Schizophrenia: dopamine beta-hydroxylase activity and treatment response.

Cerebrospinal fluid levels of dopamine beta-hydroxylase, found to be relatively constant over time in individual patients, were significantly lower in schizophrenic patients who became nonpsychotic during neuroleptic treatment than in those who remained psychotic. Dopamine beta-hydroxylase activity may delineate a subgroup of patients who have a dopamine-sensitive brain disorder.

Schizophrenia: elevated cerebrospinal fluid norepinephrine.

Concentrations of norepinephrine in cerebrospinal fluid are higher in schizophrenic patients, particularly in those with paranoid features, than in normal volunteer subjects of the same age. This observation supports recent reports of elevated concentrations of norepinephrine in specific brain areas adjacent to the cerebral ventricles of paranoid schizophrenic patients. Overflow of the amine from periventricular regions into the cerebrospinal fluid may reflect abnormally high release or diminished enzymatic destruction of norepinephrine in patients with schizophrenia.

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy.

Schizophrenic patients with high ventricle brain ratios and cortical brain atrophy, as shown by computerized tomography, had decreased spinal fluid concentrations of homovanillic acid and dopamine-beta-hydroxylase activity. These decreased cerebral spinal fluid concentrations in patients with brain atrophy support the proposal of disturbed noradrenaline and dopamine neurotransmission in a subgroup of schizophrenic patients.

Memory functions in depression.

In an attempt to elucidate the memory deficit in depression, short-term memory and long-term memory were examined by means of a memory test battery in 26 hospitalized depressed patients. Their performance was compared with a matched control group and with the performance of those 20 patients who improved after 26 days of treatment with antidepressants. Results indicate that depressed patients show marked impairment in short-term memory without an impairment in long-term memory. The greater the improvement of the clinical state, the greater the improvement in short-term memory, whereas long-term memory was not influenced by the therapeutic success.

Serotonin function and mechanism of action of antidepressant treatment. Effects of amitriptyline and desipramine.

The effects of amitriptyline hydrochloride and desipramine hydrochloride treatment on brain serotonin (5-HT) function were investigated in 21 patients. The ability of an intravenous infusion of the serotonin precursor tryptophan to raise serum prolactin (PRL) levels was determined in 13 depressed patients during placebo administration and after 28 to 35 days of treatment with either amitriptyline or desipramine. Both desipramine (N = 7) and amitriptyline (N = 6) significantly increased the PRL rise induced by tryptophan compared with a preceding placebo period. In contrast, following long-term amitriptyline and desipramine treatment, the ability of tryptophan to increase PRL was enhanced two weeks following abrupt cessation of amitriptyline therapy (N = 5), but not after discontinuation of desipramine therapy. The results of this investigation are consistent with electrophysiologic and behavioral studies in laboratory rats and suggest that desipramine- and amitriptyline-induced alterations in 5-HT function may be related to their antidepressant mechanism of action.

Serotonergic function in depression. Prolactin response to intravenous tryptophan in depressed patients and healthy subjects.

There is considerable evidence that serotonergic function may be reduced in the brains of depressed patients. Serotonin is an effective stimulant of prolactin release, and intravenous (IV) tryptophan (the amino acid precursor of serotonin), when administered to healthy subjects, produces a reliable and robust increase in serum prolactin level. To evaluate serotonergic function in depressed patients, we gave 25 patients and 19 age- and sex-matched controls tryptophan, 7 g IV. There was a marked blunting of the maximal prolactin response to the tryptophan in both the male and female patients. The patient control differences could not be accounted for on the basis of age, sex, or time without medications. The data provide strong support for a possible serotonergic abnormality in depression.

Lithium carbonate augmentation of antidepressant treatment. An effective prescription for treatment-refractory depression.

To assess whether lithium carbonate augments antidepressant effects of long-term antidepressant treatment in non-responding patients, 15 treatment-refractory patients were studied using a placebo-controlled, double-blind design. After at least 21 days of antidepressant drug therapy, and while continuing to receive the same daily dose of antidepressant drug, eight patients received lithium carbonate and seven received placebo. In comparison with placebo, lithium carbonate produced a small but statistically significant improvement in the mean daily nursing ratings of depression during the first two days of treatment. The beneficial effects of lithium carbonate were more variable during the next four days, but by the seventh through 12th day of the trial, the drug produced a significant and clinically meaningful improvement. When the seven placebo-treated patients received active lithium carbonate on the 13th day of the study, their rate of improvement was similar to that of the eight patients who had received active lithium carbonate initially. This augmentation of the anti-depressant effect was seen in patients treated with desipramine hydrochloride, amitriptyline hydrochloride, or mianserin hydrochloride. Although in five of the 15 patients, the improvement appeared as early as 24 to 48 hours after the first lithium carbonate dose, the remaining patients did not show a clear improvement until approximately five to eight days later. We concluded that lithium carbonate does augment the antidepressant effect when added to the long-term antidepressant treatment of nonresponding patients.

Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects.

Several recent investigations have raised the possibility that the sensitivity of alpha 2-adrenergic receptor may be of etiologic importance in depression. To assess whether abnormalities in presynaptic alpha 2-adrenergic receptor exist in depressed patients not taking drugs, the effects of an alpha 2 agonist, clonidine, on plasma 3-methoxy-4-hydroxyphenelethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in 15 depressed patients and 12 healthy controls of similar age. The ability of clonidine to increase growth hormone (GH) secretion was also assessed. The effect of clonidine on plasma MHPG and BP was not different between the depressed patients and controls. However, the GH response to clonidine was blunted in the depressed patients. These results suggest that in depression (1) the sensitivity of the presynaptic alpha 2-adrenergic receptor is not abnormal, and (2) the sensitivity of postsynaptic adrenergic receptors may be decreased.

CSF levels of gamma-aminobutyric acid in schizophrenia. Low values in recently ill patients.

gamma-Aminobutyric acid (GABA) levels in CSF were not significantly different in 30 drug-free schizophrenic patients and in 39 normal control subjects, because the control subjects were significantly older. Schizophrenic women had significantly lower levels than age-matched normal control women (less than 30 years). The GABA levels increased with duration of illness, number of hospitalizations, and months of hospitalizations, as well as with age. They correlated nonsignificantly with psychosis levels. After short-term pimozide treatment, GABA levels in all patients were raised, albeit nonsignificantly. The date suggest that low GABA levels may be observed only in the early years of the illness, particularly in female schizophrenic patients, and that these levels increase with time and with long-term neuroleptic treatment.

The clinical use of clonidine in abrupt withdrawal from methadone. Effects on blood pressure and specific signs and symptoms.

Clonidine hydrochloride was found to be effective in the treatment of methadone hydrochloride withdrawal. Under controlled inpatient conditions established to assess dosage guidelines and to examine specific signs and symptoms of withdrawal, 20 of 25 (80%) patients were able to withdraw completely from methadone by the end of a two-week period. In most patients, ten to 11 days of clonidine administration, with a peak mean dose of 16 micro g /kg/day, resulted in a perceived reduction in symptoms compared with previous attempts to become opiate free. At these doses clonidine significantly reduced standing blood pressure without producing clinical problems. The withdrawal symptoms of anxiety, restlessness, insomnia, and muscular aching were most resistant to clonidine treatment and were reported by the majority of patients.

CSF dopamine beta-hydroxylase in schizophrenia.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 30 schizophrenic patients and 27 normal controls. The CSF DBH activity in the patients was not significantly different from that in controls. Levels of CSF DBH activity in individual patients were highly constant over time and were not influenced by clinical state or neuroleptic treatment. Low levels of DBH in CSF did significantly relate to good social and sexual functioning, good prognosis, less symptoms between hospitalizations, and excellent clinical response to neuroleptic treatment. We speculate from these data that low brain DBH activity may produce a type of vulnerability to psychotic decompensation and thereby influence the clinical course, although it does not cause schizophrenia, in general. Low CSF DBH activity may delineate a "reactive" subgroup from the heterogenous population of patients with diagnoses of schizophrenia.

Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls.

Recent studies have found elevated levels of norepinephrine (NE) in CSF and brain specimens from schizophrenic patients. Presynaptic inhibitory alpha 2-adrenergic receptors regulate NE release in the brain. The hypothesis that the functional sensitivity of this presynaptic regulation of NE is impaired in schizophrenia was tested by evaluating, in schizophrenic patients and age-matched normal controls, the ability of clonidine, an alpha 2 agonist, to lower plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and to lower blood pressure (BP). Clonidine produced a significant decrease in plasma MHPG levels in the normal control group, but did not lower plasma MHPG levels in the schizophrenic patients. Clonidine decreased BP equally in both groups. These results suggest that there is a functional subsensitivity of the inhibitory presynaptic alpha 2-adrenergic receptor in schizophrenia, which may relate to an impaired regulation of NE turnover.

Clonidine and naltrexone. A safe, effective, and rapid treatment of abrupt withdrawal from methadone therapy.

Clonidine hydrochloride and naltrexone hydrochloride, given in combination, were found to provide a safe, effective, and extremely rapid treatment of abrupt withdrawal from methadone hydrochloride therapy. Under controlled inpatient conditions established to assess dosage guidelines and to examine specific signs and symptoms of withdrawal, ten (91%) of 11 patients were able to withdraw completely from methadone therapy by the end of a six-day period. Six days of clonidine hydrochloride treatment, with a peak mean dose of 2.9 mg/day on treatment day 2, attenuated the withdrawal-inducing effects of naltrexone. Naltrexone hydrochloride was gradually increased from an initial 1-mg dose on treatment day 2 to 50-mg maintenance dose on treatment day 5 without an associated increase in withdrawal symptoms. Clonidine significantly decreased BP without producing clinical problems. The withdrawal symptoms of anxiety, restlessness, and muscular aching were most resistant to treatment, but at discharge most patients were completely asymptomatic.

Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment.

Stimulation of presynaptic alpha 2-adrenergic receptors located on norepinephrine (NE)-containing cells in the brain decreases the firing rate and turnover of NE in these neurons. To assess whether abnormalities in the regulation of the NE system during desipramine hydrochloride treatment may be present in depressed patients, the effects of an alpha 2-agonist, clonidine hydrochloride, on plasma levels of the NE metabolite 3-methoxy-4-hydroxy/phenethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in ten depressed patients before and during long-term desipramine treatment. Long-term desipramine treatment significantly attenuated the effects of clonidine on plasma MHPG level and BP, indicating that during desipramine treatment alpha 2-adrenergic receptors had become subsensitive. In addition, plasma MHPG levels were significantly reduced during long-term desipramine treatment. These findings are discussed in relation to the hypothesized therapeutic mechanism of action of desipramine and the hypotheses relating noradrenergic function and depression.

Effects of electroconvulsive therapy on mood, parkinsonism, and tardive dyskinesia in a depressed patient: ECT and dopamine systems.

A patient suffering from delusional depression, Parkinson's disease, and tardive dyskinesia (TD) exhibited a marked improvement in mood and parkinsonian symptoms following electroconvulsive therapy (ECT). In contrast, her TD symptoms worsened. The inverse relation between the intensity of TD symptoms on the one hand and the parkinsonian and depressive symptoms on the other is discussed with respect to ECT's effect on central dopaminergic systems.

The effect of pimozide on CSF norepinephrine in schizophrenia.

The authors measured CSF norepinephrine concentrations in drug-free schizophrenic patients with and without probenecid administration and in drug-free normal control subjects. Schizophrenic patients had significantly higher baseline norepinephrine values. The dopamine metabolite homovanillic acid correlated significantly with norepinephrine. During chronic treatment with the neuroleptic pimozide, patients' norepinephrine levels were significantly decreased. The pimozide-induced decrease in norepinephrine, as well as the percent decrease, correlated significantly with the patients' decrease in global psychosis. These data are consistent with recent reports of elevated concentrations of norepinephrine in specific brain areas of schizophrenic patients, and they support a role for norepinephrine metabolism in the pharmacological effects of antipsychotic drugs.

Testing for physical illness in psychiatric patients.

The presence of causative, exacerbating, or coexisting medical illness is often missed by both psychiatric and nonpsychiatric physicians. Reasons for these misdiagnoses are examined, and it is suggested that the evaluation of psychiatric patients should include a detailed physical examination, thorough medical and psychiatric history, including the use of informants in addition to the patient, and laboratory testing. The willingness to consider nonobvious causes of psychiatric symptoms can help to avoid premature diagnostic closure and inappropriate treatment.

The effect of intravenous L-tryptophan on prolactin and growth hormone and mood in healthy subjects.

In order to assess the effects of increased central nervous system serotonergic function in humans on prolactin (PRL), growth hormone (GH) and mood, intravenous L-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more high, mellow, and drowsy following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The intravenous TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.

The effect of IV L-tryptophan on prolactin, growth hormone, and mood in healthy subjects.

In order to assess the effects of increased CNS serotonergic function in humans on prolactin (PRL), growth hormone (GH), and mood, IV L-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more 'high', 'mellow', and 'drowsy' following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The IV TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.

Biologic tests in psychiatry.

Neurobiologic research has discovered a number of abnormalities that might serve as biologic markers for specific psychiatric disorders. Tests for these markers could aid in differential diagnosis and in the choice and monitoring of treatment. Tests with potential clinical utility in affective illness (unipolar and bipolar depression and mania), panic disorder, and schizophrenia are discussed.