Shalvata Mental Health Center

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

BACKGROUND: Current antipsychotics have only a limited effect on 2 core aspects of schizophrenia: negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline that has a beneficial effect in various neurologic disorders. Recent findings in animal models and human case reports suggest its potential for the treatment of schizophrenia. These findings may be linked to the effect of minocycline on the glutamatergic system, through inhibition of nitric oxide synthase and blocking of nitric oxide-induced neurotoxicity. Other proposed mechanisms of action include effects of minocycline on the dopaminergic system and its inhibition of microglial activation. OBJECTIVE: To examine the efficacy of minocycline as an add-on treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia. METHOD: A longitudinal double-blind, randomized, placebo-controlled design was used, and patients were followed for 6 months from August 2003 to March 2007. Seventy early-phase schizophrenia patients (according to DSM-IV) were recruited and 54 were randomly allocated in a 2:1 ratio to minocycline 200 mg/d. All patients had been initiated on treatment with an atypical antipsychotic < or = 14 days prior to study entry (risperidone, olanzapine, quetiapine, or clozapine; 200-600 mg/d chlorpromazine-equivalent doses). Clinical, cognitive, and functional assessments were conducted, with the Scale for the Assessment of Negative Symptoms (SANS) as the primary outcome measure. RESULTS: Minocycline was well tolerated, with few adverse events. It showed a beneficial effect on negative symptoms and general outcome (evident in SANS, Clinical Global Impressions scale). A similar pattern was found for cognitive functioning, mainly in executive functions (working memory, cognitive shifting, and cognitive planning). CONCLUSIONS: Minocycline treatment was associated with improvement in negative symptoms and executive functioning, both related to frontal-lobe activity. Overall, the findings support the beneficial effect of minocycline add-on therapy in early-phase schizophrenia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00733057.

The H-coils are a novel development in transcranial magnetic stimulation (TMS), designed to achieve effective stimulation of deep neuronal regions without inducing unbearable fields cortically, thus broadly expanding the potential feasibility of TMS for research and for treating various neurologic disorders. This study compared the field distribution of two H-coil versions, termed H1 and H2, and of a standard figure-of-eight coil. Three-dimensional electrical field distributions of the H1 and H2-coils, designed for effective stimulation of prefrontal regions, and of a standard figure-8 coil, were measured in a head model filled with physiologic saline solution. With stimulator output at 120% of the hand motor threshold, suprathreshold field is induced by the H1-coil at lateral and medial frontal regions at depths of up to 4 to 5 cm, and by the H2-coil at medial prefrontal regions up to 2 to 3 cm, and at lateral frontal regions up to 5 to 6 cm. The figure-8 coil induced suprathreshold field focally under the coil's central segment, at depths of up to 1.5 cm. The ability of the H-coils to stimulate effectively deeper neuronal structures is obtained at the cost of a wider electrical field distribution in the brain. However, the H-coils enable simultaneous stimulation of several brain regions, whereas the depth penetration in each region can be controlled either by adjusting the stimulator output, and/or by varying the distance between various coil elements and the skull.

OBJECTIVE: Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. METHOD: We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. RESULTS: Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46-1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. CONCLUSION: Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis.

UNLABELLED: Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex. METHOD: In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964-76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison. RESULTS: There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1-4.7), seen more in females (4.3, 1.7-10.7) than in males (1.2, 0.4-3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2-5.2), also seen more in females (3.6, 1.3-9.7) than males (1.8, 0.6-5.2). CONCLUSION: These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

This study compared telephone with face-to-face interviewing in a community psychiatric survey. Two groups of women were investigated, Holocaust survivors and Europe-born respondents who were in prestate Israel during World War II. Both were administered the Psychiatric Research Interview Demoralization Scale and a short item scale investigating World War II experiences. Results showed a high compliance rate to the telephone mode. The subjects' scores in the two modes were highly correlated. Telephone interviewing seems to be a reliable and efficient method in areas with a well-developed network of subscribers.

The literature on eating disorders emphasizes the relationship between alexithymia and anorexia nervosa on the one hand, and between bulimia nervosa and affect dysregulation on the other. In our study, two questions are addressed: (1) Are there different patterns of emotional processing deficiencies in anorexia and bulimia? and (2) Is there a unique contribution of eating disorders to emotional processing deficiencies? Participants were women with anorexia nervosa (ANs, n=20), bulimia nervosa (BNs, n=20), and normal controls (NCs, n=20). Three hypotheses were examined: (1) Women with eating disorders will exhibit lower emotional awareness and more deficient emotional regulation than will NCs (emotional deficiency); (2) ANs will be less emotionally aware than BNs, whereas BNs will be less capable of effective emotional regulation than ANs (disorder specificity); and (3) emotional distress will mediate the relationships between emotional processing and eating disorders (emotional distress mediation). Results supported the emotional deficiency and distress mediation hypotheses, and partially supported the disorder specificity hypothesis. The need to move beyond alexithymia in understanding the pattern of emotional processing deficiencies in eating disorders is discussed.

BACKGROUND: A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence. OBJECTIVE: An association of paternal age with IQ in healthy adolescents may illuminate the mechanisms that link it to schizophrenia. METHOD: We examined the association of paternal age and IQ scores using the Israeli Army Board data on 44 175 individuals from a richly described birth cohort, along with maternal age and other potential modifiers. RESULTS: A significant inverted U-shaped relationship was observed between paternal age and IQ scores, which was independent from a similar association of IQ scores with maternal age. These relationships were not significantly attenuated by controlling for multiple possible confounding factors, including the other parent's age, parental education, social class, sex and birth order, birth weight and birth complications. Overall, parental age accounted for approximately 2% of the total variance in IQ scores, with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. CONCLUSION: We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.

Patients with schizophrenia show impaired emotional and social behavior, such as lack of theory of mind and misinterpretation of social situations. However, there is a paucity of work focusing on the empathic abilities of these patients. The present study was designed to examine the degree of impairment in cognitive and affective empathy in schizophrenia and to evaluate the contribution of executive prefrontal functions to empathy in these patients. To explore the neurocognitive processes that underlie the empathic ability in schizophrenic patients, the relationship between empathy scores and the performance on a cognitive flexibility task that assesses dorsolateral and orbitofrontal functioning (set shifting and reversal, respectively) was examined in 26 patients with schizophrenia and 31 healthy control subjects. Results indicated that patients with schizophrenia were significantly impaired in both cognitive and affective empathy compared with healthy control subjects. The degree of impaired empathy related to the severity of negative symptoms. In addition, patients showed impaired performance on measures of both shifting and reversal. However, while cognitive empathy was particularly related to measurements of orbitofrontal (rather than dorsolateral) functioning, affective empathy was related to measures of social functioning.

Mind-wandering (MW) is among the most robust and permanent expressions of human conscious awareness, classically regarded by philosophers, clinicians, and scientists as a core element of an intact sense of self. Nevertheless, the scientific exploration of MW poses unique challenges; MW is by nature a spontaneous, off task, internal mental process which is often unaware and usually difficult to control, document or replicate. Consequently, there is a lack of accepted modus operandi for exploring MW in a laboratory setup, leading to a relatively small amount of studies regarding the neural basis of MW. In order to facilitate scientific examination of MW the current review categorizes recent literature into five suggested strategies. Each strategy represents a different methodology of MW research within functional neuroimaging paradigms. Particular attention is paid to resting-state brain activity and to the "default-mode" network. Since the default network is known to exert high activity levels during off-task conditions, it stands out as a compelling candidate for a neuro-biological account of mind-wandering, in itself a rest-based phenomenon. By summarizing the results within and across strategies we suggest further insights into the neural basis and adaptive value of MW, a truly intriguing and unique human experience.

Despite the dominant role of the hormone oxytocin (OT) in social behavior, little is known about the role of OT in the perception of social relationships. Furthermore, it is unclear whether there are sex differences in the way that OT affects social perception. Here, we employed a double-blind, placebo-controlled crossover design to investigate the effect of OT on accurate social perception. Following treatment, 62 participants completed the Interpersonal Perception Task, a method of assessing the accuracy of social judgments that requires identification of the relationship between people interacting in real life video clips divided into three categories: kinship, intimacy and competition. The findings suggest that OT had a general effect on improving accurate perception of social interactions. Furthermore, we show that OT also involves sex-specific characteristics. An interaction between treatment, task category and sex indicated that OT had a selective effect on improving kinship recognition in women, but not in men, whereas men's performance was improved following OT only for competition recognition. It is concluded that the gender-specific findings reported here may point to some biosocial differences in the effect of OT which may be expressed in women's tendency for communal and familial social behavior as opposed to men's tendency for competitive social behavior.

OBJECTIVES: The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic field with a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1-Coil as adjuvant treatment for bipolar depression (BPD). METHODS: Nineteen patients diagnosed as having BPD and under treatment with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session. RESULTS: A significant mean decrease of 12.9 points in the HDRS-24 scale (P< 0.001) was found. Response rate was 63.2% and remission rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no significant change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complications. CONCLUSIONS: An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the efficacy and safety of the H-Coil for BPD are warranted.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. OBJECTIVE: This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). METHODS: A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. RESULTS: Mixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. CONCLUSIONS: Twice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted.

OBJECTIVE: The co-occurrence of obsessive-compulsive disorder (OCD) in adult patients with schizophrenia has been increasingly recognized. However, the rate of OCD comorbidity in adolescent schizophrenia patients has yet to be systematically evaluated. METHOD: The rate of DSM-IV OCD was evaluated in 50 adolescent inpatients with schizophrenia or schizoaffective disorder. The severity of schizophrenia and OCD symptoms was assessed with the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and Yale-Brown Obsessive Compulsive Scale. RESULTS: Thirteen schizophrenia patients (26.0%) also met the DSM-IV criteria for OCD. This subgroup scored significantly higher on the SANS subscale for affective flattening or blunting. The total SANS score positively correlated with the total Yale-Brown Obsessive Compulsive Scale score. CONCLUSIONS: A substantial proportion of adolescent schizophrenia inpatients have concomitant OCD. A prospective study is needed to evaluate the clinical course, response to treatment, and prognosis for this complex disorder.

OBJECTIVES: This 2023 update of the WFSBP guidelines for the pharmacological treatment of eating disorders (EDs) reflects the latest diagnostic and psychopharmacological progress and the improved WFSBP recommendations for the assessment of the level of evidence (LoE) and the grade of recommendation (GoR). METHODS: The WFSBP Task Force EDs reviewed the relevant literature and provided a timely grading of the LoE and the GoR. RESULTS: In anorexia nervosa (AN), only a limited recommendation (LoE: A; GoR: 2) for olanzapine can be given, because the available evidence is restricted to weight gain, and its effect on psychopathology is less clear. In bulimia nervosa (BN), the current literature prompts a recommendation for fluoxetine (LoE: A; GoR: 1) or topiramate (LoE: A; GoR: 1). In binge-eating disorder (BED), lisdexamfetamine (LDX; LoE: A; GoR: 1) or topiramate (LoE: A; GoR: 1) can be recommended. There is only sparse evidence for the drug treatment of avoidant restrictive food intake disorder (ARFID), pica, and rumination disorder (RD). CONCLUSION: In BN, fluoxetine, and topiramate, and in BED, LDX and topiramate can be recommended. Despite the published evidence, olanzapine and topiramate have not received marketing authorisation for use in EDs from any medicine regulatory agency.

Conventional rTMS in major depressive disorder (MDD) targets the dorsolateral prefrontal cortex (DLPFC). However, many patients do not respond to DLPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in 'non-reward' functions and shows hyperconnectivity in MDD. OFC-rTMS has been used successfully in obsessive-compulsive disorder, and achieved remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. Here, we assess the safety and tolerability of right OFC-rTMS, and examine the effectiveness of inhibitory right OFC-rTMS in MDD, particularly among patients with previous nonresponse to DMPFC-rTMS. We performed a chart review to retrieve data on clinical characteristics, stimulation parameters, adverse events, and clinical symptom outcomes for a series of 42 patients with medication-resistant and/or DMPFC-rTMS-nonresponsive MDD, who underwent 20-30 sessions of 1Hz right OFC-rTMS at a single Canadian clinic from 2015 to 2017. Over 882 sessions of treatment, there were no seizures, visual/ocular complications, or other serious or treatment-limiting adverse events. Pain ratings averaged 6-7/10 (10=maximum tolerable); no patient discontinued treatment prematurely due to pain. 15/42 patients (35.7%) achieved response (≥50% symptom reduction) and 10/42 (23.8%) achieved remission. Among the 30/42 patients who were previous nonresponders to DMPFC-rTMS, 9/30 (30.0%) achieved response and 7/30 (23.8%) achieved remission. Response distribution was sharply bimodal. 1Hz right OFC-rTMS appears safe and tolerable, and may achieve remission in MDD patients even when conventional rTMS has failed. Sham-controlled follow-up studies may be warranted.

BACKGROUND: To examine the relationship between anger, impulsivity and suicidality. METHODS: Thirty psychiatric inpatients admitted for suicidal behavior were compared with 30 nonsuicidal psychiatric inpatients and 32 healthy controls on measures of anger, impulsivity and suicide risk. RESULTS: The three groups were similar on demographic variables, but the suicidal group scored higher on the suicide risk scale, impulsivity scale and anger scale. Anger and impulsivity correlated significantly with suicide risk. High anger and impulsivity contributed synergistically to the suicide risk. Whereas anger was specific to both psychiatric groups, suicidals and nonsuicidals, only impulsivity was specific to the suicidal group. CONCLUSIONS: These findings may have important implications for therapists and primary prevention workers, and may pave the way for the recognition of risk factors and for effective intervention in patients with a high suicide risk.

This study examined the prevalence of post-traumatic stress disorder (PTSD) in a sample of 100 Israeli myocardial infarction (MI) patients. Chronic PTSD was diagnosed in 16% of these patients and acute (PTSD) in 9%. The appearance of PTSD following MI was found to be related to the following variables: ethnic background; prior traumatic experiences, including prior MI; and anticipation of disability following MI. Objective measures of MI severity were not related to propensity to develop PTSD. The presence of PTSD correlated with self reports of dysfunction in these MI patients and may account for the majority of failures in rehabilitation.

Harmful behaviors and low adherence to medical treatment significantly contribute to an increased rate of hospitalizations, mortality and morbidity. Leading health organizations worldwide are making great efforts to find and develop efficient strategies in order to recruit patients to adhere to medical treatment and adopt a healthier lifestyle. Motivational interviewing is an evidence-based approach that the physician can apply in numerous health care situations in order to increase patients' adherence to treatment. It is a patient-centered approach, based on principles of collaboration, autonomy and evocation. Research indicates that the patient's verbal commitment towards change is directly correlated to future behavioral change. Therefore, the approach includes learnable techniques which assist in allowing the patient to speak about the advantages of behavioral change and treatment. Thus, motivational interviewing helps patients adopt a healthier lifestyle while contributing to the professionalism of physicians and their sense of satisfaction from work.

OBJECTIVES: Repetitive transcranial stimulation (rTMS) affects dopaminergic secretion in the prefrontal cortex. Attention deficit hyperactivity disorder (ADHD) had been suggested to involve dopaminergic prefrontal abnormalities. METHODS: In this crossover double-blind randomized, sham-controlled pilot study, patients diagnosed as having adult ADHD received either a single session of high-frequency rTMS directed to the right prefrontal cortex (real rTMS) or a single session of sham rTMS. RESULTS: A total of 13 patients (seven males, six females) who fulfilled the criteria for adult ADHD, according to DSM-IV criteria gave informed consent and were enrolled. There was a specific beneficial effect on attention 10 minutes after a real rTMS course. The post-real rTMS attention score improved significantly (M=3.56, SD=0.39) compared to the pre-real rTMS attention score (M=3.31, SD=0.5) [t(12)=2.235, P < 0.05]. TMS had no effect on measures of mood and anxiety. The sham rTMS had no effect whatsoever. CONCLUSIONS: Our findings should encourage future research on the possibility of amelioration of attention difficulties in patients suffering from ADHD by using high frequency rTMS directed to the right dorsolateral prefrontal cortex. (NIH registry NCT00825708).