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Purpose: To test the hypothesis that subtle abnormalities of the autonomic nervous system underlie the chronic symptoms reported by many Gulf War veterans, such as chronic diarrhea, dizziness, fatigue, and sexual dysfunction., Methods: Twenty-two ill Gulf War veterans and 19 age-, sex-, and education-matched control veterans underwent measurement of circadian rhythm of heart rate variability by 24-hour electrocardiography, ambulatory blood pressure recording, Valsalva ratio testing, sympathetic skin response evaluation, sweat imprint testing, and polysomnography. Investigators were blinded to case- or control-group status., Results: High-frequency spectral power of heart rate variability increased normally 2.2-fold during sleep in controls but only 1.2-fold in ill veterans (P <0.0001). In ill veterans as compared with controls, it was lower at night (P = 0.0006), higher during the morning (P = 0.007), but no different during the rest of the day (P = 0.8). The mean heart rate of ill veterans also declined less at night (P = 0.0002), and their corrected QT intervals tended to be longer over the full 24 hours (P = 0.07), particularly at night (P = 0.03). Blunting of the nocturnal heart rate dip in ill veterans was confirmed by 24-hour automatic ambulatory blood pressure monitoring (P = 0.05) and polysomnography (P = 0.03). These differences remained significant after adjusting for potential confounders. Cases and controls were similar on measures of sympathetic adrenergic and sudomotor function, sleep architecture, respiratory function, and circadian variation in blood pressure and body temperature., Conclusion: Some symptoms of Gulf War syndrome may be due to subtle autonomic nervous system dysfunction.

Objective: Alcohol and drug dependence disorders have become common public health hazards. Psychiatrists encounter these problems in a major portion of their patients. However, recent data suggest that their training does not provide them the confidence to treat these disorders. Current methods of evaluating residents fail to adequately ascertain the lack of confidence in substance abuse training. Here, we present the Addiction Training Scale (ATS) that we developed to help trainers identify deficits in residents' substance abuse training., Method: We developed the ATS and conducted a pilot study with the psychiatry residents at the Creighton University Department of Psychiatry, to test the validity of the ATS as a self-report evaluation tool to measure the level of psychiatry residents' preparedness in treating substance abuse disorders., Results: Our results suggest that the ATS is related to the confidence and preparedness that residents express in their ability to treat substance abuse problems., Conclusion: The ATS may be beneficial in assessing psychiatry residents' substance abuse training and identifying deficits, which may be addressed during training.

Nefazodone is a unique serotonergic antidepressant that acts as both a presynaptic serotonin reuptake inhibitor and a postsynaptic 5-hydroxytryptamine 2A receptor antagonist. Based on the positive results of open-label trials of nefazodone, including one from our group, we tested nefazodone's efficacy in the treatment of posttraumatic stress disorder (PTSD) under placebo-controlled conditions. Forty-one patients with chronic PTSD, predominantly male combat veterans, were enrolled in a randomized, double-blind, placebo-controlled 12-week trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale. Fifteen patients were randomized to placebo and 26 were randomized to nefazodone. In a repeated-measures analysis of variance with last observation carried forward, patients on nefazodone showed a significant improvement in the percentage change of Clinician-Administered PTSD Scale Total score from baseline compared with those on placebo (P = 0.04; effect size = 0.6). Sample size was not powered to test group differences in the Clinician-Administered PTSD Scale criterion B, C, or D subscale. However, the criterion D subscale showed significant improvement in patients treated with nefazodone compared with those treated with placebo (P = 0.007). In addition, the Hamilton Rating Scale for Depression showed significant improvement compared with placebo (P = 0.008). The nefazodone group also reported an improvement on the PTSD Checklist (self-report scale; P = 0.08) and the Clinician-Administered Dissociative States Scale (P = 0.06). This pilot study supports the efficacy of nefazodone for the treatment of PTSD. However, larger placebo-controlled studies in more diverse patient population are warranted.

Objective: To report 4 cases of medication nonadherence due to presence of inert ingredients forbidden by the patients' religion., Case Summaries: We describe 4 cases in which religious concerns about prescribed medications' inert components led to discontinuation of these medications. These inert components are gelatin and stearic acid, which might be derived from pork or beef products. In these 4 cases, patients of Muslim, Orthodox Christian, and Seventh Day Adventist faiths, who consider it against their religion to consume pork products, stopped their medications on discovering this possibility. This led to relapse of their illnesses., Discussion: These cases demonstrate that, for some patients, inert medication components that are forbidden by their religion may lead to discontinuation of medications. This could lead to relapse of symptoms and might even lead to hospitalization. Therefore, it is important for prescribers to inform patients of this possibility when treating patients whose religious background might conflict with these inert medication components., Conclusions: Patients with religion prohibitions against consumption of pork and/or beef products might stop their medications when prescribed those with pork- and beef-derived gelatin and/or stearic acid. Prescribers should discuss this possibility with their patients, perhaps as part of informed consent.

Aripirazole is a novel antipsychotic that functions as a partial agonist at the dopamine D2 receptor and, thus, might theoretically worsen psychosis. We report a series of four clinical cases of exacerbation of psychosis related to initiation of aripiprazole therapy. Cases 1 and 2 demonstrated the worsening of psychosis following initiation of aripiprazole (15-30 mg daily) while tapering off the previous atypical antipsychotic. Cases 3 and 4 demonstrated worsening of psychosis following the addition of aripiprazole (15-30 mg daily) to an atypical antipsychotic. In two out of the four cases, discontinuation of arpiprazole resulted in improvement of psychotic symptoms. Although the cases presented are suggestive of a relationship between initiation of aripiprazole therapy and worsening of psychosis, further research is needed to clarify any potential association.

Objective: To report 2 cases of bipolar disorder with recent depression in remission with prominent residual hypersomnia, responding well to the addition of the psychostimulant modafinil., Case Summaries: Two patients with bipolar disorder with recent depressive episodes in remission are presented. Despite the absence of prominent depressive symptoms, both patients had significant hypersomnia, with scores ranging from 15 to 20 (maximum 24) on the Epworth Sleepiness Scale. The addition of modafinil to their medication regimen resulted in a decrease in hypersomnia and improvement in their level of functioning., Discussion: This is the first report (MEDLINE search, October 7, 2003) demonstrating the use of modafinil in the treatment of hypersomnia in bipolar disorder while mood symptoms were in remission. Hypersomnia frequently occurs in depressive episodes and can be disabling when severe. The patients had optimal mood stabilization with mood stabilizers and antidepressants, but continued to experience excessive daytime sleepiness. Conventional stimulants were not considered because of the risk of triggering mania. The addition of the selective psychostimulant modafinil resulted in significant improvement in the hypersomnia, with improvement in functioning. No adverse effects or mood changes were noted., Conclusions: Modafinil may be a well-tolerated and effective alternative to conventional stimulants in the treatment of hypersomnia, especially in bipolar disorder, where there is considerable risk of switch to mania with stimulant medications. Modafinil may be useful even when depressive symptoms are not prominent.

Treatment of alcohol dependence among older alcoholic patients should be multidimensional to address as many potential relapse factors as possible. As the literature suggests, alcohol-related disorders often are under diagnosed and under treated. More efforts are needed to identify and improve diagnosis of these disorders in older alcoholic patients. For better outcomes, age-specific programs should be implemented. Furthermore, when treating elderly patients, basic therapeutic principles like respect for privacy and a respectful attitude should be adopted. Adequate medical, pharmacologic, and psychiatric treatment should be provided when appropriate. Medication to reduce cravings should be considered in patients without contraindications to its use. Participation in individual, group, and family therapy and attendance at self-help group meetings such as AA should be encouraged (Table 8). Despite the lack of empiric testing to validate these recommendations in an elderly population, clinical experience suggests that adherence to these recommendations will benefit elderly patients just as it has the general adult population. Research is necessary to explore the benefits of alcohol treatments in elderly patients. Until then, adherence to these recommendations should be the best available approach.

Objective: To report a case of somnambulism due to a probable interaction between valproic acid and zolpidem in a patient with no prior personal or family history of somnambulism., Case Summary: A 47-year-old white man with a history of bipolar disorder was being maintained on citalopram 40 mg once daily and zolpidem 5 mg at bedtime. During treatment, he developed manic symptoms and was started on adjunctive valproic acid therapy. Soon after this, he developed episodes of somnambulism, which stopped when valproic acid was discontinued. On rechallenge with valproic acid, somnambulism returned., Discussion: To our knowledge, this is the first report in the literature describing a probable interaction between valproic acid and zolpidem leading to somnambulism. Even though valproic acid has been associated with sleep changes, there are no published reports of somnambulism with this agent. Zolpidem has been associated with somnambulism, but our patient did not experience this when he was on zolpidem monotherapy. However, within 2 days of starting adjunctive valproic acid, sleepwalking occurred. It stopped after valproic acid was withdrawn. On rechallenge with valproic acid, sleepwalking recurred. However, when zolpidem was discontinued and valproic acid was continued, somnambulism did not occur. An assessment on the Naranjo probability scale suggests probable pharmacokinetic or pharmacodynamic interactions between the 2 medications., Conclusions: Valproic acid and zolpidem are generally safe medications that are commonly prescribed and often used together. No interactions have been previously reported with combined use of valproic acid and zolpidem. This case suggests a probable interaction between these 2 agents that can have a serious consequence, somnambulism. This could be frightening to patients and put them in danger. Recognition of such interactions that place patients at risk for potentially serious adverse events is imperative for appropriate care.

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

Objective: To report a case of improvement in posttraumatic stress disorder (PTSD) after adjunctive therapy with quetiapine., Case Summary: A 49-year-old white man witnessed a traumatic event and experienced severe PTSD. He was started on paroxetine, with increases in dosage and no significant improvement. Quetiapine was added to his regimen, with increased doses resulting in improvement of PTSD symptoms, both clinically and as measured on the Hamilton-D rating scale for depression and the clinician-administered PTSD screen., Discussion: This is the first case published in the English language literature describing improvement in PTSD symptoms after treatment with quetiapine. There are several treatment options for PTSD, but some severe cases may require treatment with antipsychotic medications. Because of the lower risks of serious adverse effects, the newer atypical antipsychotics are much safer than the older antipsychotics. Although use of risperidone and olanzapine in the successful treatment of PTSD has been reported in the literature, there are no reports of quetiapine use in this clinical condition., Conclusions: Quetiapine appeared to improve clinical signs and symptoms of PTSD in this patient. It may be a treatment option in other severe cases of PTSD.

(1) Disturbances of mesolimbic and mesocortical dopamine (DA) function have been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder. (2) Utilizing the learned helplessness (LH) animal model of clinical depression and quantitative autoradiography, the authors studied the densities of D1 and dopamine-2-like receptors (D2-like receptors) in medial prefrontal cortex, septum, nucleus accumbens and caudate nucleus in rats that received inescapable stress and were subsequently tested for LH behavior. (3) Dopamine-1 receptor (D1 receptor) densities were significantly higher in the core and shell of the nucleus accumbens and in the medial caudate nucleus of rats that did not become helpless after stress, compared to rats that developed LH. (4) Densities of D2-like receptors were significantly lower in the core of the nucleus accumbens in both the LH and the nonhelpless (NH) rats compared to controls. Densities of D2-like receptors were also lower in the medial and lateral caudate nuclei in LH rats compared to the other groups. (5) Increased D1 receptor densities in NH rats in the nucleus accumbens may be associated with an adaptive or protective role of this brain region in the prevention of escape deficits after exposure to inescapable stress. (6) Decreased D2-like receptor densities in the caudate nucleus in helpless rats may reflect a motor deficit associated with LH behavior, while decreases of D2-like receptor densities in the core of the nucleus accumbens may reflect a generalized effect of exposure to inescapable stress. (7) This study highlights the importance of the mesolimbic/nigrostriatal dopaminergic systems in mediating behavioral responses to inescapable stress.

Background: We investigated the structure of manic episodes by determining whether there was evidence for distinct groups of patients differing in clinical characteristics and course of illness., Methods: The subjects were 162 patients hospitalized for manic episodes who underwent comprehensive evaluations of behavior, symptoms, and history before a treatment study. Pretreatment behavior ratings (Schedule for Affective Disorders and Schizophrenia, rated by clinicians, and Affective Disorder Rating Scale, rated by nurses) entered a principal components factor analysis, followed by a cluster analysis of the subjects based on their factor scores. Members of the resulting clusters were compared with respect to clinical characteristics and history of illness., Results: The six factors were impulsivity, hyperactivity, anxious pessimism, distressed appearance, hostility, and psychosis. The four clusters were characterized as depressive, with high anxious pessimism (n=22), delusional, with high psychosis (n=39), classic (n=72), and irritable, with high distressed appearance and hostility (n=29). Depressive manics had the earliest onset of illness and the highest density of episodes/year, while irritable manics had later onset and the fewest previous episodes., Limitations: The number of subjects was smaller than ideal for multivariate analysis, subjects were limited to those able to consent and meet criteria for a randomized clinical trial, and course of illness was determined retrospectively., Conclusions: Manic episodes have a dimensional structure but appear to fall naturalistically into types that differ with respect to previous history, symptoms, and clinical characteristics. Whether these are distinct clinical subtypes will require further research.

Behavioral sensitization to psychostimulants involves neuroadaptation of stress-responsive systems. We have identified and sequenced a glucocorticoid-induced receptor (GIR) cDNA from rat prefrontal cortex. The full-length GIR cDNA encodes a 422 amino acid protein belonging to G-protein-coupled receptor superfamily. Although the ligand for GIR is still unknown, the dendrogram construction indicates that GIR may belong to peptide receptor subfamily (e.g., substance P receptor), with more distant relationship to subfamilies of glycoprotein hormone receptors (e.g., thyrotropin receptor) and biogenic amine receptors (e.g., dopamine receptor). GIR shares 31-34% amino acid identity to the tachykinin receptors (substance P receptor, neurokinin A receptor, and neurokinin B receptor). GIR mRNA is expressed preferentially in brain, and its neuronal expression is relegated to limbic brain regions, particularly in forebrain. GIR transcript levels are increased significantly and persistently in prefrontal cortex for 7 d after discontinuation of chronic amphetamine exposure. The induction of GIR expression by amphetamine is associated with augmented behavioral activation. These findings suggest that modulation of GIR expression may be involved in behavioral sensitization, and GIR may play a role at the interface between stress and neuroadaptation to psychostimulants.

Significant advances have been made in the past 5 years in defining efficacious treatments for post-traumatic stress disorder (PTSD). Currently, sertraline is the first and only FDA-approved medication for this complex and often chronic illness. Other serotonergic antidepressants, such as paroxetine, fluoxetine and nefazodone, have well-controlled or replicated open-label evidence of efficacy. Anticonvulsants are also being studied as potential alternatives to treatment. Finally, atypical antipsychotic medications have shown promise in open-label trials. Clearly, more controlled studies are needed. This is especially true in males and in combat trauma-induced PTSD, where the effects of pharmacotherapy are less robust than in females or civilian trauma-induced PTSD. Also, there are virtually no data on pharmacotherapy for acute stress reaction or for PTSD in children. Future directions for research may focus on combination treatment in the more treatment-resistant patient populations.

Background: Many complaints of Gulf War veterans are compatible with a neurologic illness involving the basal ganglia., Methods: In 12 veterans with Haley Gulf War syndrome 2 and in 15 healthy control veterans of similar age, sex, and educational level, we assessed functioning neuronal mass in both basal ganglia by measuring the ratio of N-acetyl-aspartate to creatine with proton magnetic resonance spectroscopy. Central dopamine activity was assessed by measuring the ratio of plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenlyglycol (MHPG)., Results: The logarithm of the age-standardized HVA/MHPG ratio was inversely associated with functioning neuronal mass in the left basal ganglia (R(2) = 0.56; F(1,27) = 33.82; P<.001) but not with that in the right (R(2) = 0. 04; F(1,26) = 1.09; P =.30). Controlling for age, renal clearances of creatinine and weak organic anions, handedness, and smoking did not substantially alter the associations., Conclusions: The reduction in functioning neuronal mass in the left basal ganglia of these veterans with Gulf War syndrome seems to have altered central dopamine production in a lateralized pattern. This finding supports the theory that Gulf War syndrome is a neurologic illness, in part related to injury to dopaminergic neurons in the basal ganglia.

Learned helplessness is a behavioral deficit that can be induced by exposure to inescapable stress. Previous studies have implicated the lateral septum in mediating this phenomenon, and in this brain region, serotonin plays an important role in the development, maintenance, prevention, and reversal of learned helplessness behavior. Using the technique of in vivo microdialysis, we measured the efflux of serotonin (5-HT), dopamine (DA), and their respective metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 3, 4-dihydroxyphenylacetic acid (DOPAC), from the lateral septum of rats that either developed or did not develop learned helplessness. During the microdialysis session all rats were subjected to restraint stress. Control groups included naïve, home cage rats as well as tested control rats that were subjected to the identical handling, restraint, and shuttlebox testing as the rats that received inescapable shock. Overall, levels of 5-HIAA were significantly higher in non-helpless rats. There were no significant effects of restraint or differences in levels of 5-HT, DA, or DOPAC. We propose that this increase in 5-HIAA is indicative of an overall increase in serotonin metabolism in the lateral septum of rats that do not become helpless after inescapable stress. This increased serotonin metabolism in the lateral septum may protect the animal from adverse behavioral consequences of inescapable stress. J. Neurosci. Res. 61:101-106, 2000. Published 2000 Wiley-Liss, Inc.

Purpose: To test for neuronal brain damage in the basal ganglia and brainstem in Gulf War veterans by using magnetic resonance (MR) spectroscopy., Materials and Methods: Twenty-two Gulf War veterans with one of three factor analysis-derived syndromes (case patients); 18 well veterans matched for age, sex, and education level (control subjects); and six Gulf War veterans with syndrome 2 from a different population (replication sample) underwent long echo time (272 msec) proton (hydrogen 1) MR spectroscopy on a 4 x 2 x 2-cm voxel in the basal ganglia bilaterally and a 2 x 2 x 2-cm voxel in the pons. Syndromes 1-3 are described as "impaired cognition," "confusion-ataxia," and "central pain," respectively., Results: The N-acetylaspartate-to-creatine (NAA/Cr) ratio, which reflects functional neuronal mass, was significantly lower in the basal ganglia and brainstem of Gulf War veterans with the three syndromes than in those structures of the control subjects (P =.007). The finding was corroborated in the replication sample (P =.002). Veterans with syndrome 2 (the most severe clinically) had evidence of decreased NAA/Cr in both the basal ganglia and the brainstem; those with syndrome 1, in the basal ganglia only; and those with syndrome 3, in the brainstem only., Conclusion: Veterans with different Gulf War syndromes have biochemical evidence of neuronal damage in different distributions in the basal ganglia and brainstem.

Pyridostigmine bromide (PB), a reversible inhibitor of acetylcholinesterase (AChE), is used for the treatment of myasthenia gravis. PB has also been provided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but recently published data in mice suggest that a brief forced swim stress increases the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-lasting central cholinergic deficits, potentially explaining the neurological and neuropsychological symptoms presented by some Gulf War veterans. In undertaking to replicate these results in the Long-Evans rat, no evidence of a stress-potentiated central effect of PB, administered at doses up 5.0 mg/kg ip, was found. Three stress protocols were used: restraint, forced swim, or a combined restraint/forced swim. Wistar rats were also tested in some of the protocols to ensure that the results were generalizable across rat strains, and plasma corticosterone levels were measured to test the effectiveness of the stressors employed. In contrast to the previously reported findings in the mouse, stress significantly reduced the entry of PB into rat brain, as measured by reduced inhibition of AChE activity: a 12.5% reduction in whole brain AChE activity after treatment with 5.0 mg/kg PB under control conditions declined to 9% after stress exposure. It is apparent, therefore, that the interaction between stress and PB requires further study, and previous data should be reassessed before they are used as a basis for interpreting symptoms presented by veterans., (Copyright 2000 Academic Press.)

Background: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy., Methods: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores., Results: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores., Conclusions: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

Currently, there is no standard treatment for posttraumatic stress disorder (PTSD) because of a deficit of systematic treatment trials. The symptom overlap with other mood and anxiety disorders that respond to antidepressants and the results of a limited number of antidepressant trials indicate promise for psychopharmacologic treatment. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in the symptomatology of PTSD. In this study, a relatively new serotonergic antidepressant, nefazodone, was tested as a treatment for PTSD. Veterans with chronic PTSD (N = 36) were enrolled in an 8-week open-label trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Thirty-one patients completed at least 4 weeks of treatment, which was considered to be an adequate trial, and 26 patients completed the 8-week study. During treatment, there was a significant decrease in the total CAPS score and in each of three CAPS subscale scores, with most of the improvement occurring during the first 4 weeks. Comparable improvements were also seen on the Hamilton Rating Scales for Anxiety and for Depression. Nefazodone treatment was well tolerated by this patient population, with only four patients discontinuing because of adverse effects. In summary, nefazodone treatment improved the symptoms of PTSD, including the core symptoms. Placebo-controlled studies should be undertaken to further elucidate the efficacy of nefazodone in the treatment of PTSD.

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Much of the literature on the psychiatric consequences of stress has focused on wartime combat trauma. However, traumatic events also frequently occur in civilian life. Controlled studies on the psychiatric effects of noncombat trauma were reviewed and a meta-analysis of these data was conducted. Generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), substance abuse, phobia, and major depressive disorder (MDD) were significantly elevated compared with a pooled control group, whereas panic disorder and dysthymic disorder were not significantly increased. These data suggest that the psychiatric effects of civilian trauma include both anxiety and depressive disorders. The results are strikingly similar to those reported in combat veterans, suggesting that severe trauma, even in very different populations, may be associated with similar psychopathology.

Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic antidepressants downregulate beta AR function. Previous studies on beta AR function in PD, however, are inconsistent. We recently found increased beta AR coupling and density in neutrophils of symptomatic drug-free PD patients. This study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD patients and 8 PD imipramine-treated patients. PD patients had significantly higher coupling and receptor density, particularly in the high-conformational state. Differences were more pronounced in patients with less depressive symptomatology. Treatment with imipramine was associated with decreased beta AR coupling and density in the high-conformational state. Several beta AR binding parameters were related to severity of anxiety symptoms and treatment outcome. Antidepressants downregulate beta AR density and induce uncoupling from Gs protein in PD. Future studies may investigate beta AR coupling in relationship to treatment outcome and the role of beta AR kinase in PD.

Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.

Background: For the last several years, the Department of Veterans Affairs (VA) has been involved in the development of practice guidelines for major medical, surgical, and mental disorders. This article describes the development and content of the VA-Clinical Practice Guidelines for Bipolar Disorder, which are available in their entirety on the Journal Web site (http://www. psychiatrist.com)., Method: A multidisciplinary work group composed of content experts in the field of bipolar disorder and practitioners in general clinical practice was convened by the VA's Office of Performance and Quality and the Mental Health Strategic Health Group. The work group was instructed in algorithm development and methods of evidence evaluation. Draft guidelines were developed over the course of 6 months of meetings and conference calls, and that draft was then sent to nationally prominent content experts for final critique., Results: The Bipolar Guidelines are part of the family of the VA Clinical Guidelines for Management of Persons with Psychosis and consist of explicit algorithms supplemented by annotations that explain the specific decision points and their basis in the scientific literature. The guidelines are organized into 5 modules: a Core Module for diagnosis and assignment to mood state plus 4 treatment modules (Manic/Hypomanic/Mixed Episode, Bipolar Depressive Episode, Rapid Cycling, and Bipolar Disorder With Psychotic Features). The modules specify particular diagnostic and treatment tasks at each step, including both somatotherapeutic and psychotherapeutic interventions., Conclusion: The VA Bipolar Guidelines are designed for easy clinical reference in decision making with individual patients, as well as for use as a scholarly reference tool. They also have utility in training activities and quality improvement programs.

Some recent autopsy studies indicate that gamma-aminobutyric acid (GABA) function is decreased in brain areas that involve some of the well-described structural changes observed in schizophrenia. The current study examined the relationship between CSF and plasma GABA levels and brain structural measures in schizophrenia. Sixty-two drug-free, physically healthy male patients with schizophrenia (DSM-IIIR) were evaluated for plasma and CSF GABA, as well as brain structural measures on CT scans. Plasma levels of GABA were associated with prefrontal sulcal widening and VBRs, but not global sulcal widening in the schizophrenic patients. CSF GABA measures were not associated with brain structural measures, but were associated with age and age of onset. The significant relationship between plasma GABA, but not CSF GABA, and specific brain morphology measures in schizophrenic patients suggests that if GABA transmission is impaired in schizophrenia, it is a local, but not global, phenomenon.

The overlap in clinical phenomenology and morbidity between post-traumatic stress disorder (PTSD) and such conditions as major depression, anxiety disorders and aggression, in which a serotonin dysfunction is implicated, suggests a role for serotonin in the pathophysiology of PTSD. In this paper, we review current knowledge concerning the role of serotonergic mechanisms and interventions in PTSD. Since there is no clearly effective pharmacologic intervention for this disorder, the underlying neurochemical dysfunction needs to be carefully defined so that more effective treatment can be developed. Preclinical and clinical studies of the serotonergic mechanisms in the pathophysiology of PTSD and treatment trials involving serotonergic agents are limited, but indicate considerable promise. Further investigation of a serotonergic dysfunction in PTSD and of its treatment with serotonergic agents is warranted.

In vivo microdialysis was used to determine the effect of diazepam, flumazenil and FG-7142 upon the biogenic amine response to acute and repeated swim stress in the medial prefrontal cortex of the rat. Acute swim stress increased norepinephrine levels, although dopamine and serotonin levels remained stable. Upon re-exposure to swim stress twenty-four hours later, sustained increases (200-300% of baseline) in all three biogenic amines were detected. This enhanced response to re-stress was not seen in rats pretreated with either a benzodiazepine: agonist (diazepam, 2 mg/kg), an antagonist (flumazenil, 10 mg/kg), or an inverse agonist (FG-7142, 10 mg/kg) given prior to the first swim stress. Therefore, the sensitization of biogenic amine response to re-stress may be prevented by compounds which differ in their activity at the benzodiazepine receptor.

Background: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes., Methods and Design: In a parallel-group, double-blind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in patients with and without depressive symptoms at baseline according to nurse- or physician-rated scales., Results: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history., Conclusions: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients.

Maintenance studies in bipolar disorder have received increased attention in recent years. The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies, as well as interest in a new group of drugs with mood-stabilizing properties. The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder. We present the methodology of a recently completed randomized, double-blind, placebo-controlled, parallel-group comparison of divalproex and lithium. We examine the consequences of salient design features, along with their implications for future studies. A fundamental conclusion is that such maintenance studies should be designed and executed to emphasize enrollment of patients with relatively active, severe forms of the illness. This goal is not achieved simply, as inherent features of long-term, placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder. Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies designed to achieve adequate statistical power.

Plasma GABA concentrations (pGABA) were measured in 115 inpatients (aged 7-17) with child psychiatric disorders. Group mean pGABAs were compared for 38 patients with mood disorders only (MOOD), 29 with behavior disorders only (BEH), 48 with comorbid mood and behavior disorders (MOOD + BEH), and 14 normal controls (CON, aged 14-17). The BEH group was characterized by (a) high mean pGABAs (157 vs. 133 pmol/ml), (b) lower mean pGABAs in BEH subjects who had been receiving pharmacotherapy with SSRIs or other medications (p < 0.026), and (c) decreased pGABA with increasing age (p = 0.019). These features were not found in controls or in groups of patients with mood disorders (MOOD or MOOD + BEH). Elevated mean pGABA in the BEH group appeared specifically in patients with comorbid CD and ADHD, not in patients with ADHD or CD alone (p = 0.004). No patient in BEH (or CON) had pGABA below 100 pmol/ml, but low pGABAs were found in 15% of MOOD patients (who had no behavior disorder) and in 16% of MOOD + BEH patients. Pharmacotherapy did not change pGABAs in the MOOD or the MOOD + BEH groups. No pGABA differences were found among the anxiety disorders, either alone or with mood or behavior comorbidity. The finding that plasma GABA levels are elevated in nonmedicated behavior disorders that present in the absence of mood disorders, and appear to lower following medication treatments, merits increased attention to the pharmacological study of nonaffective behavior disorders.

Twenty-eight male patients with severe alcohol dependence (mean pretreatment consumption of 18.6 standard drinks per day) completed a placebo-controlled, double-blind clinical trial of fluoxetine (60 mg/day). They were assigned to medication group in the second of 4 weeks on a voluntary inpatient chemical dependency ward and continued medication during a 12-week follow-up phase. Fluoxetine did not reduce clinically significant relapse rates; only 8 of 15 (53%) of fluoxetine subjects remained sober at 12 weeks, compared with 9 of 13 (69%) of the placebo group (Fisher's exact test, p = 0.46). Subjects with comorbid cocaine dependence relapsed more than twice as often (3 of 4, 75%) as those with alcohol dependence alone (8 of 24, 33%), although this trend did not reach statistical significance because of the small number of dually dependent subjects (Mann Whitney U test = 68, p = 0.13). Supportive living arrangements after hospital discharge did reduce relapse rates: 8 of 9 subjects (89%) discharged to a Veterans Affairs domiciliary were sober at 12 weeks, compared with 9 of 19 (47%) subjects discharged back to the community (Mann-Whitney U test = 125, p = 0.02). Fluoxetine-treated subjects who remained sober at 12 weeks reported a significant decrease in mean subjective alcohol craving scores from 2.9 to 0.7 on a 10-point scale (t = 2.828, p = 0.02). In summary, fluoxetine did not reduce clinical relapse rates in this sample of male severe alcoholics without other axis I disorders who completed 4 weeks of inpatient alcoholism treatment.

Objective: Plasma gamma-aminobutyric acid (GABA) levels have been reported to be low in some patients with major depressive disorder. Premenstrual dysphoric disorder is often associated with major depressive disorder. Therefore, the authors sought to determine whether women with premenstrual dysphoric disorder with or without prior major depressive disorder also had low plasma GABA levels., Method: Plasma GABA levels were measured in 27 women with premenstrual dysphoric disorder and 21 comparison women during the the mid-follicular and late luteal phases of the menstrual cycle., Results: In comparison women, plasma GABA levels increased from the mid-follicular to the late luteal phase. Women with premenstrual dysphoric disorder and a past history of major depressive disorder had low plasma GABA levels during both phases. In women with premenstrual dysphoric disorder but no past major depressive disorder, plasma GABA levels decreased from the nonsymptomatic, mid-follicular phase to the symptomatic, late luteal phase., Conclusions: Decreased GABA function may represent a common biological link between subtypes of depressive and premenstrual dysphoric disorders. A trait in major depressive disorder and a state-dependent decrease in premenstrual dysphoric disorder might imply a possible continuum between the two disorders.

A subgroup of abstinent alcoholics, display low levels of plasma gamma-aminobutyric acid (GABA). Two previous studies of plasma GABA in sons of alcoholic fathers (SOAs) have yielded conflicting results. The aim of the current study was to measure plasma GABA both at baseline and after challenge with diazepam, a GABAA receptor agonist, in a group of SOAs already shown to display decreased eye movement, memory, and sedative effects of diazepam. Twenty-seven SOAs and 23 male control subjects received four logarithmically increasing doses of diazepam or placebo in randomized order on 2 days at least 1 week apart. Plasma GABA was measured at baseline and after the last dose. There were no significant differences between SOAs and controls in baseline plasma GABA levels. In the whole sample, there were significant correlations between baseline plasma GABA and both high novelty-seeking and low-harm avoidance scores on the Tridimensional Personality Questionnaire. Both SOAs and controls displayed decreases in plasma GABA over time on both testing days, but there was no effect of diazepam on plasma GABA and no significant difference between groups in plasma GABA response to diazepam. These results suggest that neither low plasma GABA at baseline nor altered plasma GABA response to diazepam is associated with increased genetic risk for alcoholism.

Both stress response and antidepressant drug action may be mediated by beta-adrenergic receptors (beta AR). Since learned helplessness is a stress-induced animal model of depression, beta AR are relevant to investigate in this model. To date, studies have measured changes in total receptor density (RT), but have not examined more detailed aspects of signal transduction mechanisms such as coupling of the receptor to GS protein. We have investigated brain beta AR coupling in the frontal cortex, hippocampus and hypothalamus of rats exposed to inescapable shock and then tested for learned helplessness, and in both tested and naive controls using [125I]-iodocyanopindolol (ICYP) as the ligand. Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the beta AR was optimized by excluding ICYP binding to 5HT1B receptors. The percentage receptor density in the high-conformational state (%RH) and the ratio of agonist (isoproterenol) dissociation constant from the receptor in the low-/high-conformational states (KL/KH) were used as indices of coupling to GS protein. No significant differences were found between rats developing learned helplessness and non-helpless rats after inescapable stress in any parameter measured in any brain region. In the frontal cortex, exposure to inescapable shock induced beta AR uncoupling from GS protein as suggested by a low KL/KH ratio both in helpless and non-helpless rats but not in either control group. In the hypothalamus, there were trends for higher RL, RT and KL/KH ratio in helpless rats and stressed controls compared to naive controls. These findings suggest that beta AR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in beta AR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rather than stress-induced behavioral depression.

Growth hormone (GH) response and baclofen levels were measured in seven healthy adult men following a 10-mg and a 20-mg dose of oral baclofen (gamma-aminobutyric acidB agonist) to determine the preferred dose in baclofen challenge studies. Multivariate analysis of variance (ANOVA) with repeated measures revealed no differences between the doses. However, when a univariate ANOVA with repeated measures was performed for each dose, the 10-mg dose showed no significant GH response over time, whereas the 20-mg dose showed a significant GH response over time. The average delta GH (change in GH from baseline) was 7.84 ng/ml (SD = 10.17) for the 10-mg dose and 3.34 ng/ml (SD = 3.64) for the 20-mg dose. The variability in the delta GH response to the 10-mg dose was significantly greater than the response to the 20-mg dose of baclofen. This variance in GH response was not explained by the differences in serum baclofen levels. Thus, a 20-mg baclofen dose appears to be preferable to a 10 mg-dose in baclofen challenge studies.

Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium, or placebo in a previously reported parallel group multicenter, double-blind, randomized, controlled acute phase treatment trial. Plasma concentrations of gamma aminobutyric acid (GABA) were measured before and after treatment. Higher pretreatment plasma GABA levels were significantly (p = .04) related to a better clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not correlate with response to either lithium (n = 13) or placebo (n = 31). Following treatment with divalproex sodium, plasma GABA levels decreased significantly (p < .05), compared to placebo. Pretreatment plasma GABA levels were not related to overall severity of manic symptoms. Plasma GABA may predict response to pharmacologic agents acting on the GABA system.

The spectrum of efficacy of the serotonin selective reuptake inhibitor (SSRI) antidepressant drugs continues to expand. In fact, no psychiatric syndrome seems to worsen with these agents, and few studies fail to demonstrate clinical improvement in some patients, regardless of any nosologic nicety, such as precise DSM diagnosis. This suggests that the biological rubric of psychopathology is dimensional rather than categorical. New research using in vivo microdialysis shows differences in neurochemistry among SSRIs, wherein fluoxetine blocks reuptake of dopamine and norepinephrine, as well as serotonin, in medial prefrontal cortex, and fluvoxamine has a relatively more selective neurochemical profile. In the animal model of learned helplessness, which is a biobehavioral model for stress-induced anxiety causing depression, the SSRIs including fluvoxamine prevent helplessness. From these and other data, a neurotransmitter balance theory of biopsychopathology is formulated. In this hypothetical construct, dopamine, norepinephrine, and GABA modulate thought, anxiety, and mood, respectively. Serotonin is a stabilizing agent, which assists in returning the mind to its homeostatic setpoint.

Thirty-three outpatients who met DSM-IV criteria for major depressive disorder (MDD) with no history of manic or hypomanic symptomatology were enrolled in an 8-week open trial of valproate. By Week 4, 15 of the 28 completers (54%) demonstrated a significant clinical response as defined by a score reduction of 50 percent or more or a total score of 9 or lower on the Hamilton Rating Scale for Depression (HRSD). Mean HRSD scores of the completers decreased 48.8 percent at Week 4 (p < .0001). At Week 8, 19 of the 22 completers (86%) showed a significant response. Mean HRSD scores decreased from 22 +/- 5 at baseline to 7 +/- 4 at Week 8 (p < .0001). With the intent-to-treat analysis at Week 8, 66 percent were responders, and total group mean HRSD scores decreased 55 percent (p < .0001). The data suggest that valproate may be an effective treatment for MDD. Double-blind, placebo-controlled trials are needed to further document its efficacy in the treatment of MDD.

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.

Objective: To explore dopaminergic mechanisms in alcohol dependence, the authors measured plasma homovanillic acid (HVA) in recently detoxified alcohol-dependent men., Method: Plasma HVA was measured in 83 male patients with a diagnosis of alcohol dependence who had maintained documented abstinence for at least 3 weeks and in 69 healthy male comparison subjects., Results: The alcoholic patients as a group had significantly lower levels of plasma HVA than the comparison subjects. This difference was not influenced by any other measured covariate, including a family history of alcohol dependence., Conclusions: These results imply that factors such as alcohol dependence should be taken into account in future studies of plasma HVA.

Aminobutyric acid (GABA) is implicated in the biochemical pathophysiology of alcohol intoxication, dependence and withdrawal. We therefore measured GABA in both cerebrospinal fluid (CSF) and plasma from 14 male alcohol-dependent patients during acute alcohol withdrawal (day 1) and again after 21 days of inpatient treatment (day 21). Plasma GABA levels on admission correlated with indices of liver function. When corrected for differences in liver function, plasma levels of GABA levels on day 1 were significantly higher than on day 21. CSF GABA concentrations were also significantly higher during withdrawal compared with concentrations after 3 weeks of abstinence. The change in plasma GABA levels correlated significantly with the change in CSF GABA levels, although there was no correlation between plasma and CSF levels at either time. These findings demonstrate that changes in CSF GABA may be reflected in plasma GABA, and they highlight the potential importance of the GABA system in alcohol dependence and withdrawal.

Behavioral deficits following inescapable stress (learned helplessness) may serve as an animal model of depression. Previous studies using foot-shock stress to induce learned helplessness and a bar-press test for the stress-induced behavioral deficit have found increased beta-adrenergic receptor density in the hippocampus of learned helpless rats. We replicated these experiments using a tail-shock stress and the shuttle-box test. In our experiments, rats that developed learned helplessness after inescapable stress did not demonstrate any significant differences in beta-adrenergic receptor density or affinity in the frontal cortex, cerebellum, or hippocampus compared to the nonhelpless rats, nor to the tested control rats. These results suggest that beta-adrenergic receptor changes in learned helplessness may depend on the specific stress and test procedures used.