Mark Fulton

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.

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.

Serotonin and impulsive/aggressive behavior in cocaine dependent subjects

1. 10 male cocaine dependent patients and 10 sex matched controls were administered several behavioral measures of aggression including the Buss-Durkee Hostility Inventory, and The Brown-Goodwin Life History of Aggression. 2. All subjects were also administered a buspirone neuroendocrine challenge as a measure of serotonin function. 3. The cocaine dependent subjects were significantly more aggressive than the controls. 4. There was a significant correlation between the growth hormone response to buspirone and behavioral measures of aggression in the cocaine dependent subjects, but not in the controls. 5. There was no difference in the overall growth hormone response between the controls and cocaine dependent subjects, possibly due to differences in metabolism of buspirone. 6. This study supports a role for serotonin in aggression in cocaine dependent subjects.

Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study.

BACKGROUND Sleep electroencephalographic (EEG) studies of individuals with major depressive disorder have identified several microarchitectural features associated with the illness. These abnormalities are also found in clinically remitted individuals, raising the question of whether they are vulnerability markers of depression. This study evaluated the sleep EEG in high-risk individuals to see if abnormalities are present in the sleep EEG prior to the onset of illness. METHODS A total of 26 subjects (13 males and 13 females) were recruited for study on the basis of 1) having a parent or grandparent treated for major depressive or bipolar affective disorder and 2) having no history of personal psychiatric illness. Polysomnographic data were collected and compared with gender- and age-matched healthy control subjects with no personal or family history of psychiatric illness. The primary outcome measures were interhemispheric and intrahemispheric coherence. RESULTS Period analysis of the sleep EEG showed that beta-delta coherence was lower bilaterally in male high-risk subjects. Right-hemispheric theta-delta coherence was also lower in male high-risk subjects, with female high-risk subjects evidencing lower beta coherence. CONCLUSIONS Sleep-EEG abnormalities associated with major depressive disorder are present in never mentally ill individuals at high risk for the illness. These markers may be useful in the prediction of illness and in family genetic studies of mood disorders.

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.

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-la receptor in the etiology of MDD, specifically at the postsynaptic site.

Evidence for the segregation of a major gene for human plasma GABA levels.

Gamma-aminobutryic acid (GABA) is a major neurotransmitter in the central nervous system, and plasma levels of GABA may reflect brain GABA activity. In 35–40% of patients with mood disorders, plasma GABA levels are low compared to psychiatrically normal controls.1 Low plasma GABA in this subgroup of patients has characteristics of a biological trait marker for mood disorders. Low plasma GABA is also found in a subset of patients with alcohol dependence, but not in schizophrenia, anxiety, or eating disorders, suggesting some diagnostic specificity.2Previous data from a small study of monozygotic twins are consistent with the hypothesis that plasma GABA levels are under genetic control.3 To better understand these mechanisms, we conducted a segregation analysis of plasma GABA levels in a sample of 157 individuals from 50 nuclear families. Analysis using the Class D regressive model indicated that the familial transmission of plasma GABA levels is compatible with the segregation of a recessive major gene. Our results suggest that plasma GABA levels are under single gene control. Future research should address the precise mechanisms which may account for the abnormality in GABA levels seen in a subset of patients with mood disorders.

Desipramine does not alter plasma GABA in patients with major depression

Low plasma GABA is a biological marker for depression in a subset of patients tested. Plasma GABA has been shown to reflect brain GABA activity. This marker has many characteristics of a trait marker for depression, including stability with time, and lack of influence by coincident factors such as gender, season, time, activity or diet. We here report that plasma GABA remained stable after 4 weeks of treatment with desipramine in patients with major depression. Since the levels of plasma GABA did not change with time, nor with clinical improvement, plasma GABA is not a state marker of depression.

Plasma γ-aminobutyric acid (GABA) predicts outcome in patients with alcohol dependence

Abstract 1. 1. Previous studies have suggested that low plasma GABA levels (≤ 100 pmol/ml) may characterize a subset of patients with alcohol dependence. 2. 2. In order to assess the clinical relevance of this biologic finding, the authors followed 49 alcohol dependent patients for up to 18 months following inpatient treatment. Treatment outcome was assessed by continuous abstinence and continued contact with research personnel. 3. 3. Alcohol dependent patients with low plasma GABA had significantly better outcome than patients with plasma GABA in the normal control range (101–150 pmol/ml). 4. 4. These findings suggest that plasma GABA measures may prove to be clinically useful in identifying alcohol dependent patients at risk for relapse.