Prof. Joseph Levine

Senior Psychiatrist


Title: Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males.

Authors: Jospeh Levine, Alexandra Lobyntseva, Shula Shazman, Fahed Hakim, Illana Gozes.

Journal of Molecular Neuroscience. Jan 29, 2024. Volume 74, article number 15. doi: 10.1007/s12031-024-02189-4.

Abstract: Activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the ADNP syndrome. From brain pathologies point of view, tauopathy has been demonstrated at a young age, implying stunted development coupled with early/accelerated neurodegeneration. Given potential genotype-phenotype differences and age-dependency, we have assessed here a cohort of 15 individuals (1-27-year-old), using 1-3 longitudinal parent (caretaker) interview/s (Vineland 3 questionnaire) over several years. Our results indicated developmental delays, or even developmental arrests, coupled with potential spurts of development at early ages. Severe outcomes correlated with the truncating high impact mutation, in other words, the remaining mutated protein length as well as with the tested individual age, corroborating the hypothesis of developmental delays coupled with accelerated aging. A significant correlation was noted between mutated protein length and communication, implying a high impact of ADNP on communicative skills. Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1-6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy.



Todder D, Gershi A, Perry Z, Kaplan Z, Levine J, Avirame K.

Immediate Effects of Transcranial Direct Current Stimulation on Obsession-Induced Anxiety in Refractory Obsessive-Compulsive Disorder: A Pilot Study.

The journal of ECT. 2017 Dec.

Abstract: Studies have shown that transcranial direct current stimulation (tDCS) has immediate effects on brain activity. The aim of this study was to investigate the potential use of tDCS to regulate obsession-induced anxiety immediately after symptom provocation in patients with refractory obsessive-compulsive disorder (OCD).Twelve patients with refractory OCD received cathode, anode, and sham transcranial direct current stimulation over the medial prefrontal cortex conjugant to pharmacological treatment in a crossover design. Before and after the DC stimulation, patients graded the intensity of their anxiety after a short exposure to a provoking stimulus using the visual analogue scale. Clinical questionnaires assessing symptoms severity were also applied before each stimulation mode.We found a statistically significant decrease in the severity of the obsession-induced anxiety (decreased visual analogue scale) as a result of cathode tDCS in comparison with the anode and sham stimulation. Reduction in obsession-induced anxiety was consistent, yet short lasting, and was independent of symptom severity.Cathode tDCS could be potentially used to regulate obsession-induced anxiety in refractory OCD patients. Further studies are warranted to confirm our results as well as to determine whether tDCS can achieve prolonged benefits in OCD and be of aid in behavioral treatments based on exposure.

Levine J, Toker L, Agam G.

Dissecting disease entities out of the broad spectrum of bipolar-disorders.

Psychiatry Research. 2017 Nov 1.

Abstract: The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology.

Isr J Psychiatry Relat Sci. 2015;52(1):6-10.

 A pilot open study of long term high dose creatine augmentation in patients  with treatment resistant negative symptoms schizophrenia 

Levental U(1), Bersudsky Y(1), Dwalatzky T(1), Lerner V(1), Medina S(1), Levine J(1).

BACKGROUND: The effects of creatine on brain metabolism and the potential

cognitive enhancing properties of this compound raise the possibility of

developing a new augmentation therapeutic strategy in schizophrenia especially in

patients demonstrating negative and cognitive symptomatology.

METHODS: Seven inpatients with chronic schizophrenia presenting with treatment

resistant negative symptoms were enrolled into exploratory treatment study with

creatine monohydrate augmentation at a daily high-dose of 10 grams, administered

for 6 months. Several clinical rating scales and a computerized cognitive

assessment battery were applied.

RESULTS: Creatine treatment mildly improved the schizophrenia symptomatology but

there were no significant changes in cognitive functions. Several ward behaviors

were also improved. Tardive parkinsonism improved numerically by above 40% in 4

out of 6 patients.

CONCLUSION: This small, open design study of high dose creatine add-on for 6

months in chronic inpatients with schizophrenia demonstrated only mild positive

effects on the patients' symptomatology and behavior and might have beneficial

effect on tardive parkinsonism.

Mol Psychiatry. 2015 Feb;20(1):126-32.

Autophagy has a key role in the pathophysiology of schizophrenia.

Merenlender-Wagner A(1), Malishkevich A(1), Shemer Z(1), Udawela M(2), Gibbons

A(2), Scarr E(2), Dean B(2), Levine J(3), Agam G(4), Gozes I(1).

Autophagy is a process preserving the balance between synthesis, degradation and

recycling of cellular components and is therefore essential for neuronal survival

and function. Several key proteins govern the autophagy pathway including beclin1

and microtubule associated protein 1 light chain 3 (LC3). Here, we show a

brain-specific reduction in beclin1 expression in postmortem hippocampus of

schizophrenia patients, not detected in peripheral lymphocytes. This is in

contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which

we have previously found to be deregulated in postmortem hippocampal samples from

schizophrenia patients, but that now showed a significantly increased expression

in lymphocytes from related patients, similar to increases in the anti-apoptotic,

beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial

stages of the disease, possibly reflecting a compensatory effect. The increase in

ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected

to clozapine treatment. ADNP haploinsufficiency in mice, which results in

age-related neuronal death, cognitive and social dysfunction, exhibited reduced

hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and

normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B

suggesting a direct association with the autophagy process and paving the path to

novel targets for drug design.

Psychiatry Res. 2013 Dec 30;210(3):769-72.

Elevated homocysteine level in siblings of patients with schizophrenia.

Geller V(1), Friger M, Sela BA, Levine J.

Increased homocysteine plasma levels were reported in patients with schizophrenia

and Levine et al. (2002) suggested that such increase characterizes mainly males.

In the following study we examined whether such increased levels also

characterize male siblings of schizophrenia patients. Forty-four pairs of

schizophrenia patients and their corresponding healthy male siblings were

recruited and sampled for homocysteine. We also had age-matched controls for each

of the sibling. The median homocysteine plasma level for patients was 13.0 µMol/L

and 11.7 µMol/L for their male siblings compared with a median of 10.9 µMol/L for

the siblings' controls. There was no significant difference between homocysteine

plasma level in patients and their siblings. Significant difference was found for

homocysteine plasma level between the siblings' group and their matched controls.

A partial correlation of Ln plasma homocysteine level between patients and their

siblings was found to be close to a zero correlation of -0.089, p=0.57 for the

whole study group and -0.15, p=0.38 in the male-male patient-sibling pairs. Our

results show that elevated homocysteine plasma level may characterize

schizophrenia patients' male siblings, a finding that seems to agree with

previous studies suggesting elevated homocysteine level as a risk factor for

developing schizophrenia.

Int Clin Psychopharmacol. 2013 May;28(3):127-33.

A pilot dose-finding clinical trial of creatine monohydrate augmentation to

SSRIs/SNRIs/NASA antidepressant treatment in major depression.

Nemets B(1), Levine J.

Creatine's effects on brain energy metabolism raise the possibility of developing

a new therapeutic strategy in depression focusing on the treatment of metabolic

hypoactive brain areas. Previous creatine augmentation studies in patients with

major depression showed a beneficial effect. Eighteen patients (14 women) with

major depression not responding to previous 3 weeks of antidepressant treatment

were enrolled into a pilot, dose finding, 4-week double-blind parallel

augmentation study where creatine monohydrate 5 or 10 g daily or placebo was

added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton

Depression Rating Scale and the Clinical Global Impression Severity scale.

Overall, there was no difference between creatine administered at 5 or 10 g daily

and its corresponding placebos. Two female patients on creatine augmentation, but

none on the placebo, showed early improvement of more than 50% reduction in

Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No

clinically relevant side effects were reported. This preliminary study seems to

suggest that the strategy using creatine augmentation in major depressive women

showing no 'real-life response' to 3 weeks of treatment with SSRIs/SNRIs/NASA

treatment is of no advantage compared with placebo. However, such creatine

augmentation may still induce a more rapid response in a small subgroup of these

female patients.

Clin EEG Neurosci. 2012 Jan;43(1):48-53.

The quantitative electroencephalogram and the low-resolution electrical tomographic analysis in posttraumatic stress disorder.

Todder D(1), Levine J, Abujumah A, Mater M, Cohen H, Kaplan Z.

The electroencephalogram (EEG) is the recording of the brain electrical activity as measured on the scalp. Using mathematical algorithms, the 3-dimensional (3D) distribution of the electrical potential inside the brain can be calculated. One of the methods to calculate it is the low-resolution electrical tomographic analysis (LORETA). In this research, we seek to find the brain structures that differentiate patients with posttraumatic stress disorder (PTSD) from controls.Ten right-handed consenting adult male patients were recruited from a PTSD clinic. All patients fulfilled Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision [DSM-IV-TR]) criteria for chronic PTSD (duration >2 years.) and were on drug treatment regimens that had been stable for at least 2 months (involving only serotonin reuptake inhibitors [SSRIs] and benzodiazepines).The control group consisted of 10 healthy hospital staff members. All study participants underwent 19 channel EEG measurements according to current standards of practice. All artifact-free EEG strips were examined for spectral as well as LORETA analysis focusing on the theta (4-7 Hz) band which is suggested to reflect the activity of the limbic system. The theta band showed a statistically significant difference (P < .05) between the 2 groups in the right temporal lobe and in both the right and left frontal lobes. Our findings support existing research data obtained via other imaging technologies, which demonstrated structural alterations in the right temporal and frontal areas in PTSD. These results indicate that combining quantitative EEG (QEEG) and the LORETA method, among other methods, may improve the neuroanatomical resolution of EEG data analysis.

Brain Stimul. 2012 Jul;5(3):267-73.

Beneficial effects of caloric vestibular stimulation on denial of illness and

manic delusions in schizoaffective disorder: a case report.

Levine J(1), Toder D, Geller V, Kraus M, Gauchman T, Puterman M, Grisaru N.

INTRODUCTION: Preliminary data suggests that caloric vestibular nerve stimulation

(CVS) single session application of cold water to the left ear induces a

clinically significant, short-lived beneficial effect on specific types of

illness denial (i.e., anosognosia) and delusions (i.e., somatic type).

METHODS: We recently studied the effect of left versus right ear ice water (4°C)

CVS on delusions and insight of illness in a patient with manic episode due to

schizoaffective disorder. The patient was evaluated at baseline, immediately

after the CVS, and then at 20 minutes, 60 minutes, and 24 hours. The method was

first applied to one ear and 4 days later to the other. To assess whether the

effect is specific to mania we employed the same procedure in two other patients

with schizophrenia who also demonstrated delusions and impaired insight.

RESULTS: All three patients showed a difference favoring left versus right ear

CVS that was maintained for 20 minutes, and diminished over a 60 minute period.

EEG analyses showed a numerically non-significant increase in bilateral frontal

and central alpha EEG band activation (more pronounced in the right hemisphere)

with left but not right ear CVS 5 minutes after the CVS, and that diminished

after 20 minutes.

DISCUSSION: The results suggest that left versus right CVS may have a short lived

beneficial effect on manic delusions and insight of illness that seem to appear

in other types of psychoses (i.e., schizophrenia).

CONCLUSION: These preliminary results suggest that single session CVS may have

short lived beneficial effects in mania and perhaps in other types of psychoses.

Further research is mandatory.

J Psychopharmacol. 2011 Jul;25(7):976-81.

Hyperhomocysteinemia does not affect global DNA methylation and nicotinamide

N-methyltransferase expression in mice

Bromberg A(1), Levine J, Belmaker R, Agam G.

DNA methylation is coupled with one-carbon metabolism involving

homocysteine/methionine interconversion. Correlation between plasma homocysteine

levels and leukocyte global DNA methylation was reported but not always

replicated. Nicotinamide N-methyltransferase (NNMT) is a determinant of plasma

homocysteine levels. Findings suggest alteration of one-carbon metabolism in

schizophrenia etiology; hyperhomocysteinemia was observed in schizophrenia. A

recent study carried out by the authors of this paper found an association

between NNMT and schizophrenia and decreased post-mortem brain NNMT mRNA levels.

The present study assessed the interrelationship between brain and leukocytes

global DNA methylation and plasma homocysteine levels, and between

hyperhomocysteinemia and brain NNMT expression. Mice were administered

homocysteine in drinking water. Percentage global genome DNA methylation was

measured using the cytosine-extension method, and NNMT expression was measured

using real-time quantitative reverse transcriptase PCR (qRT-PCR). Homocysteine

administration resulted in a 10-fold increase in plasma homocysteine. However,

there was no change in global DNA methylation in lymphocytes or in the frontal

cortex. No significant intra-individual correlation was found between global DNA

methylation in leukocytes and frontal cortex, suggesting that leukocyte global

DNA methylation may not serve as a marker for brain global DNA methylation. No

difference was found in NNMT expression in homocysteine-treated mice compared

with control mice. In conclusion, relatively short-term hyperhomocysteinemia in

mice does not reproduce or lead to alterations reported in one-carbon metabolism

in disorders associated with lifelong elevated plasma homocysteine.

Cogn Neuropsychiatry. 2011 Jan;16(1):71-91

Social cognition in schizophrenia: cognitive and affective factors.

Ziv I(1), Leiser D, Levine J.

INTRODUCTION: Social cognition refers to how people conceive, perceive, and draw

inferences about mental and emotional states of others in the social world.

Previous studies suggest that the concept of social cognition involves several

abilities, including those related to affect and cognition. The present study

analyses the deficits of individuals with schizophrenia in two areas of social

cognition: Theory of Mind (ToM) and emotion recognition and processing. Examining

the impairment of these abilities in patients with schizophrenia has the

potential to elucidate the neurophysiological regions involved in social

cognition and may also have the potential to aid rehabilitation.

METHODS: Two experiments were conducted. Both included the same five tasks:

first- and second-level false-belief ToM tasks, emotion inferencing,

understanding of irony, and matrix reasoning (a WAIS-R subtest). The matrix

reasoning task was administered to evaluate and control for the association of

the other tasks with analytic reasoning skills. Experiment 1 involved factor

analysis of the task performance of 75 healthy participants. Experiment 2

compared 30 patients with schizophrenia to an equal number of matched controls.

Results. (1) The five tasks were clearly divided into two factors corresponding

to the two areas of social cognition, ToM and emotion recognition and processing.

(2) Schizophrenics' performance was impaired on all tasks, particularly on those

loading heavily on the analytic component (matrix reasoning and second-order

ToM). (3) Matrix reasoning, second-level ToM (ToM2), and irony were found to

distinguish patients from controls, even when all other tasks that revealed

significant impairment in the patients' performance were taken into account.

CONCLUSIONS: The two areas of social cognition examined are related to distinct

factors. The mechanism for answering ToM questions (especially ToM2) depends on

analytic reasoning capabilities, but the difficulties they present to individuals

with schizophrenia are due to other components as well. The impairment in social

cognition in schizophrenia stems from deficiencies in several mechanisms,

including the ability to think analytically and to process emotion information

and cues.

Asian J Psychiatr. 2010 Jun;3(2):64-6

No gross abnormality of plasma homocysteine after acute methionine loading in

clinically stabilized patients with schizophrenia

Shlafman N(1), Shaldubin S, Applebaum J, Belmaker RH, Levine J.

Homocysteine is reported to be a risk factor for schizophrenia. The methionine

loading test evaluates the summation of a multitude of enzymatic pathways

associated with homocysteine metabolism. Using a challenge paradigm, we measured

homocysteine levels in 10 chronic schizophrenia patients and five controls at

baseline and 3h after 100mg/kg oral methionine. This pilot study failed to detect

a gross abnormality of plasma homocysteine level after acute methionine load in

patients with schizophrenia. Elevations in plasma homocysteine reported in

schizophrenia do not derive from a dynamic abnormality in methionine metabolism

in this challenge paradigm.

J Affect Disord. 2009 Nov;118(1-3):234-9

Global leukocyte DNA methylation is not altered in euthymic bipolar patients.

Bromberg A(1), Bersudsky Y, Levine J, Agam G.

BACKGROUND: Bipolar disorder is a complex disorder hypothesized to involve an

interaction of multiple susceptibility genes and environmental factors. The

environmental factors may be mediated via epigenetic mechanisms such as DNA

methylation. Since a different extent of DNA methylation has recently been

reported in lymphoblastoid cells derived from monozygotic twins discordant for

bipolar disorder, we hypothesized that bipolar patients exhibit a different

extent of leukocyte global DNA methylation compared with healthy controls.

METHODS: DNA was extracted from peripheral blood leukocytes of 49 euthymic

bipolar patients and 27 matched healthy controls. Percent of global genome DNA

methylation was measured using the cytosine-extension method. Plasma homocysteine

levels were measured by HPLC.

RESULTS: Leukocyte global DNA methylation did not differ between bipolar patients

[62.3%+/-18.0 (S.D)] and control subjects (63.9%+/-14.6), p=0.70. Bipolar

patients' plasma homocysteine levels (11.5 microM+/-4.8) did not differ from

those of healthy controls (11.4+/-2.9), p=0.92.

LIMITATIONS: The assay we used, based on restriction by

methylation-sensitive/insensitive enzymes followed by a radioactive DNA

polymerase reaction was approved to accurately measure global DNA methylation,

but has technical limitations i.e. restriction enzymes do not cleave all

potential methylation sites in the genome and restriction sites may be altered by

mutations or polymorphisms.

CONCLUSIONS: The lack of difference in leukocyte global DNA methylation between

euthymic bipolar patients and healthy controls does not rule out the possibility

that altered methylation of specific promoter regions is involved in the etiology

of the disorder.

World J Biol Psychiatry.  2009;10(4):334-6

The rate of consanguineous marriages among parents of schizophrenic patients in the Arab Bedouin population in Southern Israel.

Dobrusin M, Weitzman D, Levine J, Kremer I, Rietschel M, Maier W, Belmaker RH.

Beersheva Mental Health Center, Ben Gurion University of the Negev, Beersheva, Israel.

Consanguinity may contribute to the incidence of schizophrenia in offspring despite the usually accepted polygenic model of schizophrenia inheritance. Bedouin Arab families in southern Israel have a high rate of cousin marriages as do families throughout most Arab societies. We studied consanguinity in the parents of schizophrenic patients admitted in a defined catchment area of southern Israel, compared to a control group of parents of all infants born to Bedouin mothers in this catchment area. There was a small but significant increase in the rate of cousin marriages among the parents of schizophrenia patients compared to parents of infant controls. These results are consistent with claims that inbreeding can contribute to the incidence of schizophrenia even as a polygenic illness. However, the absence of a better matched control group limits confidence in the results.

Schizophr Res. 2008 Apr;101(1-3):50-7

No association between global leukocyte DNA methylation and homocysteine levels in schizophrenia patients.

Bromberg A, Levine J, Nemetz B, Belmaker RH, Agam G.

Faculty of Health Sciences, Stanley Research Center, Ben-Gurion University of the Negev & Beersheva Mental Health Center, Beersheva, Israel.

Meta-analysis recently suggested that a 5 muM increase in homocysteine is associated with a 70% higher risk for schizophrenia. Elevated homocysteine is reported to alter macromolecule methylation. We studied whether elevated plasma homocysteine levels in schizophrenia are associated with altered leukocyte global DNA methylation. DNA was extracted from peripheral blood leukocytes of 28 schizophrenia patients vs. 26 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Homocysteine levels were higher in schizophrenia patients than in controls. No difference in global DNA methylation between schizophrenia patients and control subjects was found (74.0%+/-14.8 vs. 69.4+/-22.0, p=0.31). A significant interaction between diagnosis and smoking on DNA methylation was obtained (F=6.8, df=1,47, p=0.032). Although leukocytes may be a useful cell model to evaluate epigenetic changes such as global DNA methylation in brain, future studies should compare global DNA methylation in peripheral tissue vs. brain in laboratory animals

Depress Anxiety. 2008;25(11):E154-7.

Elevated serum homocysteine levels in male patients with PTSD.

Levine J, Timinsky I, Vishne T, Dwolatzky T, Roitman S, Kaplan Z, Kotler M, Sela BA, Spivak B.

Department of Psychiatry, Ben Gurion University of the Negev, Beersheva, Israel.

It has been suggested that an elevated serum or plasma homocysteine level may be a risk factor for neuropsychiatric conditions such as Alzheimer's disease, schizophrenia, and depression. Because depression is closely related to anxiety disorders, and because it has been suggested that stress may be associated with an elevated homocysteine level, we studied whether serum homocysteine levels are elevated in patients with posttraumatic stress disorder (PTSD). Total serum homocysteine levels in 28 male patients with PTSD were compared to those of 223 healthy controls. The effect of PTSD on the serum homocysteine level was significant (F=42.96, P<.0001). In a regression model for the PTSD patients, the duration of PTSD was found to predict serum homocysteine levels (t=2.228, P=.035). Our results suggest that elevated levels of homocysteine in male patients with PTSD may be related to pathophysiological aspects associated with the chronicity of this disorder. 2007 Wiley-Liss, Inc.

Isr J Psychiatry Relat Sci. 2007;44(1):20-8.

The prevalence of neuroleptic drug-induced tardive movement subsyndromes among schizophrenic and schizoaffective patients residing in the southern region of Israel.

Lerner V, Libov I, Kaptsan A, Miodownik C, Dwolatzky T, Levine J.

Division of Psychiatry, Ministry of Health Mental Health Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel.

The aim of the current study was to assess the prevalence of tardive movement disorders (TMD) among a group of institutionalized schizophrenic and schizoaffective patients in southern region of Israel. Chronic schizophrenic and schizoaffective inpatients of a psychiatric hospital and its affiliated hostels were screened for the presence of TMD subsyndromes. Twenty percent (107 patients) of 523 patients with schizophrenia and schizoaffective disorder exhibited TMD. Of those with TMD, 36% had only one subsyndrome, whereas 64% had a combination of several TMD subsyndromes. With regard to patients with TMD, the most frequent TMD subsyndrome was tardive tremor (TT). TT appeared more often in males compared to females and at a younger age (44.3+/-8 vs. 54.3+/-11 years, P<0.04). TD appearing in combination with other TMD subsyndromes was significantly more prevalent among females than in males (57% vs. 35%; P<0.02). TMD generally appears in a combined fashion. Further prospective studies from different geographical areas are recommended.

J Clin Psychiatry. 2007 Jun;68(6):881-4.

Lack of efficacy of 5 grams daily of creatine in schizophrenia: a randomized, double-blind, placebo-controlled trial.

Kaptsan A, Odessky A, Osher Y, Levine J.

Faculty of Health Sciences, Department of Psychiatry, Ben Gurion University of the Negev and the Beersheva Mental Health Center, Beersheva, Israel.

OBJECTIVE: Creatine plays a pivotal role in brain energy homeostasis and has been tried in the treatment of neurologic, neuromuscular, and atherosclerotic disease with a paucity of side effects. Creatine monohydrate supplementation may enhance cognitive functions in healthy subjects. Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in schizophrenia. Creatine effects on brain energy metabolism and its possible cognitive-enhancing properties raise the possibility of developing a new therapeutic strategy in schizophrenia by focusing on treating metabolic hypoactive brain areas including frontal regions. METHOD: Twelve schizophrenia patients (DSM-IV criteria) were enrolled into a treatment study with creatine or placebo, and each treatment was administered for 3 months (dosage, 3-5 grams per day) in a randomized, double-blind crossover design. Ten patients completed the study, which was conducted from November 2004 through February 2006. Rating scales included the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, scales for the assessment of side effects, and a cognitive battery. RESULTS: Creatine treatment was not superior to placebo in improving the scores of PANSS, CGI, or the neurocognitive measures administered. Side effects of creatine treatment were few. CONCLUSION: Three months of creatine administration failed to detect any efficacy in treating symptoms of schizophrenia, but further research is suggested. CLINICAL TRIALS REGISTRATION: identifier NCT00140192.

J Clin Psychopharmacol. 2007 Apr;27(2):238-9.

Exposure to nitrous oxide may be associated with high homocysteine plasma levels and a risk for clinical depression.

Levine J, Chengappa KN.

· Letter

Clin Neuropharmacol. 2007 Jan-Feb;30(1):13-7.

High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study.

Miodownik C, Lerner V, Vishne T, Sela BA, Levine J.

Division of Psychiatry, Ministry of Health, Mental Health Center, Faculty of Health Sciences Ben-Gurion University of the Negev, Be'er-Sheva, Israel.

Vitamin B6 plays an essential role in the normal functioning of the central nervous system. Normal homocysteine (Hcy) serum level is maintained by remethylation of Hcy to methionine by enzymes that require folic acid and vitamin B12 and by catabolism to cysteine by a vitamin B6-dependent enzyme. These findings may be consistent with the hypothesis that the vitamin B6 status may influence plasma Hcy levels. The aims of this preliminary study were (1) to determine whether a correlation exists between Hcy and vitamin B6 levels in patients with schizophrenia and schizoaffective disorders and (2) to investigate whether treatment with high-dose vitamin B6 may reduce Hcy levels in these patients. METHODS: In this preliminary study, we enrolled 11 patients with schizophrenia or schizoaffective disorders (7 men and 4 women; mean age +/- SD, 50 +/- 12 years) receiving high doses of vitamin B6 treatment (1200 mg/d) for 12 weeks. Blood samples for the assessment of pyridoxal-5-phosphate and Hcy serum levels were obtained at baseline and after 12 weeks of treatment. RESULTS: Age was significantly positively correlated with Hcy levels at baseline (r = 0.392, P = 0.004). All other parameters, including diagnosis, disease duration, and pyridoxal-5-phosphate serum level, were not correlated with Hcy serum levels at baseline. After vitamin B6 treatment, Hcy serum levels significantly decreased (14.2 +/- 3.4 vs. 11.8 +/- 2.0 micromol/L, respectively, t = 2.679, P = 0.023); this decrease being statistically significant in men but not in women. CONCLUSIONS: High doses of vitamin B6 lead to a decrease in Hcy serum level in male patients with schizophrenia or schizoaffective disorder.

Int J Eat Disord. 2007 Apr;40(3):277-84.

Plasma homocysteine levels in female patients with eating disorders.

Levine J, Gur E, Loewenthal R, Vishne T, Dwolatzky T, van Beynum IM, Sela BA, Vered I, Yosef G, Stein D.

Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.

OBJECTIVE: To examine plasma homocysteine, vitamin B(12), and folate levels in females with restricting and bingeing/purging eating disorders (EDs). METHOD: Adolescent and adult female patients were compared to appropriate control groups with regard to plasma homocysteine levels. RESULTS: The plasma homocysteine level of the adult ED patients was higher than that of controls for all age groups examined. In adolescents, no significant difference was found comparing ED patients younger than 16 years of age to control data, whereas in the 16-20 year age group, the plasma homocysteine level was significantly higher among the ED group, regardless of the type of ED. Vitamin B(12) and folate levels were within normal limits in all ED groups. CONCLUSION: Elevated plasma homocysteine levels were found in adult and older adolescent female ED patients (but not in younger adolescents) compared to controls. This finding is not related to deficiencies in vitamin B(12) or folate.

J Nerv Ment Dis. 2006 Oct;194(10):753-9.

Naive theory impairment in schizophrenia: is it domain-specific?

Bonshtein U, Leiser D, Levine J.

Child Guidance Unit, Western Galilee Hospital, Nahariya, Israel.

The ability to represent mental states of self and others to account for behavior is called theory of mind (ToM). This study examined whether ToM deficit in schizophrenia patients is a specific deficit in the cognitive component of interpersonal skills or a more global deficit, involving impaired information processing skills. Schizophrenia inpatients (N = 41) were compared with a control group of healthy subjects (N = 22) and to nonschizophrenia psychiatric patients (24 with affective disorders, seven with other psychosis) over a range of ToM tasks and another naive theory (theory of biology; ToB). Psychiatric inpatients as a whole showed significant deficit compared with the control group of healthy subjects in ToM tasks. The schizophrenia patients showed significantly larger deficits compared with patients suffering from affective disorder, while the performance of patients with nonschizophrenia psychosis was intermediate. In contrast, no difference was observed in the performance of the different groups on the ToB tasks. The fact that a deficit was found in ToM but not in ToB suggests a specific deficit in a cognitive component of interpersonal skills in schizophrenia rather than a general deficit in information processing skills. Naive theories deficits in schizophrenia seem to be domain-dependent.

Am J Psychiatry. 2006 Oct;163(10):1840-1.

Observed effects of creatine monohydrate in a patient with depression and fibromyalgia.

Amital D, Vishne T, Rubinow A, Levine J.

· Case Reports

· Letter

Isr J Psychiatry Relat Sci. 2006;43(2):119-25.

Therapist-patient sexual relations: results of a national survey in Israel.

Aviv A, Levine J, Shelef A, Speiser N, Elizur A.

The Program of Psychotherapy, School of Continuing Medical Education and Abarbanel Mental Health Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.

BACKGROUND: Studies focusing on Patient-Therapist sexual relations have been carried out mainly in the U.S. This study comes to broadly explore this phenomenon in Israel. METHOD: An indirect questionnaire was sent to all 1,817 psychiatrists, psychologists and social workers who are members of the Israeli Psychiatric Association, Psychologists Association and Psychotherapy Association, respectively. RESULTS: 29% of the responding therapists reported that at least one of their patients had experienced sexual relations with the most recent, former therapist. LIMITATION: The design of our survey made it impossible for us to conduct a follow-up after termination of therapy and to differentiate intercourse from nonintercourse sexual exploitation. CONCLUSIONS: Similar numbers of the gender of the exploiting therapist and exploited patients were obtained for both the indirect current Israeli study and previous U.S. studies. This may suggest that such parameters are influenced by common norms regarding the relationships between men and women of both societies, and from the psychotherapeutic dyadic situation.

J Clin Psychiatry. 2006 May;67(5):836-7.

Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder.

Amital D, Vishne T, Roitman S, Kotler M, Levine J.

Am J Psychiatry. 2006 Mar;163(3):549-50.

Comment on:

· Am J Psychiatry. 2005 Jan;162(1):162-7.

Osteoporosis and schizophrenia.

Levine J, Belmaker RH.

Biol Psychiatry. 2006 Aug 1;60(3):265-9.

Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia.

Levine J, Stahl Z, Sela BA, Ruderman V, Shumaico O, Babushkin I, Osher Y, Bersudsky Y, Belmaker RH.

Stanley Research Center and Beersheva Mental Health Center, Ben Gurion University of the Negev, Beersheva, Israel.

BACKGROUND: An elevated homocysteine level is reported to be a risk factor for several diseases, including Alzheimer's and cerebrovascular disease. Recently, several studies have reported that homocysteine levels are elevated in many schizophrenic patients. Homocysteine levels can be lowered by oral folic acid, B-12, and pyridoxine. METHODS: Forty-two schizophrenic patients with plasma homocysteine levels >15 micromol/L were treated with these vitamins for 3 months and placebo for 3 months in a study with a randomized, double-blind, placebo-controlled, crossover design. RESULTS: Homocysteine levels declined with vitamin therapy compared with placebo in all patients except for one noncompliant subject. Clinical symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale declined significantly with active treatment compared with placebo. Neuropsychological test results overall, and Wisconsin Card Sort (Categories Completed) test results in particular, were significantly better after vitamin treatment than after placebo. CONCLUSIONS: A subgroup of schizophrenic patients with hyperhomocysteinemia might benefit from the simple addition of B vitamins.

J Clin Psychiatry. 2005 Dec;66(12):1558-63.

High serum homocysteine levels in young male schizophrenic and schizoaffective patients with tardive parkinsonism and/or tardive dyskinesia.

Lerner V, Miodownik C, Kaptsan A, Vishne T, Sela BA, Levine J.

Division of Psychiatry, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Be'er Sheva, 84170 Israel.

BACKGROUND: The pathogenesis of neuroleptic-induced tardive movement disorders (TMD), including tardive parkinsonism and tardive dyskinesia (TD), has not yet been established. An elevated serum level of total homocysteine has been implicated as a risk factor for various neuropathologic states and some movement disorders. The aim of our study was to determine whether there is an association between serum total homocysteine level and the presence of TMD among schizophrenic and schizoaffective patients. METHOD: This study was conducted in Be'er Sheva Mental Health Center from August 2002 to May 2004. Fifty-eight patients with schizophrenia or schizoaffective disorder (DSM-IV) and TMD for at least 1 year (38 men, 20 women; age range, 28-73 years) were compared to a control group of 188 patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder without TMD (123 men, 65 women; age range, 19-66 years) regarding serum total homocysteine levels. RESULTS: Men with TMD (demonstrating tardive parkinsonism and/or TD) had significantly higher mean serum total homocysteine levels compared to sex- and age group-matched controls. The difference between groups was almost entirely attributable to the homocysteine levels of young male patients (age group, 19-40 years old) with TMD. CONCLUSION: High serum total homocysteine level may constitute a risk factor for certain variants of TMD, especially in young schizophrenic or schizo-affective male patients. Further prospective studies are needed to clarify these findings.

Prog Neuropsychopharmacol Biol Psychiatry. 2005 Sep;29(7):1181-91.

High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model.

Levine J, Sela BA, Osher Y, Belmaker RH.

Ben Gurion University, Beersheva, Israel.

Elevated plasma homocysteine has been found to be a risk factor for Alzheimer's disease as well as cerebral vascular disease, suggesting that some risk factors can accelerate or increase the severity of several CNS disease processes. We screened plasma total homocysteine levels of 193 schizophrenic patients vs. 762 controls for plasma homocysteine levels. The effect of schizophrenia was marked (p<0.0001) and mean homocysteine level was 16.3+/-12 (S.D.) microM in schizophrenic patients vs. 10.6+/-3.6 (S.D.) microM in healthy controls. The increase was almost entirely in young male schizophrenic patients. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. However, no difference was found for CSF homocysteine levels between schizophrenia patients and controls. We also examined homocysteine levels in 41 euthymic outpatients with bipolar disorder. Functional deterioration in patients was rated as 'present' or 'absent' by consensus of two treating clinicians. Young male bipolar patients were found to have higher homocysteine levels than controls. Among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than other patients. We attempted to develop a model of homocysteine neurotoxicity in mice. Mice were fed homocysteine in water at a dose of 200 mg/kg per mouse per day. Independent samples of animals were studied at 2 to 6 months with behavioral tests including apomorphine-induced stereotypy and spatial learning and memory in the Morris Water Maze. Homocysteine levels were elevated up to 800% at months 5 and 6 by this procedure. No homocysteine-induced defects were found in any behavioral test until month 5 when mild but statistically significant abnormalities in the Morris Water Maze were detected.

Eur Neuropsychopharmacol. 2005 May;15(3):291-5.

Nutritional and life style determinants of plasma homocysteine in schizophrenia patients.

Stahl Z, Belmaker RH, Friger M, Levine J.

Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Recently, homocysteine levels have been reported to be elevated in young male schizophrenic patients. Since smoking, obesity, low folate or low vitamin B12 and various medications can increase homocysteine levels, we studied these variables and other clinical variables in 258 schizophrenic patients. A multiple linear regression for plasma homocysteine was performed on variables that were significantly related to plasma homocysteine. Variables predicting homocysteine levels in schizophrenic patients include gender, plasma folate levels, plasma vitamin B12 levels, mean red blood cell corpuscular volume and diastolic blood pressure. Only 24% of the variance in male patients was explained by the model. The reason for elevated plasma homocysteine in some schizophrenic populations remains unclear.

J Neural Transm. 2005 Feb;112(2):297-302.

CSF homocysteine is not elevated in schizophrenia.

Levine J, Agam G, Sela BA, Garver DL, Torrey EF, Belmaker RH.

Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimer's disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients.We now studied two groups of schizophrenia patients (N=41) and controls (N=29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p=.041 for Study A and p=.52 for Study B).

Int J Neuropsychopharmacol. 2005 Mar;8(1):65-74.

Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats.

Levine J, Kaplan Z, Pettegrew JW, McClure RJ, Gershon S, Buriakovsky I, Cohen H.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Acetyl-L-carnitine (ALCAR) is an acetyl derivative of carnitine, an endogenous molecule synthesized in vivo and supplemented by diet (mainly via meat and dairy products). Several parallel, double-blind, placebo-controlled studies have demonstrated that ALCAR treatment produces beneficial effects in geriatric depression. Since most antidepressants also have anti-anxiety effects we examined whether ALCAR shows anti-anxiety effects in a rat model of anxiety. Compared to a saline-injected control group, chronic administration of ALCAR at doses of 10 and 100 mg/kg (tested 24 h after the last dose administration) showed no effects, whereas doses of 50 and 75 mg/kg significantly reduced anxiety-like behaviours in the elevated plus-maze. Acute ALCAR (100 mg/kg), on the other hand (tested 6 h after administration), demonstrated anxiogenic effects. Our data suggest that chronic ALCAR administration may produce an inverted U-shaped curve of dose-dependent changes in anxiety-like behaviour. The precise mechanism by which ALCAR decreases anxiety-like behaviour after peripheral administration remains to be determined.

J Neural Transm. 2004 Aug;111(8):1093-8.

GSK-3beta in cerebrospinal fluid of schizophrenia patients.

Kozlovsky N, Regenold WT, Levine J, Rapoport A, Belmaker RH, Agam G.

Stanley Research Center, Department of Clinical Biochemistry, Faculty of Health Sciences, Ben Gurion University of the Negev and Mental Health Center, Beersheva, Israel.

Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970's with few definitive results. We have recently found 40% reduced protein levels of GSK-3beta in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3beta was not successful. In this study we aimed to find whether the reduction in brain GSK-3beta is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3beta protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients' postmortem brain.

J Psychiatr Res. 2004 Jul-Aug;38(4):413-6.

Homocysteine levels in newly admitted schizophrenic patients.

Applebaum J, Shimon H, Sela BA, Belmaker RH, Levine J.

Beer-Sheba Mental Health Center, Stanley Research Center, Ben Gurion University of the Negev, Beersheva, Israel.

We previously found a marked elevation of plasma homocysteine in young male schizophrenic patients in hospital. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects from an employee screening program. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. Newly admitted male schizophrenic patients have elevated homocysteine levels that cannot be explained on the basis of poor hospital nutrition. Smoking may raise homocysteine by 1-2 microM/L but this is not a large enough effect to explain our findings.

Bipolar Disord. 2004 Feb;6(1):82-6.

Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration.

Osher Y, Sela BA, Levine J, Belmaker RH.

Stanley Research Center, Ministry of Health, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

OBJECTIVE: Previous studies have found elevated plasma homocysteine levels in schizophrenic patients. This study examined homocysteine levels in euthymic bipolar patients. METHODS: Homocysteine levels in 41 euthymic outpatients with bipolar disorder (DSM IV) were compared with 305 comparison subjects from a large employee health screening program. Homocysteine levels were assessed using high-pressure liquid chromatography by fluorescence detection following labeling of homocysteine with monobromobimane. Functional deterioration in patients was rated as 'present' or 'absent' by consensus of two treating clinicians. RESULTS: Data were analyzed by two-way (sex, patient versus control) ANCOVA, with age as the covariant. Significant effects were found for age (p < 0.001) and for sex (p < 0.001) and a significant two-way interaction was found for group by sex (p < 0.001). One-way (by group) ANCOVAs were then performed separately for each sex. For the male subjects, a main effect was found for group (p = 0.001) and for age (p < 0.001): young male bipolar patients have higher homocysteine levels than controls. Among the females, bipolar patients had homocysteine levels, which were lower than controls across all age groups (p < 0.05) with homocysteine levels increasing with age for both groups (p < 0.001). ANCOVA, which divided subjects into three groups – bipolar patients with and without functional deterioration versus comparison subjects – found a significant group by sex interaction (p < 0.05). Sheffe'post-hoc comparisons revealed that among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than those of comparison subjects, while bipolar subjects without deterioration had homocysteine levels which were almost identical to the comparison subjects. CONCLUSION: Bipolar patients who show functional deterioration have plasma levels of homocysteine, which are significantly elevated as compared with controls.

J Psychiatr Pract. 2001 Nov;7(6):432-9.

Obesity and medical illnesses in psychiatric patients admitted to a long-term psychiatric facility.

Levine J, Chengappa KN, Patel A, Vagnucci A, John V, Brar JS, Chalasani L, Parepally H, Ganguli R.

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, PA 15213-2593, USA.

Obesity and associated medical conditions may have an impact on morbidity and even mortality in patients with psychiatric disorders. The authors present the results of a survey of the prevalence of obesity and selected medical conditions among 420 consecutively admitted psychiatric inpatients at a long-stay facility and compare these data with those reported in the literature.Female psychiatric subjects had considerably higher rates of being either overweight or obese (69%) as compared to women in the general U.S. population (51%). Male psychiatric subjects did not differ significantly from their counterparts in the general population in being overweight or obese (nearly 55%). The majority of psychiatric subjects with essential hypertension, diabetes mellitus, dyslipidemias, cardiovascular disease, or sleep apnea were either overweight or obese (72%-87%). In this cross-sectional study, no associations could be deduced between psychotropic drug classes and specific medical conditions. No specific psychiatric diagnostic category was associated with a significantly greater prevalence of any specific medical condition, except that subjects with schizoaffective disorder appeared to have a higher prevalence of type II diabetes mellitus (11.6%). Subjects with predominant substance or alcohol abuse or dependence disorders had a lower prevalence of obesity and associated medical conditions.Obesity-either independently or additively along with a sedentary lifestyle, unhealthy dietary habits, and nicotine dependence-may have a serious impact on coexisting medical comorbidity in psychiatric patients. Judicious monitoring for obesity and rapid pharmacological and nonpharmacological intervention, where appropriate, by concerned clinicians may improve several coexisting medical conditions in psychiatric patients and thereby improve patients' overall quality of life.

Journal of Cognitive Psychotherapy, Volume 12, Number 1, 1998 , pp. 3-12(10)

Cognitive Group Therapy for Paranoid Schizophrenics: Applying Cognitive Dissonance

Levine, Joseph; Barak, Yoram; Granek, Ilana

Psychotherapy with paranoid schizophrenics is a hard and often unrewarding task. Individual and group therapies are usually supportive only and are not aimed at changing the paranoid mode of thinking. Although cognitive therapy has been applied in schizophrenic patients, it has not gained wide acceptance. Cognitive dissonance postulates that individuals experience discomfort and tension when holding two dissonant beliefs simultaneously. We here present the group therapy of six schizophrenic paranoids treated by modified cognitive group therapy implementing cognitive dissonance as the vector of change. A control group of six age- and sex-matched paranoid schizophrenics was treated by supportive group therapy. Analysis of the results, using the Positive and Negative Syndrome Scale (PANSS), during therapy and at follow-up of 4 weeks demonstrates statistically significant improvement in total PANSS score as well as in the positive symptoms subscale.

Suicide Life Threat Behav. 1998 Fall;28(3):309-14.

Physiological reactions to a suicide film: suicide attempters, suicide ideators, and nonsuicidal patients.

Doron A, Stein D, Levine Y, Abramovitch Y, Eilat E, Neuman M.

Shalvata Mental Health Center, Hod Hasharon, Israel.

A film about two teenagers who commit suicide was shown to three groups of psychiatric inpatients: 17 who had attempted suicide, 20 who had expressed suicidal thoughts, and 10 who were not suicidal. Anxiety before and after the film was evaluated with psychometric (anxiety rating scale) and physiological tools (heart and respiration rate, blood pressure, electromyogram). Values noted before and after screening, and the degree of change in these values, were compared. In addition, psychomotor agitation was rated at several points during the film. Most results were negative. The suicide attempters had significantly lower postscreening heart rates and a significantly lesser change in heart and respiration rates than the other two groups. The suicide attempters revealed an increase in psychomotor agitation until the discovery of the suicide and a decrease thereafter, whereas the agitation of the nonsuicidal patients continued to increase from the start to the end of the film. The study suggests that on some parameters, suicide attempters reveal less anxiety than nonsuicidal psychiatric patients following exposure to a simulated suicide. The reaction of suicide ideators falls somewhere between the two groups.

Isr J Psychiatry Relat Sci. 1996;33(1):50-3. Links

Requalifying examination and employment in immigrant physicians as predictors of successful immigration to Israel.

Moldavsky D, Levin J, Elizur A.

Yehuda Abarbanel Mental Health Center, Bat Yam, Israel.

Thirty physicians who immigrated together from South America to Israel were followed during their first two years in Israel. Success in the medical requalifying examination and finding work as physicians correlated directly with permanency in Israel, and, inversely, returning to country of origin was associated with being unqualified and unemployed. Age, sex, marital status, religion and previous professional status were not associated with permanency in Israel.

Journal of Cognitive Psychotherapy, Volume 9, Number 4, 1995 , pp. 267-278(12)

Cognitive Dissonance in the Treatment of Paranoid Schizophrenia

Levine, Joseph; Barak, Yoram; Caspi, Natan

Paranoid thinking is often well organized, systemized and detailed so that treating a paranoid patient is a difficult challenge. It is suggested that cognitive dissonance, once created, may cause a person to change his cognitions in order to lower or eliminate it. The treatment of a paranoid schizophrenic is presented wherein by introducing strong group pressure the patient accepted an axiom, which created dissonance with his paranoid content. This axiom was "A wise man sees more than two alternatives in any given situation." Therefore, by stepwise pacing, alternative evaluations of affect "free" situations were made by the patient using the accepted basic axiom. This technique was gradually used with the patient's paranoid content, and later on with basic characteristics underlying the paranoid system. The patient exhibited curiosity and a willingness to investigate his paranoid inner state according to the new accepted axiom, and a significant symptomatic relief was seen within a few days, in contrast to past hospitalizations where only partial response to antipsychotic medication was noted. Research is needed in order to examine the effectiveness of this mode of treatment.

Biol Psychiatry. 1994 Jan 1;35(1):22-6.

A double-blind trial of carbamazepine in negative symptom schizophrenia.

Nachshoni T, Levin Y, Levy A, Kritz A, Neumann M.

Shalvata Mental Health Center, Kupat-Holim, Hod Hasharon, Israel.

Twenty-eight residual schizophrenics hospitalized in a chronic institution with a 9 to 30 year history of disease, with predominantly negative symptoms were given carbamazepine. Carbamazepine was administered in a double-blind trial and therapeutic effects were measured by the Scale for the Assessment of Negative Symptoms (SANS). Patients were also assessed for positive symptoms using the Brief Psychiatric Rating Scale (BPRS), for depression using the Hamilton Depression Scale, for extrapyramidal symptoms by the Simpson and Angus scale, to rule out these symptoms as sources of secondary negative symptoms. The study continued for 7 weeks with therapeutic carbamazepine levels achieved during the last 5 weeks. There was no significant positive effect of carbamazepine on negative symptoms.

Harefuah. 1993 Jun 1;124(11):692-5.

[Negative symptoms in schizophrenia]

[Article in Hebrew]

Nachshoni T, Levy A, Levin Y, Neumann M.

Publication Types:

· Review

Acta Psychiatr Scand. 1992 Jan;85(1):74-6.

Effects of antipsychotic drugs on memory functions of schizophrenic patients.

Eitan N, Levin Y, Ben-Artzi E, Levy A, Neumann M.

Shalvatah Mental Health Center, Hod-Hasharon, Israel.

In this research we investigated the effects of 4 antipsychotic drugs with different anticholinergic components on different memory functions of schizophrenic patients. Drugs were administered in cumulative doses and memory was tested 90 min after each drug was administered. The results show that chlorpromazine and thioridazine impaired short-term verbal memory after 6 h of sequential administration. Trifluoperazine and haloperidol improved short-term verbal memory from the third to the fifth administration. Immediate memory, long-term memory and visual short-term memory were not impaired by any drug.

Harefuah. 1991 Aug;121(3-4):125-7.

[Is there a linkage between mental illness and traffic accidents?]

[Article in Hebrew]

Levin Y, Ben-Artzi E, Levy A, Neumann M.

Harefuah. 1991 Jan 1;120(1):34-7.

[Inter- and intrahemispheric dysfunction in schizophrenia]

[Article in Hebrew]

Ben-Artzi E, Levy A, Levin Y, Neumann M.

Harefuah. 1990 Nov 15;119(10):323-6.

[Sudden death in psychiatric patients]

[Article in Hebrew]

Levkovitz Y, Levy A, Levin Y, Neumann M.

Isr J Psychiatry Relat Sci. 1990;27(3):168-74.

Should electroconvulsive therapy be used as an ambulatory preventive treatment?

Ezion T, Levy A, Levin Y, Neumann M.

Shalvata Mental Health Center, Kupat Holim, Hod Hasharon, Israel.

Electroconvulsive therapy (ECT) has often been withheld from patients in many instances, even when it was the preferred form of psychiatric treatment. From clinical, social, and legal points of view, it is associated with many negative connotations. This paper reviews the use of ECT as a "legitimate" form of long-term ambulatory preventive treatment for psychiatric patients who have previously received it during hospitalization. Attempts to terminate or reduce the frequency of ECT treatments may well be the cause for readmission or exacerbation of an acute attack in patients already in remission who have been discharged.

Isr J Psychiatry Relat Sci. 1990;27(4):242-6.

The hypoparathyroid syndrome: psychiatric observations and case description.

Levine Y, Gaoni B.

Shalvata Mental Health Center, Adolescent Department, Kupat Holim, Hod Hasharon, Israel.

We present a case description of a 15-year-old youth admitted in a psychotic state to the Adolescent Department of Shalvata Mental Health Center and diagnosed as having Idiopathic Hypoparathyroidism. A review of the neurological and psychiatric manifestations accompanying Hypoparathyroid Syndrome is presented, together with several aspects we feel are relevant in reaching this particular diagnosis.

Harefuah. 1988 Feb 1;114(3):144-7.

[A hundred year's quest for objective diagnosis of schizophrenia]

[Article in Hebrew]

Trieman N, Levy A, Levin Y, Neumann M.

Prog Neuropsychopharmacol Biol Psychiatry. 1987;11(1):71-8.

The effect of trihexphenidyl (Artane) on memory in schizophrenic patients.

Fennig S, Levine Y, Naisberg S, Elizur A.

The anticholinergic effect of trihexphenidyl on memory function of 20 schizophrenic patients has been investigated in a double blind crossover design. Impairment of immediate memory and short term memory was evident after trihexphenidyl treatment in comparison with placebo. Sensory short term memory tested by visual tasks and remote memory showed no significant statistical differences. Our data suggested that trihexphenidyl due to its anticholinergic effect might impair memory function.

Neurology. 1987 May;37(5):871-5.

Physostigmine improves ECT-induced memory disturbances.

Levin Y, Elizur A, Korczyn AD.

Electroconvulsive therapy (ECT) induces transient confusion and amnesia. Using a double-blind crossover method we studied the influence of physostigmine on ECT-induced memory disturbances. We found that physostigmine reverse the impairment of verbal and visual short- and long-term memory after ECT. Immediate recall was neither impaired by ECT nor improved by physostigmine.