Sharmin Ghaznavi

Rechallenging With Clozapine Following Neutropenia: Treatment Options for Refractory Schizophrenia

Clozapine, a second-generation antipsychotic, is the treatment of choice in refractory schizophrenia because of its proven efficacy over typical antipsychotics as well as other atypical antipsychotics (1). However, a major drawback to clozapine therapy is the increased risk of neutropenia and agranulocytosis (2). In patients who develop either of these serious side effects, clozapine is immediately discontinued. Unfortunately, trials of other antipsychotics often prove ineffective, and clinicians find themselves faced with the difficult decision of whether to rechallenge those patients with clozapine (3). Even more concerning for the clinician is the relative absence of any controlled data to suggest treatment options when clozapine cannot be used because of serious side effects, such as neutropenia or agranulocytosis. This case review highlights this particular aspect and provides some useful thinking points for clinicians and patients in this situation. Efforts at rechallenge with clozapine have met with some success (4–9). In a retrospective review of 53 cases of clozapine rechallenge in the United Kingdom and Ireland, 62% of the patients did not develop a blood dyscrasia on rechallenge (8). Of course, clozapine rechallenge is not without its risks. In the same retrospective review, it was found that among the 38% of cases who did develop a blood dyscrasia on rechallenge, in 85% of the cases, the blood dyscrasia occurred more quickly and was more severe than with the initial trial of clozapine. In addition, in 65% of the cases in which patients developed a blood dyscrasia on rechallenge, the blood dyscrasia lasted longer after discontinuation of clozapine following rechallenge than when clozapine was first discontinued. Thus, when deciding whether to rechallenge a patient with clozapine, the clinician must carefully weigh the risks and benefits of a clozapine rechallenge. Here we present a patient with refractory schizophrenia who successfully tolerated a clozapine challenge 2 years after developing clozapine-induced neutropenia and failing to respond to a subsequent clozapine rechallenge. We propose that polypharmacy may have contributed to the initial episode of neutropenia as well as the failed clozapine rechallenge in our patient. We also discuss logical issues in medical decision making before considering clozapine rechallenges in patients.

Rumination in bipolar disorder: evidence for an unquiet mind

Depression in bipolar disorder has long been thought to be a state characterized by mental inactivity. However, recent research demonstrates that patients with bipolar disorder engage in rumination, a form of self-focused repetitive cognitive activity, in depressed as well as in manic states. While rumination has long been associated with depressed states in major depressive disorder, the finding that patients with bipolar disorder ruminate in manic states is unique to bipolar disorder and challenges explanations put forward for why people ruminate. We review the research on rumination in bipolar disorder and propose that rumination in bipolar disorder, in both manic and depressed states, reflects executive dysfunction. We also review the neurobiology of bipolar disorder and recent neuroimaging studies of rumination, which is consistent with our hypothesis that the tendency to ruminate reflects executive dysfunction in bipolar disorder. Finally, we relate the neurobiology of rumination to the neurobiology of emotion regulation, which is disrupted in bipolar disorder.

Neural Predictors of Successful Brief Psychodynamic Psychotherapy for Persistent Depression

Background: Psychodynamic psychotherapy has been used to treat depression for more than a century. However, not all patients respond equally well, and there are few reliable predictors of treatment outcome. Methods: We used resting 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scans immediately before and after a structured, open trial of brief psychodynamic psychotherapy (n = 16) in conjunction with therapy process ratings and clinical outcome measures to identify neural correlates of treatment response. Results: Pretreatment glucose metabolism within the right posterior insula correlated with depression severity. Reductions in depression scores correlated with a pre- to posttreatment reduction in right insular metabolism, which in turn correlated with higher objective measures of patient insight obtained from videotaped therapy sessions. Pretreatment metabolism in the right precuneus was significantly higher in patients who completed treatment and correlated with psychological mindedness. Conclusions: Resting brain metabolism predicted both clinical course and relevant psychotherapeutic process during short-term psychodynamic psychotherapy for depression.

The Biochemical Profile of Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism during Pregnancy and Lactation: Two Case Reports and Review of the Literature.

Background. Primary hyperparathyroidism (PHPT) and Familial Hypocalciuric Hypercalcemia (FHH) result in different maternal and fetal complications in pregnancy. Calcium to creatinine clearance ratio (CCCR) is commonly used to help distinguish these two conditions. Physiological changes in calcium handling during pregnancy and lactation can alter CCCR, making it a less useful tool to distinguish PHPT from FHH. Cases. A 25-year-old female presented with hypercalcemia and an inappropriately normal PTH. Her CCCR was 0.79% before pregnancy and rose to 1.99% in her second trimester. The probands mother and neonate had asymptomatic hypercalcemia. Genetic analysis revealed a CaSR mutation consistent with FHH. A 19-year-old female presented with a history of nephrolithiasis who underwent emergent caesarean section at 29 weeks of gestation for severe preeclampsia. At delivery, she was diagnosed with hypercalcemia with an inappropriately normal PTH and a CCCR of 2.67%, which fell to 0.88% during lactation. Parathyroidectomy cured her hypercalcemia. Pathology confirmed a parathyroid adenoma. Conclusion. These cases illustrate the influence of pregnancy and lactation on renal calcium indices, such as the CCCR. To avoid diagnostic error of women with hypercalcemia during pregnancy and lactation, calcium biochemistry of first-degree relatives and genetic testing of select patients are recommended.

Peroxisome Proliferator Activated Receptor Gamma Co-activator-1 Alpha as a Novel Target for Bipolar Disorder and other Neuropsychiatric Disorders

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntingtons disease, Parkinsons disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials.

Multiple Drug Intolerance Syndrome and Multiple Drug Allergy Syndrome: Epidemiology and Associations with Anxiety and Depression.

The epidemiology of multiple drug intolerance syndrome (MDIS) and multiple drug allergy syndrome (MDAS) is poorly characterized. We used electronic health record (EHR) data to describe prevalences of MDIS and MDAS and to examine associations with anxiety and depression.

What happens now? The importance of naturalistic course after first mania.

aDepartment of Psychiatry, Massachusetts General Hospital, Boston bHarvard Medical School, Boston, Massachusetts. *Corresponding author: Andrew A. Nierenberg, MD, Department of Psychiatry, Massachusetts General Hospital, 50 Staniford St, 5th Floor, Boston, MA 02114 (anierenberg@mgh.harvard.edu). J Clin Psychiatry 2015;76(9):e1161–e1163 dx.doi.org/10.4088/JCP.14com09596

Human Brain Imaging of Anger

Abstract Anger is among one of the basic human emotions underlying human behavior. Here, we review the neuroimaging studies of anger, specifically those studies investigating the subjective experience of anger as well as the perception of anger. In addition, we review the findings from studies in patient populations with an increased propensity for anger. Finally, we relate the research on neural correlates of anger to the research on aggression and violence.

Bridging Technology and Psychotherapy: Toward Investigating Psychological and Neural Correlates of Psychodynamic Psychotherapy

Generations of therapists can attest to the ability of psychotherapy to effect change in people’s lives, changes that we now know undoubtedly reflect changes in the brain. At the same time, as Gabbard [1] suggests, the need to understand explicitly the neural basis of psychotherapy through scientific research is greater than ever. In this chapter, we review an ongoing study investigating psychological and neural correlates of brief psychodynamic psychotherapy in individuals suffering from major depression. The study, to the best of our knowledge, is the first of its kind; most studies to date of neural correlates of psychotherapy have focused on cognitive behavioral therapy and interpersonal therapy (IPT) ([2], Chap. 9).