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Hypersalivation is a frequent, disturbing, and uncomfortable adverse effect of clozapine therapy that frequently leads to noncompliance. The aim of this study was to examine the efficacy of metoclopramide (dopamine D2antagonist, antiemetic medication) as an option for management of hypersalivation associated with clozapine (HAC). A 3-week, double-blind, placebo-controlled trial was conducted in university-based research clinics from January 2012 to May 2014, on 58 inpatients treated with clozapine who were experiencing hypersalivation. The subjects were randomly divided into placebo and metoclopramide groups. The starting dose was 10 mg/d. Participants who did not respond were up-titrated 10 mg/d weekly to a total of 30 mg/d during the third week. The number of placebo capsules was increased accordingly up to 3 capsules per day. Primary outcome was the change from baseline to the end of study in the severity of hypersalivation as measured with the Nocturnal Hypersalivation Rating Scale and the Drooling Severity Scale. Secondary outcomes included Clinical Global Impression of Improvement scale and adverse effect scales. Significant improvement on the Nocturnal Hypersalivation Rating Scale was demonstrated in the metoclopramide group from the end of the second week (P< 0.004), and on the Drooling Severity Scale (P< 0.02) in the third week. Clinical Global Impression-Improvement scale scores revealed major improvement. Twenty subjects (66.7%) treated with metoclopramide reported significant decline or total disappearance of HAC in comparison to 8 patients (28.6%) who received placebo (P= 0.031). No adverse effects to metoclopramide were reported. Metoclopramide was found to be safe and effective for the treatment of HAC.

Depression is a widespread mental disorder in which nearly half of the affected people have recurrent symptoms. Drug combinations may produce cumulative adverse effects, especially in elderly and physically ill patients. It was demonstrated that curcumin possesses antidepressive activity in various animal models of depression, and a combination of curcumin with some antidepressants potentiates the antidepressive effect of these agents. We sought to evaluate the efficacy of curcumin as an antidepressive agent in a combination with other antidepressants in patients with major depression.

Several studies of normobaric hyperoxia in neurological conditions have found positive results. The impaired energy metabolism due to mitochondrial dysfunction and frontal lobe hypofunction in schizophrenia might be improved by increasing O2supply to the brain. Normobaric hyperoxia may be a potential treatment for schizophrenia. Participants in this study, outpatients with chronic schizophrenia and inhabitants of community-based psychiatric institutions (hostels), underwent baseline psychiatriccognitive assessment and were randomly assigned to either a treatment intervention of oxygen-enriched air inhalation (normobaric hyperoxia of 40 fraction of inspired oxygen) or regular air inhalation (21 fraction of inspired oxygen), through a nasal tube, for 4 weeks. Patients were given the airoxygen inhalations during the night (mainly while sleeping) for at least 7 hours a night. After completing 4 weeks of treatment, patients were switched (crossed over) to the other treatment intervention. Fifteen patients completed the entire study. Five additional patients completed phase A only. There was significant improvement in total Positive and Negative Symptoms Scale score of patients who received oxygen compared with the control group. There were positive effects of oxygen on memory and attention in neuropsychological performance tests. The effect size is small despite the statistical significance, but the patient group was extremely chronic and severely impaired. These results are a proof of concept, and normobaric hyperoxia should be studied in patients with milder forms of the illness and earlier in the course of illness.

The search for psychological markers or for psychological endophenotypes for bipolar affective disorder has been frustrating, and the study of neuropsychological and neurocognitive functioning may be useful in this search. This article presents the results of a study comparing Rorschach protocols from a sample of adult euthymic bipolar patients (N18) and matched healthy controls (N8). Bipolar patients showed a higher proportion of immature responses and more instances of thought disorder; patients also showed significantly more severe thought disorder. These findings are discussed in the context of 2 related previous studies. We suggest that our modest series of studies using the Rorschach Inkblot Test provides preliminary evidence that certain variables—especially the measures of thought disorder but possibly also the lack of emotional responses under cognitive “control” and the excessive proportion of immature content responses—may represent a possible endophenotype of bipolar disorder.

Background:Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega-3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega-3 fatty acids in major depression, bipolar disorder and other psychiatric disorders.Objective:The present study design evaluates the effect of EPA in the Porsolt forced swimming test.Results:EPA alone did not reduce the immobility time and did not enhance the anti-immobility effect of a low dose of imipramine. Contrary to the hypothesis, EPA slightly increased the immobility time, and in some experiments tended to reduce the anti-despair effect of imipramine.Conclusion:The present results do not provide an animal model for the antidepressant effect of EPA as demonstrated in clinical experiments. The mechanism of EPA antidepressant action is unknown and the Porsolt forced swimming test could be non-sensitive for its antidepressant properties.

Background:Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega‐3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega‐3 fatty acids in major depression, bipolar disorder and other psychiatric disorders.

Intracellular compartmentation of inositol was demonstrated in primary cultures of mouse astrocytes, incubated in isotonic medium, by determination of efflux kinetics after “loading” with [3H]inositol. Three kinetically different compartments were delineated. The largest and most slowly exchanging compartment had a halflife of ∼9 hr. This slow release leads to retention of a sizeable amount of pre-accumulated inositol in the tissue 24 hr after the onset of uptake inhibition, as confirmed by the observation that the inositol uptake inhibitor fucose caused a larger inhibition of unidirectional inositol uptake than of inositol pool size, measured as accumulated [3H]inositol after 24 hr of combined exposure to the inhibitor and the labeled isotope. Based upon the present observations and literature data, it is suggested that the large, slowly exchanging compartment is largely membrane-associated and participating in signaling via the phosphatidylinositide second messenger system, whereas inositol functioning as an osmolyte is distributed in the cytosol and located in one or both of the compartments showing a faster release.

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food–treated animals, both lithium treated and with inositol monophosphatase 1knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.

Lithium is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes, but despite extensive research, the molecular mechanisms underlying its therapeutic actions have not been fully elucidated. Signal transduction pathways are in a pivotal postion in the central nervous system, able to affect the functional balance between neurotransmitter systems and have clearly been demonstrated to be targets of lithium's actions. We investigate the hypothesis that the action of chronic lithium on PKC isozymes and substrates may be secondary to its potent effect in inhibiting the recycling of inositol. Rats received lithium for 3 weeks and also myoinositol or saline twice daily via intracerebroventricular (ICV) injections. There was a significant interaction between chronic lithium and myo-inositol administration, with the chronic ICV administration of myo-inositol attenuating lithium's effects on PKC α, PKC ε, and on pertussis toxin–catalyzed [32P]ADP-ribosylation. These results suggest that the effects of chronic lithium on signal transduction pathways may stem initially from its inhibition of inositol-1-phosphatase. Given the critical role of PKC isozymes and G proteins in modulating intracellular cross-talk between neurotransmitter systems and thereby the integrative functions of the CNS, future studies using other inhibitors of inositol monophosphatases are warranted, and offer the hope for the development of more potent and more rapidly acting mood-stabilizing drugs.

AbstractA case report is presented of a koro-like syndrome in a 34-year-old Bedouin man living in the Negev desert in Israel. The patient’s disturbance is accompanied by voyeurism and the onset appears to be related to his sexual practices. This is the first reported case among Bedouins, who are an Arab nomadic tribe living in Asia and Africa.

Linkage studies in bipolar disorder were positive for markers in the region of chromosome 22q12.1 including the gene coding for G-protein receptor kinase (GRK)3. Two of six variants of the GRK3 5'-UTR/promoter were reported to be associated with bipolar disorder. GRK3 protein levels in lymphoblastoid cell lines derived from bipolar patients originating from families with linkage to chromosome 22q11 were reported to be decreased compared to those of control subjects and correlated with disease severity. We compared GRK3 mRNA levels in fresh lymphocytes from 31 bipolar patients vs. 26 control subjects, using real-time RT–PCR. No overall difference was found between patients and controls. However, GRK3 mRNA levels were markedly and significantly reduced in the subgroup of patients with no family history of a major psychiatric disorder compared with patients with family history.

Phenytoin, a classical anticonvulsant has been little studied in bipolar disorder. We completed a trial of phenytoin in mania and schizoaffective disorder, manic type. Thirty-nine patients entered a 5-wk double-blind controlled trial of haloperidol+phenytoin vs. haloperidol+placebo; 30 patients completed at least 3 wk; 25 completed 5 wk. Significantly more improvement was observed in those patients receiving phenytoin. Phenytoin has not previously been studied prophylactically in bipolar patients. Bipolar patients were studied who had at least one episode per year in the previous 2 yr despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1–13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients. Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in bipolar disorder [Cox's F test for comparing survival in two groups: F(6, 18)=3.44, p=0.02]. This study suggests prophylactic effects of add-on phenytoin in bipolar illness. However, the number of patients was small and confirmation is necessary. Lamotrigine has recently been reported to have antidepressant effects. In the past, small studies showed antidepressant effects for carbamazepine and valproate. To determine if such effects could be a class property of other voltage-activated sodium channel blockers such as phenytoin, we performed a double-blind controlled trial of phenytoin vs. fluoxetine in unipolar depression. Thirty-three depressed patients entered the study, and 28 completed at least 3 weeks and were included in data analyses. Weekly Hamilton Depression Scales for 6 wk showed no difference between fluoxetine and phenytoin. Clearly pharmaceutical company funding for clinical trials or advertising for phenytoin is minimal and this must be taken into account in evaluating literature on phenytoin vs. other drugs. The present data suggests that effects on affective disorder may be common to many anticonvulsants.