Frederick G. Moeller

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.

A comparison of sleep EEGs in patients with primary major depression and major depression secondary to alcoholism

Polygraphic sleep recordings were compared between patients with primary major depression (MDD), patients with primary alcoholism and secondary MDD, and normals. Patients differed significantly from normals on the following measures: both patient groups showed short REM latency, and REM latency corrected, along with prolonged sleep latency. Secondary depressives differed from controls on several other measures: sleep onset time, total sleep time, delta sleep, REM percent, stage one sleep, stage three sleep, non-REM sleep, stage three and delta sleep in the first non-REM period. Prior research has shown a decrease in non-REM sleep and total sleep time in alcoholic patients who are not currently depressed, and short REM latency in patients with MDD. Thus, our findings suggest an additive effect of two disorders known to affect sleep: alcoholism and depression.

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.

Cerebellar blood flow in schizophrenic patients and normal control subjects

We used 133Xe dynamic single-photon emission computed tomography (DSPECT) to measure the resting cerebellar blood flow in 17 neuroleptic-free schizophrenic and schizophreniform patients and 13 normal control subjects. A subset of these subjects (11 patients and 7 control subjects) additionally underwent activation studies during the Wisconsin Card Sorting (WCS) and Number Matching (NM) tests. Baseline relative cerebellar blood flow was significantly lower in older patients than in age-matched control subjects. For absolute cerebellar flow, there was a significant difference between patients and control subjects in the overall activation response (patients: NM 13.4% increase, WCS 15.7% increase; control subjects: NM 3.1% decrease, WCS 0.0% change). This difference was more pronounced in older subjects. Cerebral blood flow significantly increased during NM (patients: 21.3% increase, control subjects: 6.5% increase) and WCS (patients: 16.5% increase, control subjects: 9.7% increase). The difference in the magnitude of cerebral NM activation between schizophrenic patients and control subjects, although not statistically significant, may call into question the appropriateness of using NM as a control task in schizophrenic patients. Finally, we found no differences between the effects of WCS and NM on cerebellar or cerebral blood flow. Because of the small number of subjects in each group, the results of this study should be interpreted cautiously.

Serum homovanillic acid levels in schizophrenic patients and normal control subjects

Schizophrenic patients with an early age at onset of illness had low baseline levels of homovanillic acid (HVA) in serum compared with schizophrenic patients with a late age at onset. After adjustments were made for age at onset, there was a significant partial correlation between positive symptoms and serum HVA. The relationship between positive symptom scores and serum HVA was shifted to the left in the early onset patients, suggesting a relatively increased sensitivity of dopamine-associated response. Patients with severe negative symptoms also had an earlier age at onset and a trend toward lower serum HVA. This study found no difference between mean serum HVA values in schizophrenic patients and normal control subjects.

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.

Initial platelet serotonin (5-HT) transport kinetics predict nortriptyline treatment outcome

According to the hypothesis of initial conditions, drug response may be determined by different initial states of neurotransmitter protein recognition systems. Platelet serotonin (5-HT) transport kinetics were studied as initial-conditions predictors of antidepressant response in 24 depressed patients before and after 3 weeks of treatment with nortriptyline (75 mg). The initial affinity of the 5-HT transporter (5-HTT) correctly predicted 71% of the outcome. The pretreatment affinity constant (Km) correlated (r = 0.61;p < 0.002) with that measured after 3 weeks of treatment (Kapp). Responding patients had a significantly higher initial Km before treatment and a significantly higher Kapp after treatment. Nonresponders had an initial Km significantly lower than that of 24 controls. Nortriptyline plasma levels were not statistically different between response groups. These results are consistent with two previously published observations, which indicate that the initial affinity of the 5-HTT predicted response to fluvoxamine or fluoxetine in the same way. Insofar as all three drugs increase the apparent affinity of the 5-HTT, it appears that a better response is related to those cases where the initial affinity is already higher before treatment.

Kinetic effects of desmethylimipramine treatment on platelet serotonin uptake in depressed patients: A comparison with imipramine

The kinetic effects of desmethylimipramine (DMI) on platelet serotonin (5HT) uptake were compared to those of imipramine (IMI) in eight DMI-treated depressed patients and seven IMI-treated depressed patients, and compared to values after patients were off drug for 19 (+/- 8 SD) and 33 (+/- 15) days. As expected, IMI was a stronger inhibitor of 5HT uptake than DMI during treatment, with the mean apparent Km in treated patients being elevated nearly threefold over that of the drug-free condition. In DMI-treated patients, the mean Km was elevated nearly twofold over that of the drug-free condition. Although DMI is considered a preferential norepinephrine uptake inhibitor, the results suggest the following: (1) Significant decreases in the apparent platelet 5HT affinity are achieved with DMI; (2) the inhibition kinetics in depressed patients are competitive; (3) there was a significant relationship between Km change and depression outcome with DMI discontinuation; and (4) DMI, as a metabolite, appears to contribute to the 5HT uptake inhibition of IMI in vivo.