Allen R. Doran

Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia

Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors.

Chronic corticosterone administration in rats: Behavioral and biochemical evidence of increased central dopaminergic activity

Chronic corticosteroid treatment in humans in frequently complicated by behavioral changes. The present study suggests that chronic steroid administration in rats has distinct neurochemical consequences which are behaviorally relevant. Ten male Sprague-Dawley rats received 7 daily injections of corticosterone, following which they exhibited increased caudate homovanillic acid as well as an attenuated decline in vertical and ambulatory movement (functional measures of dopamine activity) compared to placebo-treated rats. A subgroup of steroid-treated rats which was more behaviorally responsive to corticosterone also showed increased caudate 5-hydroxyindole acetic acid and decreased prefrontal cortex dopamine and serotonin. These results are discussed in relation to the known behavioral side effects of chronic corticosteroid administration in man and the psychiatric manifestations of naturally occurring states of hypercortisolemia.

Cerebrospinal fluid neuropeptide Y in depression and schizophrenia

Neuropeptide Y (a recently discovered brain peptide that is colocalized with norepinephrine within some adrenergic central nervous system neurons) was measured in the cerebrospinal fluid (CSF) from patients with major affective disorder, chronic schizophrenia, and in normal volunteers. No differences between diagnostic groups were found, suggesting that if this neuropeptide is involved in the pathogenesis of these disorders, an abnormality is not detectable in the CSF.

Structural brain pathology in schizophrenia revisited. Prefrontal cortex pathology is inversely correlated with cerebrospinal fluid levels of homovanillic acid

Computed tomography scan analysis of 35 schizophrenic patients, 26 medical patients, and 31 normal controls revealed significantly larger ventricular brain ratios and structural changes consistent with cortical atrophy in both schizophrenic and medical patients in comparison with normal controls. The schizophrenic patients, however, differed from both control groups in terms of greater prefrontal cortical markings consistent with prefrontal atrophy, and this finding correlated inversely with levels of cerebrospinal fluid homovanillic acid. Results from this study, in addition to replicating previous findings and addressing methodologic issues concerning controls, provide new evidence implicating abnormality of the prefrontal cortex in schizophrenia and link this abnormality to central nervous system dopaminergic function.

Lymphocyte Beta-Adrenoreceptor Density in Patients with Unipolar Depression and Normal Controls

Values of binding maximum (Bmax) and dissociation constant (Kd) of (-)3-[125I]iodocyanopindolol (ICYP) were determined in beta-adrenergic receptors of membranes of peripheral lymphocytes in 32 patients with unipolar depression (DSM-III-R) and 31 normal controls. Results were analyzed by a two-way Analysis of Covariance method. A significant difference was noted for group assignment (patient versus control, p less than 0.05). Mean Bmax (fmol ICYP bound/mg lymphocyte membrane fraction total protein) of patients was 31.9 +/- 3.84 (SE) and controls 46.3 +/- 3.92 (SE). A significant interaction was found between group membership and gender (p less than 0.05). In the female patient group (n = 14), mean Bmax was 30.5 +/- 5.79 (SE); in female controls, mean Bmax was 56.0 +/- 5.15 (SE). Differences between male patients and male controls were not significant. Mean values of Kd (pmol/liter) showed a trend for patient values to be lower than control values [69.0 +/- 13.66 (SE) versus 108.5 +/- 14.42 (SE), respectively]. A significant inverse relationship was noted between lymphocyte beta-receptor Bmax and frequency of panic attacks during the depressive episode in 18 patients (p = 0.05). No relationship was found between values of Kd and frequency of panic attacks in these patients. Thus, preliminary evidence is provided for relationships among altered beta-adrenergic receptor binding, gender, and indices of panic-anxiety in unipolar depressed patients.

Dexamethasone increases plasma HVA but not MHPG in normal humans

Several recent studies in animals and man indicate that corticosteroids may alter catecholaminergic activity in both the peripheral and central nervous systems. We administered 1 mg of the synthetic glucocorticoid, dexamethasone, to 12 drug-free healthy volunteers and measured plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Dexamethasone was administered at 11 p.m. and blood was collected at 4 p.m. on the preceding and subsequent days. Dexamethasone administration resulted in a significant increase in plasma HVA but did not consistently affect MHPG. All subjects showed a suppression of serum cortisol to values less than 5 micrograms/dl while prolactin levels were unaltered. In an additional group of nine volunteers, we administered 2 mg of dexamethasone and observed a similar increase in plasma HVA without change in plasma MHPG, indicating a selective effect on dopamine metabolism. Implications of these findings for an understanding of the neurochemical and behavioral changes seen with steroid administration and in explaining previous results on plasma MHPG/HVA ratios in delusional depression are discussed.

Life events in depression Relationship to subtypes

Life events that had occurred in the 6 months before the onset of depression were recorded in 40 depressed patients and 41 normal controls. The depressed patients had experienced significantly more life events and significantly more undesirable life events than the controls. The 20 patients with a DSM-III diagnosed major depressive episode (MDE) without melancholia had experienced significantly more life events in the 6 months before the onset of depression than the 20 patients with a major depressive episode with melancholia. The patients with MDE without melancholia, but not the MDE with melancholia patients, had also experienced significantly more life events than a group of age- and sex-matched normal controls.

Cerebrospinal Fluid Immunoreactive Somatostatin Concentrations in Patients with Cushing’s Disease and Major Depression: Relationship to Indices of Corticotropin-Releasing Hormone and Cortisol Secretion

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushings disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushings disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushings disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Prednisone decreases CSF somatostatin in healthy humans: Implications for neuropsychiatric illness

Several neuropsychiatric illnesses, including depression and Alzheimers disease, are reported to be characterized by hypercortisolemia and by reduced levels of cerebrospinal fluid somatostatin-like immunoreactivity (CSF-SLI). To investigate a possible causal linkage between these abnormalities we administered prednisone, 80 mg orally per day for 5 days, to 9 healthy volunteers. We observed significant prednisone-induced reductions in CSF-SLI. Moreover, the magnitude of these reductions was inversely related to the magnitude of prednisone-induced reductions in plasma ACTH levels, suggesting a functional interaction between circulating corticosteroids, central somatostatin and pituitary ACTH release.

Endogenous opioid regulation of hypothalamo-pituitary-adrenal axis activity in schizophrenia

We utilized a naloxone challenge strategy to investigate the functioning of the endogenous opioid system (EOS) in schizophrenia. Patients with schizophrenia, who were on neuroleptic medication or drug-free, demonstrated a significantly larger serum cortisol response to opioid blockade by naloxone than did age- and sex-matched normal controls. Patients, but not normal controls, also demonstrated an inverse relationship between baseline cortisol and the magnitude of the response. This enhanced cortisol response is consistent with tonic hyperactivity of the EOS in schizophrenia.