Yoram Braw

A Double-Blind, Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia

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.

H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study

Abstract 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.

Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia.

Minocycline is a second-generation tetracycline with a distinct neuroprotective profile. The current study assessed the effects of minocycline in an animal model of schizophrenia, the non-competitive NMDA antagonist (dizocilpine maleate; MK801). The effects of minocycline were compared to those of haloperidol, a dopamine antagonist used for the treatment of schizophrenia. The study protocol involved daily intraperitoneal injections of minocycline (35 mg/kg) for three consecutive days. On the fourth day, the rats were injected with MK801 and assessed for visual-spatial memory (Morris water maze) and sensorimotor gating (acoustic startle response, ASR, and the prepulse inhibition of the ASR). The findings indicate that MK801 caused cognitive visuo-spatial memory deficits and changes in sensorimotor gating, similar to those evident in schizophrenia. Minocycline reversed these cognitive effects of MK801 and this effect was similar to that of haloperidol. The results of this study suggest that minocycline may have protective properties against the cognitive effects of the MK801 animal model of schizophrenia. The discussion addresses potential mechanisms underlying the effects of minocycline and possible directions for future research.

Executive functioning among patients with borderline personality disorder (BPD) and their relatives

BACKGROUND Studies focusing on executive functioning in patients with borderline personality disorder (BPD) have shown divergent results. Moreover, little attention has been paid to the potential role of deficits in executive functions as markers of familial vulnerability to BPD. Thus, the aim of the present study was to investigate executive functions in both patients BPD and their unaffected first-degree relatives (parents). METHOD We examined executive functions in four groups: patients with BPD (n=27), age-matched healthy controls (n=29), healthy unaffected parents of patients in the BPD group (n=20) and their respective age-matched controls (n=22). We administered tests that tapped three domains of executive functions: cognitive planning, sustained attention, and spatial working memory. All tests form part of the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery. RESULTS BPD patients displayed deficient executive functioning as compared to healthy controls in the domains of cognitive planning, sustained attention and working memory. Both BPD patients and their parents showed reduced latency to initiate the first move on the planning task [CANTABs Tower of London]. All other measurements of executive functions did not differ significantly between parents of BPD patients and their respective healthy controls. LIMITATION Results should be replicated with a larger sample size. CONCLUSIONS BPD patients demonstrate a generalized profile of executive dysfunction. In the group comprising their parents, however, we found a lack of evidence for executive dysfunctions. Hence, executive dysfunctions do not appear to be markers of familial vulnerability for BPD.

The effect of age on frontal lobe related cognitive functions of unmedicated depressed patients

BACKGROUND Aging is associated with a decline in frontal lobe related cognitive functioning of healthy subjects (i.e., executive functioning and higher-order cognition). Unipolar depression is associated with dysfunctions in similar cognitive domains--deficits that impact the functioning and quality of life of these patients. The effect of age on frontal lobe related cognitive functions of depressed patients, however, has not been adequately studied. The current study therefore assessed a wide age range of depressed patients and compared their frontal lobe related cognitive functions to that of matched healthy controls. Recruitment of unmedicated patients minimized the confounding effect of psychiatric medications. METHOD Depressed patients and healthy controls were divided into three age groups (<25, 25-45, and 46-65 years of age) and matched in gender, age and education level (N total=170). Cognition was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS The depressed patients had deficits in cognitive planning/organization, working memory, and sustained attention compared to the healthy controls. Aging was associated with a decrease in frontal lobe related functioning. Except for working memory, no significant interactions were found between the age groups and the study group (depressed/healthy). CONCLUSIONS Depressed patients are impaired in most domains of frontal lobe related cognitive functions. These deficits are already evident at an early age and persist in older age cohorts (despite an overall age related decline). These findings may help clarify the profile and course of cognitive deficits among depressed patients while providing tentative support for a developmental model of cognitive impairment in depression.

Stress hormones and emotion-regulation in two genetic animal models of depression

Children of depressed parents often exhibit emotion-regulation deficits, characterized by either excessive withdrawal or approach strategies toward the mother. The current study examined behavioral and physiological emotion-regulation in preweanling pups (postnatal day 17-19) belonging to two different genetic animal models of depression, Wistar-Kyoto (WKY) and Flinders Sensitive-Line (FSL) rats. The study also examined the effects of stress on the two animal models, hypothesizing an interactive effect of hereditary vulnerability and exposure to stress. Chronic-stress was simulated by providing limited bedding to the dam and litter for a week, in the early postnatal period. Acute-stress was generated by exposure to an adult male rat, an ethologically valid stressor. Emotion-regulation of the pups was examined using a Y-maze preference test and radioimmunoassay of Hypothalamic-Pituitary-Adrenal (HPA) axis hormones (corticosterone & adreno-corticotropin/ACTH). WKY and FSL pups exhibited reduced approach-behavior toward the dam, an emotion-regulation profile reminiscent of avoidant attachment evident in many children of depressed parents. In contrast, the two animal models did not show similar HPA axis activity. FSL pups exhibited markedly lower ACTH levels compared to controls, while WKY pups did not differ from controls. With regard to the stress manipulations, the limited-bedding condition had no effect, while the acute-stressor induced overall effects on all groups, with more pronounced reactivity evident in the WKY and FSL pups. Taken together, the experiments indicate a similar behavioral profile of the two strains at the preweanling period, while suggesting HPA dysfunction in only one of the strains.

Executive functioning during full and partial remission (positive and negative symptomatic remission) of schizophrenia

BACKGROUND Despite the upsurge of research regarding cognitive impairment in schizophrenia we still lack adequate understanding of the executive functioning of patients in symptomatic remission. Moreover, the cognitive functioning of patients in partial remission has not been studied previously although they comprise a significant proportion of schizophrenia patients. The current study therefore examined the executive functioning of patients in full symptomatic remission and for the first time assessed two sub-groups of patients in partial remission. METHODS Executive functioning of five groups was compared; symptomatic patients, patients in positive symptomatic remission, negative symptomatic remission, full symptomatic remission (SP, PSR, NSR, and FSR; N=101) and healthy controls (N=37). RESULTS A graded cognitive profile was evident between the groups. SP patients exhibited widespread executive dysfunction while the performance of FSR patients was comparable to that of the healthy controls. Both PSR and NSR patients had working memory deficits, with PSR patients showing additional deficits in cognitive planning. CONCLUSIONS The findings are encouraging, tentatively suggesting intact executive functioning among patients in full symptomatic remission. The graded cognitive profile of the patient groups strengthens earlier findings indicating the significant role of negative symptoms in determining executive dysfunction in schizophrenia. The findings point toward potential targets for therapeutic efforts and emphasize the need for further research of sub-groups of schizophrenia patients in partial remission.

Executive dysfunction in bipolar disorder and borderline personality disorder

OBJECTIVE The boundary between bipolar disorder (BD) and borderline personality disorder is a controversial one. Despite the importance of the topic, few studies have directly compared these patient groups. The aim of the study was to compare the executive functioning profile of BD and BPD patients. METHOD Executive functioning (sustained attention, problem-solving, planning, strategy formation, cognitive flexibility and working memory) was assessed in BD (n=30) and BPD outpatients (n=32) using a computerized assessment battery (Cambridge Neuropsychological Test Automated Battery, CANTAB). The groups were compared to one another as well as to healthy controls. RESULTS BD patients showed deficits in strategy formation and in planning (indicated by longer execution time in the ToL task) in comparison to BPD patients and healthy controls. BPD patients showed deficits in planning (short deliberation time in the ToL task) in comparison to BD patients and in comparison to healthy controls. In comparison to healthy controls, BPD patients displayed deficits in problem-solving. CONCLUSIONS Differences in executive dysfunction between BD and BPD patients suggest that this cognitive dimension may be relevant for the clarification of the boundary between the disorders.

The correlation between impaired attention and emotional reactivity in depressed adolescent patients.

A group of 20 drug-naïve depressed adolescents and 20 matched controls underwent cognitive evaluations and assessment of emotional reactivity. Emotional reactivity correlated only with attention and only in depressed patients. The cognitive-emotional construct may enhance the understanding of adolescent depression and aid diagnosis.

Methylphenidate Reduces State Anxiety During a Continuous Performance Test That Distinguishes Adult ADHD Patients From Controls.

Objective: We hypothesized that patients with ADHD were typified by distress more than by functional difficulties. Thus, a decline in state anxiety while performing a cognitive task when taking methylphenidate would discriminate between ADHD patients and controls. Method: State anxiety and cognitive performance on a continuous performance test were assessed in ADHD patients and controls with and without taking methylphenidate. Results: State anxiety and cognitive performance improved from baseline in 36 ADHD adults after taking methylphenidate. In 25 controls, cognitive performance improved, but state anxiety did not abate after a recess. In two additional studies, 5 controls were evaluated at baseline and after receiving methylphenidate, and showed improvement in cognitive assessment but not in state anxiety. Five ADHD adults were assessed at baseline and after a recess, and showed no improvement. Conclusion: Our results support the hypothesis that adult ADHD patients are characterized by distress and the relief of this distress under effective therapy as expressed by a decline in state anxiety while they perform a cognitive task.