Inflammation, Antipsychotic Drugs, and Evidence for Effectiveness of Anti-inflammatory Agents in Schizophrenia.

In recent years, there is a new optimism in schizophrenia therapeutics with the emergence of immunomodulation as a potential treatment approach. Current evidence points to various immunological abnormalities in schizophrenia, including cell-mediated processes, acute phase proteins, cytokines, and intracellular mediators. Trait- and state-related immune dysfunction appears to exist, and a strong case can therefore be made for immunomodulation therapies in the prevention, treatment, and/or moderating the course of schizophrenia.Immunomodulation approaches include use of nonsteroidal anti-inflammatory agents to stop or moderate an over-activated inflammatory process, anti-oxidants, nutrients, vitamins, herbal products, and other neuroprotection agents that inhibit pro-inflammatory processes, optimal use of antipsychotic drugs (APDs) that may have anti-inflammatory actions or in certain cases such as clozapine may enhance blunted inflammatory responses, and biological agents to antagonize specific immune mediators such as the cytokines. A combination of two or more of the above approaches is also worthy of consideration.In this chapter, the available data for each of the above approaches is reviewed and discussed. Strengths and limitations of current studies are identified, and suggestions are made for future studies. For example, identifying patients with high levels of specific biomarkers such as C-Reactive Protein, IL-6, IFN-γ, TNF-α, and genetic polymorphisms of cytokines, and match them with clinical subgroups such as prodromal, first episode psychosis, chronic psychosis, and negative symptoms with the aim of developing targeted treatment approaches and more personalized medicine. Meanwhile, since the science and trial data are not advanced enough to make definitive recommendations, clinicians should stay up to date with the literature, obtain detailed immunological histories, and review the risk-benefit ratio of adding available immune modulating agents to standard therapies, to provide optimal and state-of-the-art care to patients.

Caffeine Sodium Benzoate for Electroconvulsive Therapy Augmentation.

OBJECTIVES: Because of an ongoing manufacturer shortage of injectable caffeine sodium benzoate (CSB), patients at our health system were given CSB compounded in-house to increase seizure response during electroconvulsive therapy (ECT). Therefore, we aimed to evaluate its effectiveness and safety as an ECT augmentation agent. METHODS: Medical records of patients who received compounded CSB at Virginia Commonwealth University Health System were reviewed to identify adults receiving it as part of an index ECT treatment course between June 2012 and December 2016. The primary outcome was change in electroencephalogram seizure duration from pre-caffeine session to initial caffeine session. Data were also collected on demographics, motor seizure duration, maximum heart rate, mean arterial pressure, and concurrent medication use for these sessions and the last caffeine session. RESULTS: Seven-one patients were included in the study, predominantly white females with a mean age of 58.6 years. The most common indication for ECT was major depressive disorder resistant to pharmacotherapy (71.8%), followed by catatonia associated with another mental disorder (19.7%). Electroencephalogram seizure duration increased by 24.1 seconds on average with first CSB use (P < 0.0001), allowing 24 more patients overall to achieve goal of at least 30 seconds (P < 0.0001). No clinically significant changes in maximum heart rate or mean arterial pressure were observed, nor did any patients require an abortive agent for prolonged seizure. Five patients (7%) discontinued CSB prematurely: 4 related to adverse effects and 1 secondary to ineffectiveness. CONCLUSIONS: We confirm results of prior studies of the utility of CSB and add that compounded CSB is effective for ECT augmentation, maintaining effectiveness throughout the index course with minimal safety concerns.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING: Abbott (previously St Jude Medical).

A pilot study of body image perceptions, and attitudes toward obesity in hospitalized psychotic and non-psychotic patients.

OBJECTIVE: Body image perceptions, and attitudes toward obesity were examined and compared between psychotic and non-psychotic patients with a mood disorder. METHODS: 80 psychotic patients and 36 non-psychotic patients with a mood disorder admitted to an acute inpatient psychiatric unit participated in the study. On admission, each patient completed a visual silhouettes scale of actual self and ideal self, as well as the Attitudes Toward Obese Persons (ATOP) scale. RESULTS: Analogous to the general population, psychotic and non-psychotic patients had similar body image perceptions, and experienced discrepancy between actual and ideal body image. Female patients with serious mental illness (SMI) picked a heavier actual self body image, and experienced greater discrepancy between actual and ideal body image compared to male patients with SMI. Psychotic and non-psychotic patients experienced similar mostly neutral attitudes toward obese persons, however there was a trend for depressed patients to have more negative attitudes toward obese persons compared to non-depressed patients. DISCUSSION: The presence of an acute psychotic episode did not affect body perceptions, or obesity attitudes; however depressed patients had more negative obesity attitudes. Similar to the general population, females with SMI overassessed their body size, and experienced more body dissatisfaction compared to males with SMI.

Augmentation Therapy With Serial Intravenous Ketamine Over 18 Months in a Patient With Treatment Resistant Depression.

Major depressive disorder is a severe illness that affects 3% to 7% of adults annually in the United States. About 30% of these individuals are refractory to multiple treatment trials. Recent reports have found a significant and almost immediate improvement in depressive symptoms after single or multiple ketamine intravenous infusions (IVIs) in such patients. We present the case of A.B., a patient with treatment-resistant depression (TRD) including to subgenual deep brain stimulation, who went into remission after augmentation with 6 ketamine IVIs (0.5 mg/kg) over a 3-week period. However, she had a reemergence of depressive symptoms 4 months later and received a second series of 3 ketamine IVIs over the course of a week. A.B. again went into remission and maintained this for the next 8 months. At this time, she experienced a reemergence of depressive symptoms and was treated with the third series of ketamine IVIs (3 infusions over the course of a week). Because A.B. has now been in remission for 6 months. A.B. has received a total of 12 ketamine IVIs over the course of 18 months. No significant adverse events have occurred. To our knowledge, this is the first case of long-term ketamine efficacy as augmentation therapy in TRD over the course of 18 months. There is a need for studies examining the long-term management of TRD with IV ketamine. Guidelines for maintenance ketamine IVIs in TRD also need to be developed.

Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports.

Recently, both the manufacturer of quetiapine and the US Food and Drug Administration warned healthcare providers and patients about quetiapine-induced QTc interval prolongation and torsade de pointes (TdP) when using this drug within the approved labeling. We reviewed the case-report literature and found 12 case reports of QTc interval prolongation in the setting of quetiapine administration. There were no cases of quetiapine-induced TdP or sudden cardiac death (SCD) among patients using quetiapine appropriately and free of additional risk factors for QTc interval prolongation and TdP. Among the 12 case reports risk factors included female sex (nine cases), coadministration of a drug associated with QTc interval prolongation (eight cases), hypokalemia or hypomagnesemia (six cases) quetiapine overdose (five cases), cardiac problems (four cases), and coadministration of cytochrome P450 3A4 inhibitors (two cases). There were four cases of TdP. As drug-induced TdP is a rare event, prospective studies to evaluate the risk factors associated with QTc prolongation and TdP are difficult to design, would be very costly, and would require very large samples to capture TdP rather than its surrogate markers. Furthermore, conventional statistical methods may not apply to studies of TdP, which is rare and an 'outlier' manifestation of QTc prolongation. We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, TdP, and SCD so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as quetiapine.

Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem.

We reviewed the literature and found 31 adult cases and 1 newborn case of methadone-associated QTc interval prolongation and/or torsade de pointes (TdP). Parametric statistics may not be useful in studying this issue because methadone-associated TdP is a very rare event and, hence, "an extreme outlier" consistent with scalable randomness. We may have to rely upon narrative medicine in the form of case reports with all its limitations and hazards to provide our best understanding. We report risk factors for methadone-associated QTc interval prolongation and TdP based on review of published case reports. We believe both drug manufacturers and the FDA would better serve our patients and inform clinicians if they more readily reported drug-induced outliers such as methadone-associated TdP using a case report format.

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports.

RATIONALE: A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced IKr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP). OBJECTIVES: The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP. METHOD: We identify case reports using PubMed, Medline, EMBASE, and Cochrane. RESULTS: Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, "elderly", 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n = 10), older age (n = 4), heart disease (n = 3), hypokalemia (n = 2), bradycardia (n = 1), liver disease (n = 1), QTc interval prolonging drugs other than risperidone (n = 8), and metabolic inhibitors (n = 2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP. CONCLUSION: Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.

Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports.

OBJECTIVE: In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP? METHOD: We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP. RESULTS: A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose. CONCLUSION: Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an 'extreme outlier'. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.

Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling?

Recently, both the manufacturer of citalopram and the US Food and Drug Administration have warned health care providers and patients about new information implicating drug-induced QTc interval prolongation and torsade de pointes when using citalopram in doses >40 mg/day. This warning is not placed in the context of either benefits or risks in real-world clinical practice, leaving clinicians with an untenable choice between depriving patients of high-dose citalopram or malpractice litigation. We reviewed the literature and found no cases of citalopram-induced sudden cardiac death among patients taking up to 60 mg/day of citalopram and free of risk factors for QTc interval prolongation and torsade de pointes. Because psychotropic drug-induced sudden cardiac death is an outlier in the absence of identified risk factors for QTc interval prolongation and torsade de pointes, we do not believe current Phase 3 and Phase 4 studies provide sufficient information to limit current prescribing practices for citalopram (20 mg to 60 mg/day). We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, torsade de pointes, and sudden cardiac death so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as citalopram.

Depression screening in patients with coronary heart disease: a critical evaluation of the AHA guidelines.

OBJECTIVE: We lack evidence that routine screening for depression in patients with coronary heart disease (CHD) improves patient outcome. This lack has challenged the advisory issued by the American Heart Association (AHA) to routinely screen for depression in CHD patients. We assess the AHA advisory in the context of well-established criteria of screening for diseases. METHODS: Using principles and criteria for screening developed by the World Health Organization and the United Kingdom National Screening Committee, we generated criteria pertinent to screening for depression in CHD patients. To find publications relevant to these criteria and clinical setting, we performed a broadly based literature search on "depression and CHD," supplemented by more focused literature searches. RESULTS: Evidence for an association between depression and CHD is strong. Despite this, the AHA advisory has several limitations. It did not account for the complexity of the association between depression and CHD. It acknowledged there was no evidence that screening for depression leads to improved outcomes in cardiovascular populations but still recommended routine screening without providing an alternative evidence-based explanation. It ignored the paucity of literature about the safety and cost-effectiveness of routine screening for depression in CHD and failed to define the nature and extent of resources needed to implement such a program effectively. CONCLUSION: We conclude that the AHA advisory is premature. We must first demonstrate the efficacy, safety, and cost-effectiveness of screening and define the resources necessary for its implementation and monitoring. Meanwhile, organizations representing cardiologists, psychiatrists, and general practitioners must coordinate efforts to manage depression and CHD through collaborative care, and work with the policy makers to develop the necessary infrastructure and services delivery system needed to optimize the outcome of depressed and at-risk-for-depression patients suffering from CHD.

Depression, stress, and heart disease in earthquakes and Takotsubo cardiomyopathy.

The preponderance of evidence links depressive disorder and coronary heart disease (CHD). Despite this evidence, multiple clinical trials have failed to show that effective treatment of depression favorably modifies the development, clinical course, or outcome of comorbid CHD. Possible reasons for these failures include the heterogeneity of depression, limitations of assessment instruments, limited understanding of the biology of depressive disorders, lack of biological markers, and the observation that depression may be more a product of CHD than a true risk factor for it. In this commentary, to better address the effects of externally provoked stress on physical health, we examine evidence about 2 specific examples of stress and subsequent heart disease: earthquake-induced adverse cardiac events among individuals with coronary artery disease, and stress-induced Takotsubo cardiomyopathy. In the former case, existing studies suggest that the stress and distress of earthquakes accelerate the development of poor cardiac outcomes for individuals with established coronary artery disease. In the latter example, existing case studies indicate that the profound left ventricular dysfunction of Takotsubo cardiomyopathy tends to quickly normalize once the acute stress is relieved. Together, these examples indicate that the presence or absence of prestress medical illness and its severity may better determine the outcome of the medical illness than the nature and severity of the stress, including depression. That is, any effort to look at depression among individuals with medical illness must look carefully at the medical illness itself and consider depression a possible nonspecific stress. In patients with comorbid depression and CHD, we propose using the more firmly established CHD outcome measurements to better understand how depression or other stressors and their associated treatments influence the prognosis and outcome of this medical illness.

Review of major measuring instruments in comorbid depression and coronary heart disease.

Depression and coronary heart disease (CHD) are common comorbid conditions in which each may be a risk factor for the other condition. However, treating depression does not appear to favorably alter cardiac outcome when depression and CHD are comorbid. The National Heart Lung and Blood Institute working group convened in August, 2004 reviewed and recommended instruments to assess and treat depression in subjects with CHD. This paper focuses on these instruments and their limitations when compared and contrasted with the robust instruments available to assess CHD. As a result of our observations about the limitations of instruments and scales available to assess depression and depressive symptoms in subjects with comorbid CHD, we propose using the objectivity of CHD parameters to assess the efficacy of psychiatric interventions in patients with comorbid depression and to better define the link between depression and these cardiac conditions.

Assessing the presence and severity of depression in subjects with comorbid coronary heart disease.

Our understanding of how depression alters the origin and course of coronary heart disease is derived from subjective methodologies. Many psychiatric instruments were not tested for reliability and validity in subjects with comorbid medical illness, particularly coronary heart disease. They largely use scales of categoric or ordinal variables. Instruments used to assess coronary heart disease are considerably more objective and often use interval variables. By searching the websites of Circulation and the Journal of the American College of Cardiology, we entered the word "depression" on August 28, 2009. We ignored articles using "depression" in the context of cardiovascular concepts such as "ST-segment depression." By searching articles dating back to 1995, we selected publications that studied the prognostic association of depression and coronary heart disease. There were 5 relevant publications: 3 from Circulation and 2 from the Journal of the American College of Cardiology. The methods used to assess coronary heart disease (specifically, myocardial infarction) are largely homogenous across the studies, but the methods used to assess depression are heterogeneous. Parameters used to diagnose myocardial infarction and determine its severity are precise, objective, and reliable, whereas those used to assess depression and its severity exhibit less precision and lack comparable objectivity and reliability. This mismatch may compromise our understanding of the link between coronary heart disease and depression in depressed patients with comorbid coronary heart disease. We propose using precise instruments to identify and quantitate coronary heart disease as outcome variables to assess psychiatric interventions and to better define depression in depressed patients with comorbid coronary heart disease. This should lead to a better understanding of the link between depression and comorbid coronary heart disease.