Danny Koren

A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses

Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.

Sex differences in olfactory identification and Wisconsin card sorting performance in schizophrenia: Relationship to attention and verbal ability

We investigated the hypothesis that different prefrontal brain systems (i.e., dorsal vs. ventral) and sex contribute differentially to cognitive deficit in schizophrenia. Performance was assessed among clinically stable, chronic schizophrenic outpatients and matched normal control subjects on olfactory identification [on the University of Pennsylvania Smell Identification Test (UPSIT)] and on executive functions [using the Wisconsin Card Sorting Test (WCST)]. Patients were impaired on both tests compared to controls, and male schizophrenics were impaired on the WCST compared to female schizophrenics. The pattern of results suggests that gender differences on the UPSIT are mildly accentuated in schizophrenia. The data support our previous study indicating that UPSIT performance is largely independent of the executive or attentional deficits typically associated with schizophrenia, with the exception of verbal ability. Further research with larger samples is required to test the hypothesis that there is a severely impaired subgroup of male patients with diffuse prefrontal dysfunctions.

Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham- controlled pilot study

BACKGROUND The aim of this study was to extend our previous work on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depression to patients with schizophrenia. METHODS Thirty-five inpatients with schizophrenia were randomly assigned to either right prefrontal rTMS or sham treatment and were rated before and after treatment for positive, negative, and depressive symptoms. RESULTS Thirty-one subjects (rTMS = 16, sham = 15) completed a 2-week treatment protocol. No serious adverse effects were reported; however, rTMS was not superior to sham treatment on any of the clinical ratings. CONCLUSIONS In contrast to our previous positive findings in major depression, right prefrontal slow rTMS does not appear to have a beneficial effect for actively psychotic patients with schizophrenia.

Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study.

UNLABELLED Preponderance of serotonin 5-HT2A antagonism over dopamine D2 blockade exerted by atypical antipsychotics may contribute to their cognitive-enhancing effect. In a double-blind placebo-controlled study we examined the effect of add-on mianserin (15 mg/day), an agent with marked 5-HT2A antagonism, on cognitive functioning in 30 chronic hospitalized DSM-IV schizophrenia patients stabilized on typical antipsychotics. The Automated Neuropsychological Assessment Metrics (ANAM) battery was used to assess learning, memory and sustained attention; Wisconsin Card Sorting Test (WCST) to assess executive function at baseline and endpoint (4 weeks). Clinical assessment included appropriate rating scales. The mianserin group overperformed the placebo group on selective ANAM memory/learning tests, reflected in moderate-to-high effect size values. No between-group differences were revealed in WCST and clinical ratings. CONCLUSIONS Improved performance on selective neurocognitive tests with addition of the 5-HT2A antagonist mianserin to typical antipsychotics indicates a possible role of the 5-HT system in cognitive-enhancing effects. The effect of flexible doses of mianserin on cognitive deficits in a broader schizophrenia population merits further investigation.

Sleep complaints are not corroborated by objective sleep measures in post-traumatic stress disorder: A 1-year prospective study in survivors of motor vehicle crashes.

Disturbed sleep is a common complaint among patients with post‐traumatic stress disorder (PTSD). However, laboratory studies of sleep in PTSD have provided inconsistent evidence of objective sleep disturbances. A major shortcoming of most previous studies is the fact that they were performed retrospectively in patients with chronic PTSD, often complicated by comorbid psychiatric disorders and drug abuse. Thus, little is known about the development of sleep disturbances in recently traumatized subjects. In this study, 102 motor vehicle collision (MVC) survivors were followed from the time of collision throughout 1 year. Nineteen subjects hospitalized for elective surgery served as a comparison group. Subjective quality of sleep was assessed using the mini‐Sleep Questionnaire and the Sleep Habit Questionnaire. In addition, a 48‐h actigraphic recording was obtained 1 week, 3 and 12 months after the collision. At 12 months, a structured clinical interview (SCID) was administered to reach a formal diagnosis of PTSD. Twenty‐six of the MVC survivors, but none of the comparison subjects, met the diagnostic criteria for PTSD. While MVC survivors with PTSD reported markedly poorer sleep as reflected by significantly higher scores on the mini‐Sleep Questionnaire, there were no significant differences between the three groups on the actigraphic measures that were largely normal. These results, which were obtained in subjects with no evidence of active psychiatric symptoms at the time of trauma and free of psychotropic or hypnotic medications, further support previous polysomnographic (PSG) studies suggesting that altered sleep perception, rather than sleep disturbance per se, may be the key problem in PTSD.

Long-term effects of early parental loss due to divorce on the HPA axis

We investigated the long-term effects of divorce and early separation from one parent on HPA axis reactivity, in young adults without psychopathology. Participants were 44 young subjects, 22 whose parents divorced before they reached age 10, and 22 controls. Psychiatric symptomatology was measured with the Brief Symptom Inventory (BSI), family perceived stress by the Dyadic Adjustment Scale (DAS), and bonding by the Parental Bonding Instrument (PBI). Assessment of HPA axis function included baseline morning cortisol and ACTH and cortisol response to a CRH stimulation test. No baseline or stimulated group differences were observed for ACTH. Cortisol levels were consistently but insignificantly lower in the divorce group throughout the CRH stimulation reaching statistical significance only at 5 min (p<0.03). Group by time effect reached a trend level (p<0.06). A correlation was found between psychiatric symptomatology and PBI scores; however, both parameters did not correlate with HPA axis activity. A significant correlation was found between DAS scores and ACTH. A regression model revealed a contributing effect for both family stress and child-parent bonding to stimulated ACTH levels. These preliminary findings suggest that even in the absence of adult psychopathology, a history of childhood separation from one parent due to divorce may lead to detectable, albeit mild, long-term alterations in HPA axis activity. Furthermore, they suggest that level of stress at home and parental bonding are important determinants of this effect. It is likely that divorce has significant and sustained effects on childrens HPA axis only in the context of a traumatic separation.

Injury increases the risk for PTSD: an examination of potential neurobiological and psychological mediators.

A growing number of common traumatic events involve both physical and emotional injuries. In contrast to previously held beliefs, the rapidly growing body of literature shows quite convincingly that physical injury, over and above exposure to the traumatic event itself, increases rather than decreases the risk for posttraumatic stress disorder (PTSD). A pertinent question becomes how bodily injury contributes to the risk of developing PTSD. In this article, we review contemporary findings regarding the neurobiological and psychological mechanisms by which bodily injury may augment or independently contribute to chronic posttraumatic stress. In addition, we propose three theoretical pathways through which physical injury can increase the risk for PTSD. These pathways are: additive, unique, and recovery impeding. Finally, we highlight unresolved issues pertaining to each one of these pathways and propose directions for future research to address them.

Neuropsychological effects of prefrontal slow rTMS in normal volunteers: a double-blind sham-controlled study.

Recent reports have suggested that repetitive transcranial magnetic stimulation (rTMS) is effective in major depression. Unlike ECT, rTMS does not involve a seizure and is associated with minimal side-effects, including cognitive difficulties. However, the effect of rTMS on cognitive functioning has not been systematically evaluated. This study was designed to examine the neuropsychological effects of slow rTMS in normal volunteers. Forty-six normal volunteers were randomly assigned to receive one session of right (N16) or left prefrontal (N15), or sham (N15) rTMS at1HZ. Patients were assessed before and after stimulation by a computerized neurospychological battery. All three groups showed significant improvement over time in processing speed (reaction time) and efficiency (correct responses per unit of time). However, no time by group interaction was found for any of the neuropsychological tests. These findings suggest that a single session of slow rTMS does not interfere with neurospychological functioning in normal volunteers, supporting clinical reports of no adverse cognitive effects.

Acute stress reactions among medical and non‐medical personnel in a general hospital under missile attacks

Background: Recent mass level traumatic events further boosted the growing interest in understanding the effects of primary (direct) and secondary (indirect) traumatic exposure on “helping professionals.” The objectives of this study are: (1) to assess the rates and severity of PTSD symptoms (PS) among hospital workers operating under fire while treating war‐related injured patients, (2) to explore the effect of PS on level of functioning in real time, and (3) to estimate the added effect of secondary traumatization over and above that of primary traumatization. Methods: Rates of PS, level of psychological distress, and level of functioning were assessed in 412 medical and non‐medical personnel working in a hospital that was under missile attacks during the Second Lebanon War in the summer of 2006. The Posttraumatic Stress Disorder Scale (PSS) was used to assess severity of PS, as well as to estimate probable DSM‐IV diagnosis of PTSD. Results: The mean number of reported PS was 8.6 (SD=4.4). Forty‐three (10.2%) of the participants met the symptom and severity threshold for a probable diagnosis of PTSD, however only 13 of these 43 reported impaired level of functioning. There were no significant differences between personnel who had direct exposure to injured or traumatized casualties of the war and those who were not on PS severity and frequency of probable PTSD. Conclusions: These findings suggest that hospital workers operating under prolonged life‐threatening conditions are at moderate risk for PTSD. However, they do not support an incremental effect of secondary traumatic exposure. Depression and Anxiety, 2009.

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: A double-blind sham-controlled study

BACKGROUND Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent and long lasting effects on cortical excitability. In a previous open study, we demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) in major depression (MD). The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using a double-blind, sham-controlled design. METHODS Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n=15) or sham cTBS (n=14) for 10 consecutive work days. After the 10th session, patients who received sham TBS were crossed over to active cTBS which consisted of 10 daily sessions. Patients who received active cTBS continued with the same treatment protocol for additional 10 treatments. Each treatment session consisted of 3600 stimuli at an intensity of 100% of the active motor threshold. Severity of depression was assessed weekly. RESULTS Overall, there was no significant difference in the degree of clinical improvement between active and sham cTBS groups. However, in patients whose medication status remained unchanged before the trial (n=8) and in those who were medication-free (n=3), active cTBS resulted in a significantly greater reduction of Hamilton depression scores as compared to sham cTBS. LIMITATIONS A small sample size, confounding effect of medication and short treatment period. CONCLUSIONS Our results suggest that the antidepressant effect of cTBS is modest, yet it might be beneficial to patients nonresponsive to ongoing pharmacological treatment. A direct comparison between cTBS and conventional rTMS protocols is warranted.