Cloning, expression, and regulation of a glucocorticoid-induced receptor in rat brain: effect of repetitive amphetamine.

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.

Depression during mania. Treatment response to lithium or divalproex.

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.

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.

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.

Depression secondary to cancer.

Depression is the most frequent psychiatric complication experienced by cancer patients. Recent surveys indicate that 17--25% of patients hospitalized with neoplastic disease suffer from depression severe enough to warrant psychiatric intervention. The disorder tends to be reactive in nature and occurs mot frequently among the severely ill. Despite an increased risk of suicide, self-destruction remains a rare occurrence in cancer victims. The most important etiologic factors are associated with the disease itself but additional factors have to do with its treatment. Those related to the illness include the psychological reaction to cancer, reaction to physical distress, central nervous system metastases, paraneoplastic syndromes, and metabolic disturbances. Factors related to the treatment include reaction to surgical procedures, radiation therapy, chemotherapy, and hormone therapy. Treatment for depression secondary to cancer should begin with careful assessment leading to identification of specific mechanisms and may include antidepressant drugs, psychotherapy, and a variety of adjunctive techniques. Little research has been done in this area, and most of it suffers from the use of inadequate diagnostic criteria. Controlled trials of available pharmacologic and nonpharmacologic treatments are urgently needed.

Is plasma GABA of peripheral origin?

Plasma levels of gamma-aminobutyric acid (GABA) appear to be altered in affective disorders and alcoholism. Plasma levels of GABA were not affected by menstrual cycle, exercise, gender, gut flora, nor by cholinergic stimulation by bethanechol. An obvious peripheral source for plasma GABA could not be demonstrated.

Low plasma gamma-aminobutyric acid levels in male patients with depression.

Plasma levels of gamma-aminobutyric acid (GABA) were significantly lower in males with primary unipolar major depressive disorder than in healthy controls. Although the difference in means between control and symptomatic depressed patient groups was small, the distribution of plasma GABA in the depressed patients was markedly different from controls. Forty percent of depressed patients had plasma GABA levels below those of controls. Plasma GABA levels correlated positively with duration of illness, and negatively with age at onset of the mood disorder and the total Endogenomorphic Symptom Score on the Hamilton Rating Scale. Plasma GABA levels may be a biochemical marker of vulnerability to depression, as opposed to a consequence of the illness. A low GABA condition in depression fits and complements the prevailing biogenic amine hypotheses of depression.

Learned helplessness sensitizes hippocampal norepinephrine to mild restress.

A proportion of rats exposed to inescapable tailshock stress displayed a performance deficit, termed learned helplessness, in a subsequent shuttlebox avoidance task. The technique of in vivo microdialysis was used to determine hippocampal norepinephrine levels in learned helpless, nonhelpless and nonprestressed control rats. Similar basal norepinephrine levels were detected in samples between rat groups. Following an exposure to a milder form of inescapable shock, an increase in norepinephrine output was detected in learned helpless rats, which was significantly greater than nonhelpless, nonprestressed, or control animals. Thus, inescapable stress appears to sensitize the hippocampus to increase norepinephrine release in response to a subsequent smaller stressor. This hypersensitivity might underlie the avoidance impairment of learned helplessness. Therefore, the possibility exists that similar neurochemical changes may also be responsible for some of the symptoms of human posttraumatic stress disorder (PTSD), such as the poor coping associated with seemingly mild stress.

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.

Learned helplessness increases 5-hydroxytryptamine1B receptor mRNA levels in the rat dorsal raphe nucleus.

Learned helplessness is a behavioral condition induced by exposure to inescapable stress that models aspects of stress-related disorders including depression and posttraumatic stress disorder, and has been associated with diminished serotonin release in the rat frontal cortex. Our hypothesis was that presynaptic 5-hydroxytryptamine1B (5-HT1B) receptors, which inhibit the synthesis and release of serotonin in nerve terminals, may be increased in learned helplessness. Postsynaptic 5-HT1B mRNA hybridization levels in the hippocampus or frontal cortex were unchanged following induction of learned helplessness; however, presynaptic 5-HT1B mRNA hybridization signal in the dorsal raphe nucleus of helpless rats was 25% higher than control values. There was no change in dorsal raphe serotonin transporter mRNA level. The detection of increased 5-HT1B mRNA levels in the dorsal raphe nucleus suggests an increased capacity to synthesize presynaptic 5-HT1B receptors and could account for diminished serotonin neurotransmission in learned helplessness.

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.

Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression.

The biology of mood disorders involves gamma-aminobutyric acid (GABA), a neurotransmitter whose levels in plasma likely reflect brain GABA activity. Previous research has shown that a subset of patients with primary unipolar major depression have low plasma GABA levels, which parallels findings from studies of cerebrospinal fluid. We have completed a 4-year follow-up on 46 male patients with primary unipolar depression. Plasma levels of GABA were stable over this time. For the group, mean plasma GABA levels on follow-up did not change significantly from entry levels. Plasma GABA levels measured on follow-up were significantly (p < .001) correlated with entry levels. Patients with low plasma GABA levels (< 100 pmol/ml) on entry into the study were likely to remain low on follow-up, and patients with plasma GABA levels in the control range (> or = 100 pmol/ml) at entry similarly remained in this category (chi 2 = 7.23, p = .007). This was true whether or not the patient had recovered from depression on follow-up. Levels of plasma GABA did not significantly correlate with severity of depression at either entry (p = .40) or follow-up (p = .52), nor was there a significant correlation between change in plasma GABA and change in the 17-item Hamilton Depression Rating Scale score from entry to follow-up (p = .89). These data are consistent with the notion that plasma GABA is independent of clinical state in patients with primary unipolar depression. Low plasma GABA may be a trait marker of illness in a subset of patients with mood disorder.

D-fenfluramine challenge in posttraumatic stress disorder.

BACKGROUND: Much progress has been made in understanding the role of catecholamines in the pathophysiology of posttraumatic stress disorder (PTSD). Recent research has broadened the scope of neuroregulation of PTSD to include serotonin. METHODS: We used the serotonin-releasing agent and reuptake inhibitor, d-fenfluramine, to assess the integrity of the serotonin-mediated prolactin release in 8 men with combat-induced PTSD and 8 healthy men. RESULTS: The veterans with PTSD had a significantly lower prolactin response to d-fenfluramine as compared to healthy control subjects. The prolactin response to d-fenfluramine was inversely correlated with the patient's level of PTSD symptomatology and measures of aggression. CONCLUSIONS: This study demonstrates a central serotonin dysfunction, as reflected in a lower prolactin response to d-fenfluramine, in patients with PTSD.

Plasma GABA predicts acute response to divalproex in mania.

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.

Plasma GABA levels in chronic alcoholics.

Ethanol intoxication has been noted to cause marked changes in brain and CSF levels of gamma-aminobutyric acid (GABA). Using plasma GABA levels to assess brain GABA activity, the authors found that 85 chronic alcoholics had significantly lower levels than control subjects.

Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder.

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.

Low plasma homovanillic acid levels in recently abstinent alcoholic men.

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.

Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group.

OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group. CONCLUSIONS: The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.

Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels.

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.

A preliminary neuroendocrine study with buspirone in major depression.

We administered the serotonin-1a agonist buspirone (0.4 mg/kg orally) as a neuroendocrine challenge agent to a group of male patients with DSM-III-R major depressive disorder (MDD) (n = 13) and a group of male healthy controls (n = 10). The primary hypothesis of the study was that the prolactin response to buspirone would be blunted in the depressed patients. The prolactin response was significantly lower in depressed patients than in controls. There was no significant relationship between placebo corrected-peak prolactin level and severity of depression or suicidality. There was a nonsignificant trend for the melancholic (n = 5) depressed patients to have a lower placebo corrected-peak prolactin level than nonmelancholic depressed patients (n = 8). Our findings support a role for the serotonin-1a receptor in the etiology of MDD, specifically at the postsynaptic site.

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.