Frederick Petty

GABA and mood disorders: a brief review and hypothesis

Considerable evidence implicates the neurotransmitter gamma-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. Animal models of depression show regional brain GABA deficits and GABA agonists have antidepressant activity in these models. Somatic treatments for depression and mania upregulate the GABAB receptor, similar to the effect of GABA agonists. Clinical data indicate that decreased GABA function accompanies depressed or manic mood states. GABA agonists are effective antidepressant and antimanic agents. Low GABA levels are found in brain, cerebrospinal fluid and plasma of patients with depression and in plasma of patients with mania. Plasma GABA levels, which reflect brain GABA, are not normalized with treatment and clinical remission in depression, suggesting low GABA is not a marker for mood state. Some somatic treatments, including valproic acid and electroconvulsive shock, reduced plasma GABA and response to these correlates with higher levels of baseline plasma GABA. From these data, a GABA hypothesis for mood disorders is formulated. Low GABA function is proposed to be an inherited biological marker of vulnerability for development of mood disorders. Environmental factors, including stress and excessive alcohol use, may increase GABA, causing symptoms of depression or mania. Treatment, or the passage of time, then returns GABA to its presymptomatic baseline as the symptoms remit. This hypothesis, applicable to a subset of mood disordered persons, is testable.

Maintenance efficacy of divalproex in the prevention of bipolar depression

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.

Sexual assault in women veterans: An examination of PTSD risk, health care utilization, and cost of care

Objective: This study examines the differential impact of military, civilian adult, and childhood sexual assault on the likelihood of developing posttraumatic stress disorder (PTSD). It also examines the relationship of military sexual assault (MSA) to service utilization and health care costs among women who access services through Veterans Affairs (VA). Methods: A convenience sample of 270 veteran women receiving medical and/or mental health treatment at the VA North Texas Healthcare System participated in the study. Participants were interviewed using the Clinician Administered PTSD Scale (CAPS) and categorized into a sexual assault group using the Interview of Sexual Experiences (ISE). A chart review was also conducted to determine the frequency of diagnoses among the women. Data regarding health care utilization was obtained from self-report using the Utilization and Cost Patient Questionnaire (UAC-PQ) and VA administrative records. Results: Compared with those without a history of sexual assault, women veterans were 9 times more likely to have PTSD if they had a history of MSA, 7 times more likely if they had childhood sexual assault (CSA) histories, and 5 times more likely if they had civilian sexual assault histories. An investigation of medical charts revealed that PTSD is diagnosed more often for women with a history of MSA than CSA. CSA was associated with a significant increase in health care utilization and cost for services, but there was no related increase in use or cost associated with MSA. Conclusion: Women veterans have differential rates of PTSD due to sexual assault, with higher rates found among those assaulted while on active duty. Although women with MSA are more likely to have PTSD, results suggest that they are receiving fewer health care services. PTSD = posttraumatic stress disorder; MSA = military sexual assault; CSA = civilian sexual assault; ChSA = childhood sexual assault; VA = Veterans Affairs; UAC-PQ = Utilization and Cost Patient Questionnaire; ISE = Interview of Sexual Experiences; CAPS = Clinician Administered PTSD Scale; NSA = no sexual assault; SD = standard deviation; ER = emergency room; SE = standard error.

Prevention of learned helplessness: In vivo correlation with cortical serotonin

Learned helplessness (LH) is prevented by pretreatment with acute benzodiazepines (BDZs), subchronic tricyclic antidepressants (TCAs), or escapable stress (ES). We have investigated the role of serotonin (5-HT) in LH prevention by these three prevention paradigms, using microdialysis to measure in vivo 5-HT release in frontal cortex (FC) after LH testing. Rats receiving pretreatment before inescapable stress with any of the three methods of prevention--BDZs, TCAs, or ES--showed escape behavior in the shuttle-box test for LH comparable to naive unstressed controls. K(+)-stimulated 5-HT release in all three groups receiving pretreatment was also similar to naive unstressed controls. Rats receiving saline before inescapable stress showed significantly more LH behavior in the shuttle-box task and had significantly lower 5-HT release as well. This suggests that LH correlates with a significant decrease in intracellular releasable 5-HT in FC, and that three different techniques for LH prevention, acute BDZs, subchronic TCAs, and ES all similarly prevent this 5-HT depletion.

Nicotinic receptor desensitization and sensory gating deficits in schizophrenia

BACKGROUND Nicotinic receptor dysfunction is a possible mechanism of the abnormal sensory gating observed in schizophrenia with the P50 auditory event-related potential. Although nicotinic receptors normally desensitize after activation by acetylcholine or nicotine, pathologically increased desensitization might cause receptor dysfunction in schizophrenia. To examine this possibility, central cholinergic neuronal activity was diminished by allowing schizophrenic patients to sleep briefly, after which they experienced a transient period of normal P50 gating, consistent with receptor resensitization during the absence of cholinergic stimulation. A critical test of the mechanism is whether this resensitization is blocked by concurrent administration of nicotine, which would provide continuous receptor stimulation. METHODS Six schizophrenic patients repeated the sleep experiment during nicotine exposure from a dermal patch, in a double-blind, placebo-controlled design. RESULTS The normalization of P50 gating immediately postsleep was replicated in the placebo arm, but this effect was decreased in all six patients during exposure to nicotine. CONCLUSIONS The results suggest that nicotinic receptor desensitization is responsible for the loss of P50 gating in schizophrenia.

Benzodiazepines as antidepressants: does GABA play a role in depression?

Benzodiazepines, the most widely prescribed psychotropic drugs, are often used in patients with depressive disorders, either alone or in combination with standard antidepressants. This review evaluates the efficacy of benzodiazepines (alprazolam, diazepam, chlordiazepoxide) as established in acute-phase, randomized controlled trials (RCTs) in major depressive disorder. Metaanalyses using intent-to-treat, as well as adequate treatment exposure samples, revealed an overall efficacy of 47-63% and a drug-placebo difference of 0-27% for all benzodiazepines. Alprazolam, the best studied of the benzodiazepines, had a 27.1% (sd = 6.1%) greater response than placebo, which is comparable to standard antidepressants. Alprazolam, in particular, may be a useful treatment option for patients in whom standard antidepressant medications are contraindicated, poorly tolerated, or possibly ineffective. Alprazolam may have a more rapid onset of action for some patients. Benzodiazepines do not primarily affect biogenic amine uptake or metabolism, although they do augment gamma-amino butyric acid (GABA) activity. The antidepressant efficacy of benzodiazepines, which are GABAA receptor agonists, is consistent with the GABA theory of depression.

Comprehensive review of the psychiatric uses of valproate

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.

Plasma GABA levels in psychiatric illness

In two separate studies, we have obtained plasma levels of GABA in 134 psychiatric patients and 22 normal controls. Patients with a unipolar affective disorder had levels significantly lower than control (n = 58) as did patients with alcoholism (n = 10). Patients with a bipolar affective disorder had levels significantly higher than control when manic (n = 28) and also when euthymic on lithium prophylaxis (n = 17), but levels in the control range when depressed (n = 4). Patients with schizophrenia demonstrated a high degree of variability in their levels of plasma GABA but were not statistically different from control (n = 36). Patients with unipolar depression who received a dexamethasone suppression test had no correlation between nonsuppression of cortisol secretion and plasma levels of GABA. Diagnostic and research implication of plasma GABA in psychiatric illness are discussed.

Olanzapine treatment for post-traumatic stress disorder : an open-label study

Post-traumatic stress disorder (PTSD) is a common and increasingly diagnosed mental illness. Recent pharmacotherapeutic research on treatments for this condition has focused on antidepressant drugs with scrotonergic actions. However, the presence of intrusive, psychotic-like symptoms in a substantial portion of PTSD patients raises the possibility that antipsychotics with serotonergic properties might also prove useful in treating PTSD. We conducted an open-label 8-week study of olanzapine treatment in veterans with combat-induced PTSD. Primary outcome measures in this study were the Clinician Administered PTSD Scale (CAPS) and the Clinical Global Impressions Improvement scale. Secondary outcome measures included the Hamilton Rating Scales for Depression (HRSD) and Anxiety (HRSA). Forty-eight patients enrolled in the study, and 30 completed the 8-week trial. Results of intent-to-treat and completer analyses demonstrated that all outcome measures improved significantly during treatment. Secondary analyses indicate that improvement in the intrusive symptom cluster of the CAPS was independent of improvement on the HRSD and HRSA. In conclusion, the study indicates that olanzapine treatment is useful in alleviating the symptoms of combat-induced PTSD.

Low plasma GABA is a trait-like marker for bipolar illness.

Plasma gamma-aminobutyric acid (pGABA) is an index of brain GABA activity and a peripheral marker of mood disorder. Previous research has indicated that pGABA is abnormally low in approximately 40% of patients symptomatic with primary unipolar depression. We have now measured pGABA in a series of patients with bipolar disorder. Blood samples for GABA determinations were collected soon after admission to hospital or clinic while patients were symptomatic. In both manic and depressed phase bipolar patients, mean levels of pGABA were significantly lower than in healthy control subjects. The distribution of pGABA in bipolar patients, whether manic or depressed, was similar to that in symptomatic unipolar depression, with 30% to 40% having pGABA levels lower than the control range. These data indicate that low pGABA is not specific to the depressed state, as it is also found in the manic phase of bipolar disorder. Low pGABA may represent a shared biologic correlate between bipolar and unipolar illness.