Cerebrospinal fluid somatostatin and psychiatric illness

Somatostatin is a tetradecapeptide that is assuming increasing importance as a regulator of central nervous system activity. Originally identified as the hypothalamic growth hormone release-inhibiting factor, somatostatin has subsequently been shown to be extensively and selectively distributed throughout the central nervous system, to alter neuron excitability, to regulate and be regulated by the activity of classical neurotransmitters and neuropeptides, to exert a number of direct behavioral actions, and to display neuropsychiatric disorder-related alterations. In this article, a three-part study of cerebral spinal fluid (CSF) somatostatin in affective illness and schizophrenia is presented. In part 1, significant reductions in CSF somatostatin were observed in 49 bipolar and unipolar depressed patients relative to 47 controls. Values during depression were also significantly lower than those observed in affective disorder during the improved state or in schizophrenia. Diurnal studies involving paired AM and PM lumbar punctures revealed that depressed patients and normal volunteers had similar somatostatin values in the evening, despite having significantly different values in the morning. In part 2, the effects of several psychopharmacological agents on CSF somatostatin were examined, particularly the tricyclic anticonvulsant carbamazepine. A significant reduction of CSF somatostatin during treatment with carbamazepine was observed. The effect of carbamazepine on somatostatin could be related to its anticonvulsant, analgesic, or psychotropic effects. Part 3 deals with somatostatin as a major regulator of hypothalamic-pituitary-adrenal (HPA) axis activity. Somatostatin affects HPA activity by inhibiting, at a number of cellular levels, the stimulated release of adrenocorticotrophic hormone (ACTH) from the pituitary. A significant negative relationship between CSF somatostatin and the postdexamethasone plasma cortisol level in 22 depressed and 16 schizophrenic patients was observed. This relationship between low CSF somatostatin and escape from dexamethasone suppression was observed irrespective of diagnosis (i.e., depression or schizophrenia). Thus, there is indirect supporting evidence for a role for somatostatin dysregulation in the most consistently observed biological abnormality in depression, escape from dexamethasone suppression. Further study of somatostatin in neuropsychiatric disorders, and particularly depressive illness, offers great promise for better understanding their underlying affective, vegetative, cognitive, and physiological dysregulations.     

Endogenous opioid activity and beta-endorphin immunoreactivity in CSF of psychiatric patients and normal volunteers

The authors measured total opioid activity by radioreceptor assay in the CSF of 41 normal subjects and 89 unmedicated psychiatric patients, including schizophrenic, schizoaffective, depressed, and manic diagnostic groups. Schizophrenic men had significantly lower levels of opioid activity than the normal men, although these levels did not significantly differ from levels of other male patients. The authors observed higher opioid activity during mania than during depression in paired samples for 4 manic-depressive patients. beta-Endorphin immunoreactivity in a subsample of the same subjects was no different in the patient group than in the normal group, suggesting that the differences in CSF opioid activity between schizophrenic men and normal patients may be related to opioids other than beta-endorphin.     

Relationship between urinary free cortisol and CSF opioid binding activity in depressed patients and normal volunteers

We investigated the relationship between hypothalamic-pituitary-adrenal (HPA) activity, as measured by 24-hour mean urinary free cortisol (MUFC), and cerebrospinal fluid (CSF) opioid activity in patients with major affective disorder and normal volunteers. Among depressed patients, but not normal volunteers, mean 24-hour urinary cortisol values were significantly correlated with CSF opioid activity measured by radioreceptor assay, but were not significantly correlated with beta-endorphin immunoreactivity measured by radioimmunoassay. MUFC, as expected, was significantly higher in depressed patients than in normal volunteers. Mean values of CSF opioid activity and beta-endorphin immunoreactivity did not differ significantly in the two groups. The positive opioid-MUFC correlation found in the depressed group appeared to depend on patients who were cortisol hypersecretors. These data, using relatively crude measures of cortisol and opioid activity, are suggestive of a relationship between these two systems, particularly under "activated" conditions such as those observed in depression.     

CSF and plasma beta-casomorphin-like opioid peptides in postpartum psychosis

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.     

Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone

Over the last few years, there has been a growing tendency for opioid addicts to abuse multiple drugs, although many patients are in substitution therapy with methadone. Abuse of multiple drugs leads to a more complicated withdrawal syndrome; it is therefore necessary to investigate new drug strategies as a treatment for detoxification. Buprenorphine appears to be an effective and safe drug in opioid-addicted patient detoxification. In this study, we have compared the short-term efficacy of an 11-day low-dose buprenorphine/14-day carbamazepine regime [BPN/CBZ] (n = 14) to an 11-day methadone/14-day carbamazepine regime [MET/CBZ] (n = 12) in a double-dummy, randomized 14-day inpatient detoxification treatment study. Twenty-six inpatients met the DSM-IV criteria for opioid dependence and were included in this study. All patients abused various additional drugs. Fourteen of 26 patients (53.8 %) completed the study. Seven non-completers (seven of 12 = 58.3 %) were treated with methadone/carbamazepine and five non-completers (five of 14 = 35.7 %) received buprenorphine/carbamazepine, but the difference in the dropout rate was not significant. However, patients with buprenorphine/carbamazepine showed significantly fewer withdrawal symptoms after the first two weeks of treatment. The present study supports the hypothesis that buprenorphine/carbamazepine is more effective than methadone/carbamazepine in detoxification strategies for opioid addict with additional multiple drug abuse. No severe side effects occurred during treatment in either group.     

The effect of morphine upon CSF opioids in dogs

Cerebrospinal fluid opioid activity was measured in dogs before and after morphine administration in order to investigate whether morphine results in an increase in CSF endogenous opioid levels. CSF was fractionated on a gel filtration column, and these fractions were assayed using a radioreceptor assay. Several peaks of opioid activity were seen in dog CSF both before and after morphine treatment. The predominant change in opioid peak patterns was the appearance after morphine treatment of a large peak in the elution position of morphine itself. Radiotracer studies verified that micromolar concentrations of morphine were present in CSF, which is enough morphine for potent binding activity. In addition to the increased activity in the elution position of morphine, several peaks of endogenous opioid activity showed increases after morphine treatment which were statistically significant.     

CSF somatostatin in affective illness and normal volunteers

Somatostatin is a hypothalamic tetradecapeptide with many central nervous system actions. We investigated a potential role for altered somatostatin activity in affective disorder by measuring somatostatin in the cerebrospinal fluid (CSF) of 47 patients with affective disorder and of 39 normal volunteers. Medication-free depressed patients showed significantly lower levels of CSF somatostatin than normal volunteers (p less than .001) or patients during the improved state (p less than .01). Somatostatin levels were significantly and inversely correlated with duration of sleep on the night of the lumbar puncture (p less than .05). Treatment with carbamazepine reduced CSF somatostatin (p less than .01) in contrast to the absence of effect of imipramine, desmethylimipramine, and lithium carbonate and the significant increase in CSF somatostatin seen in a small group of patients treated with zimelidine. The implications of these findings with respect to attempts to explore the neurobiology of depression are discussed.     

Carbamazepine lowering effect on CSF somatostatin-like immunoreactivity in temporal lobe epileptics

The effect of carbamazepine treatment on CSF-somatostatin-like immunoreactivity (SLI) in patients suffering from temporal lobe epilepsy was investigated. A baseline lumbar puncture was performed on 12 patients and 10 normal volunteers. A second tap was repeated only in patients when they were on peak of carbamazepine concentration for 10 days. Levels of CSF-SLI were measured by RIA. No significant differences were found in CSF-SLI basal concentrations between epileptics and controls, whereas a significant decrease (p less than .0002 Duncan's multiple range test) of CSF peptide levels occurred in 9 of 12 patients under medication. Although the neural mechanism through which carbamazepine lowers CSF-SLI is still unknown, the results of the present study suggest that the reported effect might be part of the apparatus by which carbamazepine exerts its anticonvulsant action.     

CSF beta-endorphin and dynorphin in bulimia nervosa.

OBJECTIVE: Preclinical and clinical evidence suggests that central opioid dysfunction may play a role in the pathophysiology of the eating disorders. In particular, endogenous opioids are known to regulate feeding behavior, mood, perception, and neuroendocrine function, all of which are disturbed in patients with eating disorders. Although low concentrations of CSF beta-endorphin have been reported in low-weight patients with anorexia nervosa, central opioid activity in normal-weight patients with bulimia nervosa has not been reported. The authors therefore measured CSF concentrations of beta-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. METHOD: After 4 days of a low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) from 11 women with bulimia and 17 normal comparison subjects (eight women and nine men). RESULTS: The women with bulimia had significantly lower CSF concentrations of beta-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. beta-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale of the Eating Disorders Inventory. CONCLUSIONS: These data support a role for central opiates in the mediation of the pathophysiology of the signs and symptoms of bulimia nervosa, although it is impossible to rule out the effects of depression on the results.     

Clinical studies of the endogenous opioid system

The role of the endogenous opioid system in humans was studied using three clinical research strategies. High doses of the opiate antagonist naloxone (up to 4 mg/kg) were administered to normal volunteers. Dose-dependent increases in self-ratings of tension-anxiety and anger-hostility were observed, supporting the hypothesized involvement of the endogenous opioid system in the modulation of human mood and feelings of well-being. Accompanying dose-dependent increases in systolic blood pressure and respiratory rate were found, suggesting that the lower doses of naloxone utilized in previous clinical studies were not sufficient to block the endogenous opioid system. CSF opioid activity in psychiatric patients and normals was measured using a sensitive radioreceptor assay developed by the authors. Results suggest diminished endogenous opioid system activity in some schizophrenics, and a relationship between opioid activity and state change in manic-depressive illness and anorexia nervosa. A complex but consistently observed relationship between ratings of anxiety and CSF opioid activity in normals and patients is consistent with basic science and clinical data suggesting interactions between CNS noradrenergic and opioid systems. General surgery was used as a strategy for studying the relationship of the endogenous opioid system to stress in humans; robust increases in levels of plasma beta-endorphin immunoreactivity accompanying surgical stress and an inverse relationship between patient levels of plasma beta-endorphin immunoreactivity and postoperative analgesic requirement were observed. These data support the involvement of the endogenous opioid system in the human stress response and suggest that hormonal stress response and endogenous opioid system activity may relate to human endogenous analgesic mechanisms.     

Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects

The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in nine epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a three-times-daily or four-times-daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in five patients and showed an intermittent pattern in four. Side effects were never found at total carbamazepine levels less than 34 mumol/L but invariably appeared at levels greater than 38 mumol/L. At levels between 34 and 38 mumol/L adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels greater than 7.2 mumol/L. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.     

Relationship between cerebrospinal fluid somatostatin and peripheral thyroid hormones with carbamazepine treatment

The relationship between CSF somatostatin and peripheral thyroid hormones was assessed in 11 affectively ill patients before and during carbamazepine treatment. A direct relationship between CSF somatostatin and plasma thyroxine and free thyroxine, but not triiodothyronine, was observed both while patients were medication-free and during carbamazepine treatment. These first data in man are consistent with those in animals, suggesting a close interrelationship between somatostatin and thyroid regulation.     

Adverse effect of antiepileptic drugs on the visual recognition--a contrast sensitivity function study]

Contrast sensitivity function (CSF) was measured in 16 patients (14-60 yr.) with epilepsy to investigate adverse effect of antiepileptic drugs on the central nervous system. Eight patients were treated with phenytoin, while 8 were given polytherapy (phenytoin in combination with phenobarbital, carbamazepine or valproic acid). Thirty-one normal controls (19-59 yr.) were also subjected to this study. Vertical sinusoidal gratings with various spatial frequencies (0.5-20.0 c/deg) were presented on a video monitor. Contrast sensitivity (reciprocal of threshold contrast) was determined at each spatial frequency. CSF of normal subjects showed an inverted U-shaped function against the spatial frequencies with a peak at 6 c/deg (medium size pattern). There was no significant difference in CSF values between normal controls and patients with epilepsy. However, 3 patients with polytherapy showed the significant reduction of contrast threshold. Since these patients did not complain of visual disturbance with normal visual acuity, CSF abnormality was considered as having subclinical visual dysfunction. These results suggest that CSF is useful for evaluating the adverse effect of antiepileptic drugs on the visual recognition, and that polytherapy is responsible for CSF abnormality. Therefore, monotherapy should be scheduled from the onset of therapy.     

Carbamazepine, a possible adjunct or alternative to lithium in bipolar disorder

The effect of carbamazepine in bipolar disorder has been studied by several groups. According to these studies carbamazepine appears to exert a "lithium-like" effect. Twelve patients with lithium-resistant bipolar disorder and without epilepsy were prophylactically treated for 3 years with carbamazepine in an open study. In most patients carbamazepine was added to lithium, neuroleptics and/or antidepressants. Four patients did not complete the minimum treatment period of 6 months required for evaluation. In the remaining eight patients carbamazepine seemed to be effective in four patients, had a possible or slight effect in two, and no effect in the remaining two. It is concluded that carbamazepine can be safely combined with lithium, and that carbamazepine, eventually combined with lithium, can be effective in lithium(-alone)-resistant bipolar disorder.     

The measurement of endorphins in body fluids

The measurement of endorphins in body fluids has been an important advance in clinical research attempting to link the endogenous opioid system to psychiatric illness and symptomatology. The consideration of methodologic differences in assay technique and in clinical methods is important in evaluating results of studies. Whereas findings in early clinical studies supported the notion of increased endorphin system function in patients with schizophrenia, cumulative data from the considerable number of studies carried out throughout world centers have been unable to demonstrate a consistent abnormality in levels of endorphins in CSF or plasma of patients with schizophrenia. Among the affective disorders, data suggest the possibility of relative changes in levels of opioids within individual manic-depressive patients when studied across state change from depression to mania. In studies of depressive illness there is accumulating evidence that the endogenous opioid system may relate or contribute to abnormality of the HPA axis. In our work measuring opioids in CSF we have observed relationships between anxiety and CSF opioids in normals and psychiatric patients and changes in CSF opioid activity in patients with anorexia nervosa accompanying weight change. These data are consistent with other evidence linking endorphins to CNS noradrenergic systems and to biologic response to stress.     

Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine,Phenobarbital, Phenytoin,and Primidone

Summary: : In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic-clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.     

Tears as the Best Practical Indicator of the Unbound Fraction of an Anticonvulsant Drug

Phenobarbital and carbamazepine concentrations were determined by the EMIT technique in tears, saliva, cerebrospinal fluid (CSF), and plasma of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios for the two agents. The phenobarbital CSF/serum ratio was in good agreement with data in the literature, and the higher ratio found for carbamazepine may be caused by an EMIT assay cross-reaction for the free fraction of carbamazepine-10,11-epoxide. In our hands, tears seem to represent the best practical indicator of the unbound fraction of an anticonvulsant drug, and the noninvasiveness of the method makes it specifically useful in pediatric neurology.     

Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients

Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies.     

Elevated CSF beta-endorphin immunoreactivity in Rett's syndrome: report of 158 cases and comparison with leukemic children.

Because some symptoms of Rett's syndrome are suggestive of excessive endogenous opioid activity, we measured the levels of beta-endorphin-like immunoreactivity in lumbar CSF from 158 affected female patients and from 13 female controls. The mean (+/- SE) control level of beta-endorphin immunoreactivity in CSF was 35.3 +/- 2.8 pg/ml (range, 23 to 48 pg/ml), whereas those with Rett's syndrome had a mean level of 95.3 +/- 3.6 pg/ml (range, 31 to 293 pg/ml). The levels of beta-endorphin immunoreactivity in initial CSF samples exceeded the control range in 90% of the patients with Rett's syndrome. The mean beta-endorphin immunoreactivity was also elevated in CSF from leukemic children (119.2 +/- 16.9 pg/ml; range, 40 to 159 pg/ml), relative to the control group. These results are consistent with the hypothesis that some symptoms of Rett's syndrome may be associated with excessive endogenous opioid levels in the CNS.     

CSF levels of receptor-active endorphins in schizophrenic patients: correlations with symptomatology and monoamine metabolites

Cerebrospinal fluid (CSF) levels of an opioid receptor-active, chromatographically separated endorphin fraction (Fraction I) were measured in 45 schizophrenic patients and 18 healthy volunteers. Significantly increased levels of Fraction I differentiated the patient group from controls, with no difference being found between newly admitted untreated and chronic previously neuroleptic-treated subjects. Fraction I levels did not correlate with age, weight, height, duration of illness, total time hospitalized, or age when symptoms first appeared. No differences were found between patients with or without a family history of schizophrenia. Fraction I levels were negatively correlated with "hallucinations" and "indecision" on the Comprehensive Psychopathological Rating Scale. Increased levels of Fraction I were associated with low levels of the dopamine metabolite homovanillic acid in drug-free schizophrenics. This relationship was not present after neuroleptic treatment or in healthy controls. No relationship was found between Fraction I and the serotonin metabolite 5-hydroxyindoleacetic acid. Neuroleptic treatment did not significantly change Fraction I levels; when only patients above the control range were considered, however, a significant decrease was observed. The data support our previous hypothesis of an increased opioid activity in schizophrenia and further indicate a concomitant dysfunction of brain endorphin and dopamine activity in schizophrenic patients.