We investigated the long-term effects of divorce and early separation from one parent on HPA axis... more 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 children's HPA axis only in the context of a traumatic separation.
Background: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent a... more 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, shamcontrolled design. Methods: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n ¼15) or sham cTBS (n ¼ 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 ¼8) and in those who were medication-free (n ¼3), 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.
During the Holocaust and since the establishment of the state of Israel in 1948, Jews and Israeli... more During the Holocaust and since the establishment of the state of Israel in 1948, Jews and Israelis were repeatedly exposed to traumatic events. This has made Israel a live laboratory for the research of trauma and posttraumatic stress disorder (PTSD). The horrors of the Holocaust and its emotional scars in the survivors, followed by seven wars and waves of terror have unfortunately served as an experimental field for the study of trauma and its consequences. This article reviews key findings from studies done in Israel on trauma and PTSD during the last 3 decades and highlights their contribution to the existing body of knowledge in this field.
Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effecti... more Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effective in the treatment of major depression. We administered rTMS chronically to rats in order to determine whether this procedure affected serotonergic neurotransmission in the prefrontal cortex. Basal 5-HT levels, and the effects of challenges with the 5-HT 1A receptor agonist 8-OH-DPAT and the 5-HT 1B antagonist GR 127935 on 5-HT levels were determined using in vivo microdialysis. Rats which had undergone chronic rTMS showed reduced responses to both challenges, indicating subsensitivity of both the presynaptic 5-HT 1A autoreceptors situated somatodendritically in the raphe nuclei and the 5-HT 1B autoreceptors situated on nerve terminals. Since such subsensitivity has been demonstrated after other antidepressant treatments, our results indicate that these treatments and rTMS may have a common mechanism of action. NeuroReport 11:2925±2929 & 2000
Previous studies have indicated that the endogenous peptide, melanotropin release inhibiting fact... more Previous studies have indicated that the endogenous peptide, melanotropin release inhibiting factor (MIF) and its analog cyclo(Leu-Gly) (CLG) facilitate dopamine (DA) receptor agonist binding and inhibit DA receptor supersensitivity induced by neuroleptics and opiates. The effect of CLG was tested on [3-adrenergic hypersensitivity induced by reserpine to ascertain whether CLG has effects on other neuronal systems besides DA. Administration of reserpine to rats induced hypomotility and enhanced binding of [3H]dihydroalprenolol (DHA) to cortical membranes. Concurrent administration of CLG blocked both the hypomotility and the enhanced [3H]DHA binding to cortical membranes. Lithium has also been shown to prevent reserpine induced hypomotility and increased cortical [3H]DHA binding. These studies suggest that CLG may be producing its effect either like lithium or by an amphetamine like action. If CLG can be shown to have lithium like activity, it could prove to be useful in the treatment of mania.
Current Therapeutic Research-clinical and Experimental, Sep 1, 1995
Compared with benzodiazepines that have long half-lives, those with short half-lives have been as... more Compared with benzodiazepines that have long half-lives, those with short half-lives have been associated with a higher risk of discontinuation difficulties. The nature of the anxiety disorder for which treatment is prescribed might also have a bearing on successful medication discontinuation. In a blinded trial, the ability to discontinue treatment with the immediate-release formulation of alprazolam (alprazolam compressed tablet CCTI) was examined in 35 patients with generalized anxiety disorder (GAD) and 36 patients with panic disorder. The patients were randomized to receive adjunctive treatment with carbamazepine or placebo during discontinuation of alprazolam CT. In the placebo group, the dropout rate was significantly higher among 18 patients with panic disorder than among 17 patients with GAD. In individuals with panic disorder, the dropout rate was significantly lower among 18 patients treated with carbamazepine than in 18 patients treated with placebo. Data from 52 patients evaluated 12 to 18 months after completion of the study showed that 25% were asymptomatic and not taking any medications, 56% were taking alprazolam, and 25% were taking other medications (mostly benzodiazepines). In a double-blind trial of 215 patients with panic disorder, the mean number of weekly panic attacks after drug discontinuation was comparable among patients who had received an extended-release formulation of alprazolam (alprazolam XR) or placebo and was nonsignificantly higher among those who had received alprazolam CT. In a doubleblind trial of 112 patients with GAD, physicians assessed withdrawal difficulties during discontinuation of alprazolam XR or bromazepam. Withdrawal difficulties were rated as absent in 66% of the alprazolam XR group versus 46% of the bromazepam group; mild in 26% versus 33%, respectively; moderate in 16% versus 211, respectively; and severe in 4% versus none, respectively. Alprazolam XR provides therapeutic efficacy comparable to that of alprazolam CT, but may offer advantages during drug tapering and withdrawal.
Eating disorders may be associated with alterations in sleep. There is evidence that some bulimia... more Eating disorders may be associated with alterations in sleep. There is evidence that some bulimia nervosa (BN) patients have sleep abnormalities. No studies of their sleep-wake cycles in a natural environment have as yet been reported. The purpose of this study was to evaluate an objective and subjective sleep-wake cycle of BN compared to a healthy age-equated control group (CON). Twenty-nine BN female and eighteen CON subjects were recruited. Sleep-wake patterns were monitored using ambulatory monitoring, mini-actigraphs (Min-Act), for 1 week. Each subject completed self-report questionnaires. The self-reporting questionnaires revealed that BN complained of significantly more sleep disturbances than CON. The ambulatory sleep data revealed significant differences between BN and CON in sleep onset and offset time. BN had sleep onset and sleep offset of 1 hr later, which may be connected to binge-purge patterns during the day. It is suggested that future research should focus on BN after remission.
This experiment examined the hypothesis that schizophrenics are less able than normals to make us... more This experiment examined the hypothesis that schizophrenics are less able than normals to make use of information concerning self movement when performing auditory localization tasks, and, therefore apply an alternative localization strategy, probably involving use of the pinnae. In this study three groups (healthy controls, schizophreniform patients and chronic schizophrenics) were compared in four experimental conditions: (1) head-movement and free pinnae; (2) static head and free pinnae; (3) head movement and covered pinnae; and (4) static head and covered pinnae. All subjects perform better with head movement than without it, with pinnae than with covered ones. Schizophreniform patients were affected more than normals by pinnae covering. This difference did not reach significance when normals were compared with chronic schizophrenics. A pronounced susceptibility to pinnae manipulation, correlated with medication level, appeared in the combined patient group in the moving condition. It was suggested that schizophreniform subjects, as compared to healthy controls are more depended on pinnae generated information for auditory localization and less able to compensate for its absence with movement generated information. The possibility that the effect is related to psychosis as such, rather than to schizophrenia in particular, was considered.
Compared with benzodiazepines that have long half-lives, those with short half-lives have been as... more Compared with benzodiazepines that have long half-lives, those with short half-lives have been associated with a higher risk of discontinuation difficulties. The nature of the anxiety disorder for which treatment is prescribed might also have a bearing on successful medication discontinuation. In a blinded trial, the ability to discontinue treatment with the immediate-release formulation of alprazolam (alprazolam compressed tablet CCTI) was examined in 35 patients with generalized anxiety disorder (GAD) and 36 patients with panic disorder. The patients were randomized to receive adjunctive treatment with carbamazepine or placebo during discontinuation of alprazolam CT. In the placebo group, the dropout rate was significantly higher among 18 patients with panic disorder than among 17 patients with GAD. In individuals with panic disorder, the dropout rate was significantly lower among 18 patients treated with carbamazepine than in 18 patients treated with placebo. Data from 52 patients evaluated 12 to 18 months after completion of the study showed that 25% were asymptomatic and not taking any medications, 56% were taking alprazolam, and 25% were taking other medications (mostly benzodiazepines). In a double-blind trial of 215 patients with panic disorder, the mean number of weekly panic attacks after drug discontinuation was comparable among patients who had received an extended-release formulation of alprazolam (alprazolam XR) or placebo and was nonsignificantly higher among those who had received alprazolam CT. In a doubleblind trial of 112 patients with GAD, physicians assessed withdrawal difficulties during discontinuation of alprazolam XR or bromazepam. Withdrawal difficulties were rated as absent in 66% of the alprazolam XR group versus 46% of the bromazepam group; mild in 26% versus 33%, respectively; moderate in 16% versus 211, respectively; and severe in 4% versus none, respectively. Alprazolam XR provides therapeutic efficacy comparable to that of alprazolam CT, but may offer advantages during drug tapering and withdrawal.
J: Antidepressantassociated seizures (ltr). Journal ofClinical Psychiatry 55:267, 1994 13. Tohen ... more J: Antidepressantassociated seizures (ltr). Journal ofClinical Psychiatry 55:267, 1994 13. Tohen M: Bias and other methodological issues in follow-up (cohort) research studies, in Research Designs and Methods in Psychiatry.
The risk of developing PTSD following a traumatic experience depends on several vulnerability fac... more The risk of developing PTSD following a traumatic experience depends on several vulnerability factors that may be classified into three distinct categories: pre-traumatic, peri-traumatic, and posttraumatic vulnerability factors. Accordingly, while we attempted to create a profile of the high-risk PTSD patient, the following factors should be included, among others: small hippocampus, previously altered HPA axis, vulnerable genetic profile, associated body injury, increased post-trauma noradrenergic activity. Some protective factors have been identified and included, but are not limited to coping, resources (e.g., social support, self-esteem, optimism), and finding meaning. Finally, human beings are resilient and in general are able to cope with adverse situations. Therefore, discovering possible resilience factors may assist in identifying the patients at risk and may contribute to developing the strategies to prevent the development of PTSD.
This study was conducted to further evaluate HPA axis activity by the measurement of plasma ACTH ... more This study was conducted to further evaluate HPA axis activity by the measurement of plasma ACTH and cortisol and ACTH corticotropin-releasing hormone (CRH) in the cerebrospinal fluid (CSF) of nervous and normal dogs
Immediate-release (IR) benzodiazepines have a short duration of therapeutic effect and are genera... more Immediate-release (IR) benzodiazepines have a short duration of therapeutic effect and are generally less effective for anxiety than selective serotonin reuptake inhibitors in reducing concomitant depressive symptomatology. Common criticisms of benzodiazepines also include the patient's tendency to develop a tolerance to the anxiolytic effect and a dependence on the drug itself. The newer extended-release (XR) benzodiazepine formulation was designed to increase efficacy, duration of therapeutic effect, tolerance, compliance, and ease of discontinuation. The XR benzodiazepine alprazolam has shown efficacy in panic disorder and generalized anxiety disorder comparable to the older benzodiazepine formulations. Pharmacokinetic data show that the XR formulation has a longer therapeutic effect compared with IR formulations, which reduces the potential for breakthrough anxiety symptoms. Data also indicate that the XR formulation has less abuse liability than the IR formulation. This article reviews the efficacy, safety, and discontinuation data from clinical trials of IR and XR benzodiazepines in the treatment of anxiety disorders and provides guidelines to minimize the risk of withdrawal syndrome during benzodiazepine discontinuation.
Genetically nervous pointer dogs have been characterized in earlier works as an animal model for ... more Genetically nervous pointer dogs have been characterized in earlier works as an animal model for pathological anxiety. 1-3 Individual differences in fearfulness were initially used to create two lines ofpointer dogs. 4,5 These lines have been maintained now for more than 20 years with continuous selection for the most fearful dogs in the nervous line and for the least fearful dogs in the normal line. Each line originated from a single male-female pair of each type. The behavioral traits of both fearfulness and normality have bred essentially true since the first generation. 2 The nervous dogs begin to demonstrate from the age of 3-9 months a highly characteristic and reproducible pattern of fear-related behaviors to certain exogenous stimuli. 6 In the absence of such stimuli, these dogs do not appear to be markedly different from the normal dogs: they move freely, play with other dogs, breed as well as the normal dogs, and adequately rear their pups or foster pups from the normal line. I In contrast to these normal behaviors, exposure to humans, a sudden blast of a loud noise, and certain other stimuli elicit a dramatic expression of fearrelated behaviors such as excessive timidity, hyperstartle, reduced exploratory activity, marked avoidance of the human observer, catatonic freezing cardiovascular changes, urination, and defecation. I ,2 The normal dogs behave differently under those conditions as evidenced by friendly play with humans. They are active and inquisitive and comply without protest to experimental tasks,I.3 and despite such tasks they continue to approach man in a friendly fashion. 1,3 The phenotypic expression of the nervous behavior in these dogs is not prevented by cross-rearing or by extra home-rearing, which produces only temporary changes compared to kennel rearing. 7 Studies done in our group with these dogs included the evaluation of a hearing deficit and its relation to the abnormal behavior. Evaluation of Deafness and Abnormal Behaviors In the course of our work with these dogs, the existence of a hearing deficit was suspected. Obviously such a deficit could contribute to or largely determine this abnormal behavior. We thus decided to evaluate the hearing status of both nervous B. Lerer et al. (eds.
Carbamazepine has recently been reported to have therapeutic potential in mania. We studied carba... more Carbamazepine has recently been reported to have therapeutic potential in mania. We studied carbamazepine plus haloperidol v placebo plus haloperidol in excited psychoses in a controlled double-blind design. Twenty-three patients completed five weeks of carbamazepine-haloperidol therapy, and 20 patients placebo-haloperidol therapy. Brief Psychiatric Rating Scale ratings showed superior improvement in the group receiving carbamazepine plus haloperidol. This benefit was as apparent in excited schizophrenia as in mania. No unusual toxicity was observed because of the combination of haloperidol with carbamazepine.
Alprazolam treatment is effective for panic disorder, but its major disadvantages include possibl... more Alprazolam treatment is effective for panic disorder, but its major disadvantages include possible dependence and withdrawal symptoms upon discontinuation. The authors report three cases in which carbamazepine, a clinically effective anticonvulsant without abuse potential, successfully attenuated alprazolam withdrawal symptoms.
International Journal of Psychiatry in Medicine, Aug 1, 2011
Background: Traumatic injuries are usually associated with increased secretion of pro-inflammator... more Background: Traumatic injuries are usually associated with increased secretion of pro-inflammatory cytokines, and are sometimes followed by the development of acute stress symptoms (ASS) and posttraumatic stress symptoms (PTSS). Aims: To measure serum pro- and anti-inflammatory cytokines in accident casualties and to associate it with ASS at hospitalization, and with PTSS 1 month later. Methods: Participants were 48 patients, aged 20–60, hospitalized following various orthopedic injuries including bone fractures, and 13 healthy volunteers matched for gender. At hospitalization (Time 1), 30 ml heparinized venous blood were drawn and cytokines levels in serum were assessed; participants filled out the Acute Stress Disorder Inventory (ASDI), COPE, and injury-related questionnaires. One month later (Time 2), 26 participants filled out the Posttraumatic Disorder Symptom Scale (PDS). Results: High serum levels of IL-6, IL-8, and TGF-β and low levels of serum IL-4 and IL-10 were found in injured patients as compared with controls. When controlling for age and severity of injury in the regression analysis, higher levels of IL-6 and IL-8 and lower TGF-β were predicted by higher ASS and higher use of and emotion-focused coping. Higher PTSS scores at Time 2 were predicted by higher levels of IL-8, lower levels of TGF-β, and higher ASS measured at Time 1. Conclusions: High levels of the pro-inflammatory cytokine IL-6 and IL-8 and lower levels of the regulatory cytokine TGF-β should be further assessed as a possible risk factor or a bio-marker of PTSS in accident casualties.
We investigated the long-term effects of divorce and early separation from one parent on HPA axis... more 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 children's HPA axis only in the context of a traumatic separation.
Background: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent a... more 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, shamcontrolled design. Methods: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n ¼15) or sham cTBS (n ¼ 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 ¼8) and in those who were medication-free (n ¼3), 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.
During the Holocaust and since the establishment of the state of Israel in 1948, Jews and Israeli... more During the Holocaust and since the establishment of the state of Israel in 1948, Jews and Israelis were repeatedly exposed to traumatic events. This has made Israel a live laboratory for the research of trauma and posttraumatic stress disorder (PTSD). The horrors of the Holocaust and its emotional scars in the survivors, followed by seven wars and waves of terror have unfortunately served as an experimental field for the study of trauma and its consequences. This article reviews key findings from studies done in Israel on trauma and PTSD during the last 3 decades and highlights their contribution to the existing body of knowledge in this field.
Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effecti... more Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effective in the treatment of major depression. We administered rTMS chronically to rats in order to determine whether this procedure affected serotonergic neurotransmission in the prefrontal cortex. Basal 5-HT levels, and the effects of challenges with the 5-HT 1A receptor agonist 8-OH-DPAT and the 5-HT 1B antagonist GR 127935 on 5-HT levels were determined using in vivo microdialysis. Rats which had undergone chronic rTMS showed reduced responses to both challenges, indicating subsensitivity of both the presynaptic 5-HT 1A autoreceptors situated somatodendritically in the raphe nuclei and the 5-HT 1B autoreceptors situated on nerve terminals. Since such subsensitivity has been demonstrated after other antidepressant treatments, our results indicate that these treatments and rTMS may have a common mechanism of action. NeuroReport 11:2925±2929 & 2000
Previous studies have indicated that the endogenous peptide, melanotropin release inhibiting fact... more Previous studies have indicated that the endogenous peptide, melanotropin release inhibiting factor (MIF) and its analog cyclo(Leu-Gly) (CLG) facilitate dopamine (DA) receptor agonist binding and inhibit DA receptor supersensitivity induced by neuroleptics and opiates. The effect of CLG was tested on [3-adrenergic hypersensitivity induced by reserpine to ascertain whether CLG has effects on other neuronal systems besides DA. Administration of reserpine to rats induced hypomotility and enhanced binding of [3H]dihydroalprenolol (DHA) to cortical membranes. Concurrent administration of CLG blocked both the hypomotility and the enhanced [3H]DHA binding to cortical membranes. Lithium has also been shown to prevent reserpine induced hypomotility and increased cortical [3H]DHA binding. These studies suggest that CLG may be producing its effect either like lithium or by an amphetamine like action. If CLG can be shown to have lithium like activity, it could prove to be useful in the treatment of mania.
Current Therapeutic Research-clinical and Experimental, Sep 1, 1995
Compared with benzodiazepines that have long half-lives, those with short half-lives have been as... more Compared with benzodiazepines that have long half-lives, those with short half-lives have been associated with a higher risk of discontinuation difficulties. The nature of the anxiety disorder for which treatment is prescribed might also have a bearing on successful medication discontinuation. In a blinded trial, the ability to discontinue treatment with the immediate-release formulation of alprazolam (alprazolam compressed tablet CCTI) was examined in 35 patients with generalized anxiety disorder (GAD) and 36 patients with panic disorder. The patients were randomized to receive adjunctive treatment with carbamazepine or placebo during discontinuation of alprazolam CT. In the placebo group, the dropout rate was significantly higher among 18 patients with panic disorder than among 17 patients with GAD. In individuals with panic disorder, the dropout rate was significantly lower among 18 patients treated with carbamazepine than in 18 patients treated with placebo. Data from 52 patients evaluated 12 to 18 months after completion of the study showed that 25% were asymptomatic and not taking any medications, 56% were taking alprazolam, and 25% were taking other medications (mostly benzodiazepines). In a double-blind trial of 215 patients with panic disorder, the mean number of weekly panic attacks after drug discontinuation was comparable among patients who had received an extended-release formulation of alprazolam (alprazolam XR) or placebo and was nonsignificantly higher among those who had received alprazolam CT. In a doubleblind trial of 112 patients with GAD, physicians assessed withdrawal difficulties during discontinuation of alprazolam XR or bromazepam. Withdrawal difficulties were rated as absent in 66% of the alprazolam XR group versus 46% of the bromazepam group; mild in 26% versus 33%, respectively; moderate in 16% versus 211, respectively; and severe in 4% versus none, respectively. Alprazolam XR provides therapeutic efficacy comparable to that of alprazolam CT, but may offer advantages during drug tapering and withdrawal.
Eating disorders may be associated with alterations in sleep. There is evidence that some bulimia... more Eating disorders may be associated with alterations in sleep. There is evidence that some bulimia nervosa (BN) patients have sleep abnormalities. No studies of their sleep-wake cycles in a natural environment have as yet been reported. The purpose of this study was to evaluate an objective and subjective sleep-wake cycle of BN compared to a healthy age-equated control group (CON). Twenty-nine BN female and eighteen CON subjects were recruited. Sleep-wake patterns were monitored using ambulatory monitoring, mini-actigraphs (Min-Act), for 1 week. Each subject completed self-report questionnaires. The self-reporting questionnaires revealed that BN complained of significantly more sleep disturbances than CON. The ambulatory sleep data revealed significant differences between BN and CON in sleep onset and offset time. BN had sleep onset and sleep offset of 1 hr later, which may be connected to binge-purge patterns during the day. It is suggested that future research should focus on BN after remission.
This experiment examined the hypothesis that schizophrenics are less able than normals to make us... more This experiment examined the hypothesis that schizophrenics are less able than normals to make use of information concerning self movement when performing auditory localization tasks, and, therefore apply an alternative localization strategy, probably involving use of the pinnae. In this study three groups (healthy controls, schizophreniform patients and chronic schizophrenics) were compared in four experimental conditions: (1) head-movement and free pinnae; (2) static head and free pinnae; (3) head movement and covered pinnae; and (4) static head and covered pinnae. All subjects perform better with head movement than without it, with pinnae than with covered ones. Schizophreniform patients were affected more than normals by pinnae covering. This difference did not reach significance when normals were compared with chronic schizophrenics. A pronounced susceptibility to pinnae manipulation, correlated with medication level, appeared in the combined patient group in the moving condition. It was suggested that schizophreniform subjects, as compared to healthy controls are more depended on pinnae generated information for auditory localization and less able to compensate for its absence with movement generated information. The possibility that the effect is related to psychosis as such, rather than to schizophrenia in particular, was considered.
Compared with benzodiazepines that have long half-lives, those with short half-lives have been as... more Compared with benzodiazepines that have long half-lives, those with short half-lives have been associated with a higher risk of discontinuation difficulties. The nature of the anxiety disorder for which treatment is prescribed might also have a bearing on successful medication discontinuation. In a blinded trial, the ability to discontinue treatment with the immediate-release formulation of alprazolam (alprazolam compressed tablet CCTI) was examined in 35 patients with generalized anxiety disorder (GAD) and 36 patients with panic disorder. The patients were randomized to receive adjunctive treatment with carbamazepine or placebo during discontinuation of alprazolam CT. In the placebo group, the dropout rate was significantly higher among 18 patients with panic disorder than among 17 patients with GAD. In individuals with panic disorder, the dropout rate was significantly lower among 18 patients treated with carbamazepine than in 18 patients treated with placebo. Data from 52 patients evaluated 12 to 18 months after completion of the study showed that 25% were asymptomatic and not taking any medications, 56% were taking alprazolam, and 25% were taking other medications (mostly benzodiazepines). In a double-blind trial of 215 patients with panic disorder, the mean number of weekly panic attacks after drug discontinuation was comparable among patients who had received an extended-release formulation of alprazolam (alprazolam XR) or placebo and was nonsignificantly higher among those who had received alprazolam CT. In a doubleblind trial of 112 patients with GAD, physicians assessed withdrawal difficulties during discontinuation of alprazolam XR or bromazepam. Withdrawal difficulties were rated as absent in 66% of the alprazolam XR group versus 46% of the bromazepam group; mild in 26% versus 33%, respectively; moderate in 16% versus 211, respectively; and severe in 4% versus none, respectively. Alprazolam XR provides therapeutic efficacy comparable to that of alprazolam CT, but may offer advantages during drug tapering and withdrawal.
J: Antidepressantassociated seizures (ltr). Journal ofClinical Psychiatry 55:267, 1994 13. Tohen ... more J: Antidepressantassociated seizures (ltr). Journal ofClinical Psychiatry 55:267, 1994 13. Tohen M: Bias and other methodological issues in follow-up (cohort) research studies, in Research Designs and Methods in Psychiatry.
The risk of developing PTSD following a traumatic experience depends on several vulnerability fac... more The risk of developing PTSD following a traumatic experience depends on several vulnerability factors that may be classified into three distinct categories: pre-traumatic, peri-traumatic, and posttraumatic vulnerability factors. Accordingly, while we attempted to create a profile of the high-risk PTSD patient, the following factors should be included, among others: small hippocampus, previously altered HPA axis, vulnerable genetic profile, associated body injury, increased post-trauma noradrenergic activity. Some protective factors have been identified and included, but are not limited to coping, resources (e.g., social support, self-esteem, optimism), and finding meaning. Finally, human beings are resilient and in general are able to cope with adverse situations. Therefore, discovering possible resilience factors may assist in identifying the patients at risk and may contribute to developing the strategies to prevent the development of PTSD.
This study was conducted to further evaluate HPA axis activity by the measurement of plasma ACTH ... more This study was conducted to further evaluate HPA axis activity by the measurement of plasma ACTH and cortisol and ACTH corticotropin-releasing hormone (CRH) in the cerebrospinal fluid (CSF) of nervous and normal dogs
Immediate-release (IR) benzodiazepines have a short duration of therapeutic effect and are genera... more Immediate-release (IR) benzodiazepines have a short duration of therapeutic effect and are generally less effective for anxiety than selective serotonin reuptake inhibitors in reducing concomitant depressive symptomatology. Common criticisms of benzodiazepines also include the patient's tendency to develop a tolerance to the anxiolytic effect and a dependence on the drug itself. The newer extended-release (XR) benzodiazepine formulation was designed to increase efficacy, duration of therapeutic effect, tolerance, compliance, and ease of discontinuation. The XR benzodiazepine alprazolam has shown efficacy in panic disorder and generalized anxiety disorder comparable to the older benzodiazepine formulations. Pharmacokinetic data show that the XR formulation has a longer therapeutic effect compared with IR formulations, which reduces the potential for breakthrough anxiety symptoms. Data also indicate that the XR formulation has less abuse liability than the IR formulation. This article reviews the efficacy, safety, and discontinuation data from clinical trials of IR and XR benzodiazepines in the treatment of anxiety disorders and provides guidelines to minimize the risk of withdrawal syndrome during benzodiazepine discontinuation.
Genetically nervous pointer dogs have been characterized in earlier works as an animal model for ... more Genetically nervous pointer dogs have been characterized in earlier works as an animal model for pathological anxiety. 1-3 Individual differences in fearfulness were initially used to create two lines ofpointer dogs. 4,5 These lines have been maintained now for more than 20 years with continuous selection for the most fearful dogs in the nervous line and for the least fearful dogs in the normal line. Each line originated from a single male-female pair of each type. The behavioral traits of both fearfulness and normality have bred essentially true since the first generation. 2 The nervous dogs begin to demonstrate from the age of 3-9 months a highly characteristic and reproducible pattern of fear-related behaviors to certain exogenous stimuli. 6 In the absence of such stimuli, these dogs do not appear to be markedly different from the normal dogs: they move freely, play with other dogs, breed as well as the normal dogs, and adequately rear their pups or foster pups from the normal line. I In contrast to these normal behaviors, exposure to humans, a sudden blast of a loud noise, and certain other stimuli elicit a dramatic expression of fearrelated behaviors such as excessive timidity, hyperstartle, reduced exploratory activity, marked avoidance of the human observer, catatonic freezing cardiovascular changes, urination, and defecation. I ,2 The normal dogs behave differently under those conditions as evidenced by friendly play with humans. They are active and inquisitive and comply without protest to experimental tasks,I.3 and despite such tasks they continue to approach man in a friendly fashion. 1,3 The phenotypic expression of the nervous behavior in these dogs is not prevented by cross-rearing or by extra home-rearing, which produces only temporary changes compared to kennel rearing. 7 Studies done in our group with these dogs included the evaluation of a hearing deficit and its relation to the abnormal behavior. Evaluation of Deafness and Abnormal Behaviors In the course of our work with these dogs, the existence of a hearing deficit was suspected. Obviously such a deficit could contribute to or largely determine this abnormal behavior. We thus decided to evaluate the hearing status of both nervous B. Lerer et al. (eds.
Carbamazepine has recently been reported to have therapeutic potential in mania. We studied carba... more Carbamazepine has recently been reported to have therapeutic potential in mania. We studied carbamazepine plus haloperidol v placebo plus haloperidol in excited psychoses in a controlled double-blind design. Twenty-three patients completed five weeks of carbamazepine-haloperidol therapy, and 20 patients placebo-haloperidol therapy. Brief Psychiatric Rating Scale ratings showed superior improvement in the group receiving carbamazepine plus haloperidol. This benefit was as apparent in excited schizophrenia as in mania. No unusual toxicity was observed because of the combination of haloperidol with carbamazepine.
Alprazolam treatment is effective for panic disorder, but its major disadvantages include possibl... more Alprazolam treatment is effective for panic disorder, but its major disadvantages include possible dependence and withdrawal symptoms upon discontinuation. The authors report three cases in which carbamazepine, a clinically effective anticonvulsant without abuse potential, successfully attenuated alprazolam withdrawal symptoms.
International Journal of Psychiatry in Medicine, Aug 1, 2011
Background: Traumatic injuries are usually associated with increased secretion of pro-inflammator... more Background: Traumatic injuries are usually associated with increased secretion of pro-inflammatory cytokines, and are sometimes followed by the development of acute stress symptoms (ASS) and posttraumatic stress symptoms (PTSS). Aims: To measure serum pro- and anti-inflammatory cytokines in accident casualties and to associate it with ASS at hospitalization, and with PTSS 1 month later. Methods: Participants were 48 patients, aged 20–60, hospitalized following various orthopedic injuries including bone fractures, and 13 healthy volunteers matched for gender. At hospitalization (Time 1), 30 ml heparinized venous blood were drawn and cytokines levels in serum were assessed; participants filled out the Acute Stress Disorder Inventory (ASDI), COPE, and injury-related questionnaires. One month later (Time 2), 26 participants filled out the Posttraumatic Disorder Symptom Scale (PDS). Results: High serum levels of IL-6, IL-8, and TGF-β and low levels of serum IL-4 and IL-10 were found in injured patients as compared with controls. When controlling for age and severity of injury in the regression analysis, higher levels of IL-6 and IL-8 and lower TGF-β were predicted by higher ASS and higher use of and emotion-focused coping. Higher PTSS scores at Time 2 were predicted by higher levels of IL-8, lower levels of TGF-β, and higher ASS measured at Time 1. Conclusions: High levels of the pro-inflammatory cytokine IL-6 and IL-8 and lower levels of the regulatory cytokine TGF-β should be further assessed as a possible risk factor or a bio-marker of PTSS in accident casualties.
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Papers by Ehud Klein