Rakesh Karmacharya

Catatonia in Psychotic Patients: Clinical Features and Treatment Response

The authors report clinical features and treatment response in 25 patients with catatonia admitted to an inpatient psychiatric unit specializing in psychotic disorders. Electroconvulsive therapy, benzodiazepines, and clozapine had beneficial effects on catatonic features, whereas typical antipsychotics resulted in clinical worsening.

Delirious mania: Clinical features and treatment response

OBJECTIVE To examine clinical characteristics and treatment responses of patients presenting with delirium and mania to a psychiatric inpatient unit. METHOD Chart review of 16 cases admitted to McLean Hospital with delirium and mania was conducted. We examined the demographics, psychiatric symptoms, clinical course, and response to treatment with medications and electroconvulsive therapy (ECT). RESULTS Patients with delirium and mania had negative medical and neurological work-ups and were more likely to be younger, female and with a prior diagnosis of bipolar disorder. Sudden onset of symptoms, incontinence/inappropriate toiletting, and denudativeness are distinctive features of the syndrome. Consistent and significant benefit was seen with ECT. In many cases, high dose benzodiazepines were helpful. In a small number of cases, clozapine was also beneficial but this effect took an average of four weeks to be seen, while atypical antipsychotics, lithium and valproate produced variable results and took an average of three and a half weeks to work, if at all. Typical antipsychotics and anticholinergic drugs led to clinical worsening. LIMITATIONS Most patients were on more than one medication and hence treatment responses cannot be definitively ascribed to a specific intervention. Studies of larger groups of such patients in different clinical settings need to be done to confirm our observations. CONCLUSIONS Delirious mania is a severe psychiatric syndrome which can be accurately recognized and effectively treated. The definitive treatment for this condition is ECT. In cases where ECT is not available, high dose benzodiazepines should be used. Clozapine, quetiapine, lithium and valproate cannot be considered first-line treatments and these medications take an unacceptably long time to work even when helpful; typical antipsychotics and anticholinergic drugs should be avoided.

Clozapine Interaction with Phosphatidyl Inositol 3-Kinase (PI3K)/Insulin-Signaling Pathway in Caenorhabditis elegans

Clozapine has superior and unique effects as an antipsychotic agent, but the mediators of these effects are not known. We studied behavioral and developmental effects of clozapine in Caenorhabditis elegans, as a model system to identify previously undiscovered mechanisms of drug action. Clozapine induced early larval arrest, a phenotype that was also seen with the clozapine metabolite N-desmethyl clozapine but not with any other typical or atypical antipsychotic drug tested. Mutations in the insulin receptor/daf-2 and phosphatidyl inositol 3-kinase (PI3K)/age-1 suppressed clozapine-induced larval arrest, suggesting that clozapine may activate the insulin-signaling pathway. Consistent with this notion, clozapine also increased the expression of an age-1∷GFP reporter. Activation of the insulin-signaling pathway leads to cytoplasmic localization of the fork head transcription factor FOXO/daf-16. Clozapine produced cytoplasmic localization of DAF-16∷GFP in arrested L1 larvae, in contrast to stressors such as starvation or high temperature, which produce nuclear localization of DAF-16∷GFP in arrested L1 larvae. Clozapine also inhibited pharyngeal pumping in C. elegans, an effect that may contribute to, but did not explain, clozapine-induced larval arrest. Our findings demonstrate a drug-specific interaction between clozapine and the PI3K/insulin-signaling pathway in C. elegans. As this pathway is conserved across species, the results may have implications for understanding the unique effects of clozapine in humans.

HDAC6 Inhibitors Modulate Lys49 Acetylation and Membrane Localization of β-Catenin in Human iPSC-Derived Neuronal Cells

We examined the effects of isoform-specific histone deacetylase (HDAC) inhibitors on β-catenin posttranslational modifications in neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs). β-catenin is a multifunctional protein with important roles in the developing and adult central nervous system. Activation of the Wnt pathway results in stabilization and nuclear translocation of β-catenin, resulting in activation of multiple target genes. In addition, β-catenin forms a complex with cadherins at the plasma membrane as part of the adherens junctions. The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.

Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus.

Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapines therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapines biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapines behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice.

Disease signatures for schizophrenia and bipolar disorder using patient-derived induced pluripotent stem cells.

Schizophrenia and bipolar disorder are complex psychiatric disorders that present unique challenges in the study of disease biology. There are no objective biological phenotypes for these disorders, which are characterized by complex genetics and prominent roles for gene-environment interactions. The study of the neurobiology underlying these severe psychiatric disorders has been hindered by the lack of access to the tissue of interest - neurons from patients. The advent of reprogramming methods that enable generation of induced pluripotent stem cells (iPSCs) from patient fibroblasts and peripheral blood mononuclear cells has opened possibilities for new approaches to study relevant disease biology using iPSC-derived neurons. While early studies with patient iPSCs have led to promising and intriguing leads, significant hurdles remain in our attempts to capture the complexity of these disorders in vitro. We present here an overview of studies to date of schizophrenia and bipolar disorder using iPSC-derived neuronal cells and discuss potential future directions that can result in the identification of robust and valid cellular phenotypes that in turn can lay the groundwork for meaningful clinical advances.

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876s mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.

Principles and neurobiological correlates of concentrative, diffuse, and insight meditation.

T he term meditation encompasses a broad variety of mental-training practices that vary between cultures and traditions, ranging from techniques designed to promote physical health, relaxation, and improved concentration, to exercises performed with farther-reaching goals, such as developing a heightened sense of well-being, cultivating altruistic behaviors, and, for some, attaining enlightenment. Meditation can be conceptualized as complex emotional and attentional regulatory practices in which mental and somatic events are affected by specific mental-training practices. Meditation is typically associated with a concurrent state of heightened vigilant awareness and reduced metabolic activity—which lead to improved physical health, psychological balance, and emotional stability. Not all meditation practices focus on the training of specific cognitive skills, and in those that do, the methodologies and outcomes often vary. It is therefore essential to be explicit about the type of meditation practice under investigation. Different types of meditation can be classified based on how the practitioner’s attentional processes are regulated and directed. In this article we focus on the two most common styles of meditation derived from Buddhist traditions: (1) concentrative, or focused-attention, meditation, and (2) diffuse, or open-monitoring, meditation. Concentrative meditation involves maintaining and continually refocusing attention on a chosen object, such as a body sensation, single point in space, color, object, sound, or affective state such as compassion. Open-monitoring meditation involves developing a present-centered and unattached/neutral mode of observation toward all sensational phenomena, including thoughts.

Quantum proton transfer coupled to a quantum anharmonic mode

Many model studies of proton tunneling in condensed phase employ a reaction coordinate that is coupled to a bath of harmonic oscillator modes. The nature of the coupled modes and the effect of the coupling parameters on reaction rate is an active area of investigation. Recent experimental results from the Fleming group showed that the spectral density for solvation can be temperature dependent [A. Passino, Y. Nagasawa, and G. R. Fleming, J. Chem. Phys. 107, 6094 (1997)]. Translated from the Langevin picture, this result implies that bath modes are anharmonic, or that a different set of harmonic modes are needed at each temperature. In addition, calculations of proton transfer rates have shown that quantum dynamics can be significantly affected by the variation of spectral densities in the low frequency regime [D. Antoniou and S. D. Schwartz, J. Chem. Phys. 109, 5487 (1998)]. We report a study of proton transfer in which the reaction coordinate is coupled to a Morse oscillator with nonlinear coupling. Comp...

McLean OnTrack: a transdiagnostic program for early intervention in first-episode psychosis

Most programs specializing in the treatment of first‐episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first‐episode psychosis.