future research vista.

Valproate-Induced Hyperammonemic Encephalopathy in General Hospital Patients With One or More Psychiatric Disorders

BACKGROUND Divalproex sodium/valproic acid (VPA) is an antiepileptic drug approved for use in epilepsy and bipolar disorder. Valproate-induced hyperammonemia occurs in up to 50% of VPA-treated patients, some of whom may become encephalopathic. Valproate-induced hyperammonemic encephalopathy (VHE) is thought to be rare, and for a variety of reasons, the diagnosis requires a high index of suspicion. OBJECTIVE The studys goals are to determine how common VHE is, and the quality of treatment provided when diagnosed. METHODS Retrospective, cross-sectional survey of general hospital patients. The hospitals laboratory and pharmacy databases were combined to identify a cohort of all VPA-treated patients who developed hyperammonemia during a 5-year period. Hospital records of the subset of patients with a psychiatric disorder were selected and reviewed for data collection. RESULTS Twenty of 793 (2.52%) VPA-treated patients had signs and symptoms consistent with VHE. The majority were White males on multiple psychotropic agents. Valproate was appropriately discontinued in 8 (40%) patients. Lactulose was the only ammonia-lowering drug used, and it was administered to 6 patients and only one among them had VPA discontinued. CONCLUSION Study results indicate that VHE may be more common in psychiatric patients than previously assumed but underrecognized and inadequately treated. The diagnosis of VHE requires a high index of suspicion. Outcome is favorable once it is recognized and treated appropriately.

Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project

BACKGROUND Cognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia. METHOD A post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations. RESULTS A total of 369 adults with DSM-IV-TR-defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery-Åsberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007). CONCLUSIONS These preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.