Maju Mathew Koola

Kynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine.

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7), Glutamate (NMDA) Receptor, Metabotropic 1 (GRM1) gene, Dystrobrevin Binding Protein 1 (DTNBP1) and kynurenine 3-monooxygenase (KMO) gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway.

Galantamine-memantine combination effective in dementia: Translate to dementia praecox?

Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine receptor (α-7nAChR) and N-methyl-D-aspartate (NMDA) receptor are strongly implicated with cognitive impairments in Alzheimers disease (AD). Donepezil, a frequently used drug in the treatment of AD, is only an acetylcholinesterase inhibitor (AChEI), whereas galantamine is an AChEI and a positive allosteric modulator of the α4β2 and α-7nAChR. Memantine is an NMDA receptor antagonist. Donepezil (Aricept), galantamine (Razadyne), memantine (Namenda), and donepezil-memantine combination (Namzaric) are US Food and Drug Administration (FDA)–approved medications for the treatment of AD. Several randomized controlled trials (RCTs) and meta-analyses have shown that the donepezil-memantine combination was better than either drug alone for cognition in AD. Based on these data and the unique properties of galantamine, several studies were conducted evaluating the efficacy of galantamine-memantine combination in AD. In a 1-year RCT with 232 participants with mild-to-moderate AD, a galantamine-memantine combination was not superior to galantamine alone for cognition (Peters et al., 2015). However, this combination was effective in AD prodrome (Peters et al., 2012) and AD (Matsuzono et al., 2015). These studies are summarized in Table 1. This letter sheds light on the galantamine-memantine combination, which showed significantly better cognitive improvements compared to galantamine alone in prodrome AD and donepezil-memantine combination in AD. The recommended daily dose of galantamine in AD is 16–24 mg. Peters and colleagues used galantamine 16 mg daily; 24 mg would have enhanced cognition even further. The studies described in Table 1 used the maximum dose of memantine 20 mg. In schizophrenia, studies have been done with the maximum dose of 20 mg; one study used memantine XR 21 mg (Koola et al., in press). In AD, the new FDA-approved treatment dose of memantine is 28 mg, which may further enhance cognition in schizophrenia. Galantamine-memantine combination was effective for cognition in “rabbits, rodents, and rhesus”; hence, these findings could be translated to all “races” with schizophrenia (Koola, in press). Kynurenine pathway (KP) metabolites are abnormal in AD and are associated with cognitive impairments. Kynurenic acid (KYNA) is an antagonist to α-7nAChR and NMDA receptor. Galantamine and memantine via α-7nACh and NMDA receptors, respectively, may counteract the effects of KYNA, thereby improving cognition in schizophrenia (Koola et al., in press). In the Matsuzono study (Table 1), the concurrent action of galantamine-memantine combination on the α-7nAChR and NMDA might have modulated the KP metabolites. This is an additional benefit of this combination and is the most parsimonious explanation for its effects. Because of the involvement of cholinergic and glutamatergic systems, α7nAChR, NMDA receptor, and KP in schizophrenia, the galantamine-memantine combination may be effective in schizophrenia as well. In fact, in a small open-label study, the galantamine-memantine combination improved several cognitive domains with concurrent improvement in KP metabolites (Koola et al., in press). If these findings are validated in RCTs, this may address the clinically unmet need in schizophrenia—treatment for cognitive impairments. If this combination is effective in schizophrenia, the FDA may be able to approve it for both dementia and dementia praecox.

Methodological issues in cytokine measurement in schizophrenia

There is mounting evidence that inflammation is a major factor in the pathophysiology of schizophrenia. Inflammatory status is commonly ascertained by measuring peripheral cytokine concentrations. An issue concerning research on inflammation and schizophrenia relates to assay methodology. Enzyme-linked immunosorbent assay (ELISA) is the most widely used and the gold standard method used to measure cytokine concentrations. ELISA has a number of limitations. Both ELISA and multiplex are limited by not being able to distinguish between bioactive and inactive molecules and the matrix and heterophilic (auto-) antibody interference. Multiplex assays when combined with gene expression analysis and flow cytometry techniques such as fluorescence-activated cell sorting may be useful to detect abnormalities in specific immune pathways. Peripheral blood mononuclear cells cultures, to evaluate in vitro lipopolysaccharide-induced cytokine production, may be a better technology than measuring cytokines in the serum. The purpose of this paper is to shed light on major methodological issues that need to be addressed in order to advance the study of cytokines in schizophrenia. We make a few recommendations on how to address these issues.

Cytokines in schizophrenia: Hope or hype?

Although there is a cumulative evidence for the inflammation pathophysiology in schizophrenia, it has not been conclusively proven yet. One reason for this is the lack of studies that have controlled for major confounding factors such as obesity, smoking, antipsychotic use, and stress. The studies in which the major confounding factors were controlled were done in subjects in acute relapse and in treatment-resistant schizophrenia. To date, no studies have been done in stable outpatients with schizophrenia controlling for major confounding factors. Data on cerebrospinal fluid cytokines in large sample independent of confounding factors are also lacking. The efficacy signal from anti-inflammatory medications in schizophrenia has been modest. In this study, the inconsistent and nonvalidated cytokine findings independent of the confounding factors are discussed.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

Purpose/Background Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. Methods/Procedures Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5–15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. Findings/Results Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. Implications/Conclusions Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Dyke-Davidoff-Masson syndrome presenting with bipolar I mania with psychosis

Indian Journal of Psychiatry Volume 60, Issue 1, January-March 2018 149 instruct patients to take half of a 75 mg tablet of the tricyclic in the initial week to improve tolerability; we were reluctant to instruct patients to raise the dose to two tablets in later weeks because we wished to first evaluate the patients before increasing the dose. In this regard, we were proven right because even with this slow-dose uptitration, nearly half of the patients who received tricyclics reported the experience of adverse events as an explanation for drop out.