TSH response to TRH and haloperidol response latency in psychoses

Thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) was measured in 19 acutely psychotic (DSM-III schizophrenia, 7; schizophreniform, 2; schizoaffective, 3; affective, mood-incongruent psychosis, 5; manic, mood-congruent psychosis, 2) drug-free patients prior to systematic trials of lithium and/or haloperidol. TSH response was not associated with sex, age, baseline T4, or baseline TSH. A reduced TSH response was associated with affective diagnosis and was a significant predictor of a positive, rapid response to neuroleptic treatment.     

Abnormal neuroendocrine responsivity to acute i.v. clomipramine challenge in depressed patients

The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.     

Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects

OBJECTIVE: This study was designed to compare central serotonergic function in depressed patients and healthy comparison subjects by examining neuroendocrine and mood responses to intravenous L-tryptophan. METHOD: One hundred twenty-six drug-free patients with DSM-III-R major depression (109 unipolar, 17 bipolar; 68 melancholic, 58 nonmelancholic; 28 psychotic, and 98 nonpsychotic patients) and 58 healthy comparison subjects participated. After an overnight fast, subjects received an intravenous infusion of L-tryptophan, 7 g. Blood was obtained for determination of serum prolactin, serum growth hormone (GH), and plasma tryptophan levels. Visual analogue scales were used to assess mood. RESULTS: Prolactin responses were blunted in nonmelancholic and higher in melancholic and psychotic depressed patients, while GH responses were blunted in combined unipolar, nonmelancholic, and nonpsychotic depressed patients. Controlling for baseline biological, clinical, and demographic factors eliminated the higher prolactin response in the melancholic and psychotic patients, attenuated the blunted GH response in the unipolar patients, and revealed a blunted GH response in the melancholic patients. Patients and comparison subjects differed on five of 13 mood responses, primarily because of baseline differences. CONCLUSIONS: These findings are consistent with previous studies demonstrating blunted neuroendocrine responses to intravenous L-tryptophan in depression. Restriction of these findings to specific subtypes of depression may reflect a differential role of serotonergic abnormalities in these subtypes.     

Plasma prolactin response to domperidone in acute schizophrenia and schizophreniform illness

The prolactin (PRL) response to 20 mg of domperidone, a peripheral dopamine (DA) blocking agent, was evaluated in a group of 16 drug-free, acute, young schizophreniform and schizophrenic males and in a group of age-matched normal males. Although basal plasma PRL levels were normal, the PRL responses following domperidone were blunted in both patient groups. The PRL response was more blunted in the schizophreniform patients than in the schizophrenic patients. Possible explanations for these results include pharmacokinetic factors or abnormalities of the pituitary D2 DA receptors.     

Exploration of dimensions of psychopathology in neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-na?ve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-na?ve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-na?ve schizophrenic patients.     

Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects.

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.     

Fenfluramine stimulation of prolactin in obsessive-compulsive disorder.

The success of serotonergic reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) has suggested that serotonergic neurotransmission may play a role in the pathogenisis of this disorder. Prolactin responses to a 60-mg oral dose of fenfluramine in 26 medication-free patients with a DSM-III-R diagnosis of OCD were compared with those of 20 controls subjects. Fenfluramine produced a significant elevation of prolactin levels in both OCD patients and controls. Prolactin responses were significantly blunted in OCD patients compared with responses in control subjects. Female subjects in both groups showed greater prolactin responses to fenfluramine than did their male counterparts. There was a significant interaction between sex and the presence of OCD such that female patients had lower prolactin responses than their controls, while the difference between male patients and controls was not significant. Prolactin responses were not correlated with age, weight, drug level, depression, anxiety, or degree of OCD symptoms. The results are consistent with a relative reduction in serotonergic efficacy in the setting of OCD.     

Prolactin response to low-dose haloperidol challenge in schizophrenic, non-schizophrenic psychotic, and control subjects

Haloperidol was administered IV to 46 male psychotic inpatients and 28 male control subjects. A two-way analysis of covariance, with age as the covariate, revealed that DSM-III schizophrenics (n = 27) had a lower prolactin response to haloperidol than did the controls (n = 28). There were no significant differences between the prolactin responses in schizophrenics, patients with affective disorders (n = 7), and those with other psychoses (n = 12), which included patients with paranoia, schizophreniform, schizoaffective disorder, and atypical psychoses. These findings support the proposition that tuberoinfundibular dopaminergic dysfunction may occur in certain patients with DSM-III schizophrenia.     

Prolactin responses to haloperidol in drug-free and treated schizophrenic patients

Summary The prolactin response to 5 mg haloperidol i.m. was studied in 12 schizophrenic patients in a drug-free state and after a month treatment with haloperidol, as a possible index of dopamine receptor sensitivity and occupancy. Blood samples were taken at times 0, 60, 90 and 120 minutes. The increase in PRL observed in the drug-free state disappeared after drug treatment. The PRL plasma levels after treatment with 60 mg haloperidol per os were higher than the maximal PRL responses after 5 mg i.m. The increases in baseline PRL caused by the treatment correlated positively to the reduction in the BPRS score. The test was also performed in a group of 11 patients chronically treated with haloperidol during a daily dose of 60 mg, and 15 days after reduction of the dose to 30 mg. PRL increases after 5 mg haloperidol i.m. were observed only after reduction of the dose. It is suggested that the prolactin response to haloperidol is an index of the occupancy of receptors that are involved in the PRL releasing mechanisms, and could be used to verify their blockade by the neuroleptics, especially in patients that do not respond positively to drug treatment.     

Prolactin in childhood obsessive-compulsive disorder: clinical correlates and response to clomipramine

Basal prolactin concentrations were measured before treatment in 18 children and adolescents with obsessive-compulsive disorder as well as in 15 of these patients after 4 and 8 weeks of clomipramine treatment. Basal prolactin levels were influenced by a history of chronic tic disorder and by the duration and severity of obsessive-compulsive symptoms. Clomipramine administration significantly increased basal prolactin levels. A slight decline in prolactin levels during the last 4 weeks of clomipramine treatment was positively correlated with a favorable treatment response and negatively correlated with duration of illness. If the changes in prolactin levels observed during clomipramine treatment are due primarily to changes in serotonergic neurotransmission, these data suggest that clomipramine treatment of obsessive-compulsive disorder produces an adaptive decrease in the responsiveness of serotonergic receptors.     

Norepinephrine in acute exacerbations of chronic schizophrenia. Negative symptoms revisited.

In recent years the dopamine hypothesis has failed to explain the complexities of schizophrenia. Because both negative symptoms and noradrenergic activity appear to increase with psychotic relapse, we studied negative symptoms, psychosis, cerebrospinal fluid norepinephrine, and cerebrospinal fluid monoamine metabolites in 32 male patients with a DSM-III diagnosis of schizophrenia while both receiving and not receiving long-term haloperidol treatment. Drug-free cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol levels correlated significantly with the severity of negative symptoms and psychosis ratings. When the patients were divided into those who did and did not relapse while not receiving the drug, significant positive correlations between negative symptoms and cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol were observed only in the patients who relapsed. Non significant but negative correlations were observed between the same variables in the nonrelapsers. Thus, increased norepinephrine activity in drug-free patients is associated with intensification of schizophrenic symptoms without necessarily causing the symptoms.     

Lateral ventricular enlargement and clinical response in schizophrenia

The relationship between enlargement of the lateral ventricles in the brains of schizophrenic patients and clinical response to neuroleptic treatment, as assessed by the ventricle-brain ratio (VBR) and psychopathology scores, was studied in a sample of 39 patients with schizophrenia or schizoaffective psychosis during a drug-free washout and after 3 1/2 weeks of treatment with either haloperidol or thioridazine. There was a weak, but statistically significant positive relationship between VBR and improvement on BPRS Psychosis factor scores after 3 1/2 weeks of treatment, and a negative correlation between VBR and baseline (washout) scores on the BPRS Anergia factor. Patients with enlarged VBRs, as defined by two criteria, also tended to show a better response to neuroleptics than patients below these criterion values.     

Computed tomography of the brain morphology of patients with first-episode schizophrenic psychosis

OBJECTIVE: To report computed tomographic (CT) scan ratings of various aspects of brain morphology of a large representative sample of patients with a first episode of schizophrenic psychosis and to compare these ratings with those from a previously reported sample of patients with chronic schizophrenia. METHODS: A brain CT scan was performed on 114 patients with a diagnosis of first episode of schizophrenia or schizophreniform psychosis. Ratings on sulcal and ventricular enlargement and sylvian fissure were obtained using the Computed Tomographic Rating Scale for Schizophrenia. The influence of age, sex, age of onset, duration of illness and clinical psychopathology on CT ratings was assessed using bivariate correlations and multiple regression analyses. The CT ratings were also compared with those from a sample of patients with chronic schizophrenia. RESULTS: First-episode patients showed a modest enlargement of sulci and ventricles and a reversed asymmetry of the sylvian fissure. Age was the only independent predictor of these regional changes. Clinical symptoms, sex or duration of untreated psychosis showed no relation to CT ratings. A comparison of first-episode patients with chronically ill patients, with the effect of age covaried, revealed the sylvian fissure was significantly larger (right and left sides) in the chronically ill patients. CONCLUSIONS: Patients with a first episode of schizophrenic psychosis showed evidence of morphological changes generally associated with chronic schizophrenia. Such changes are not likely related to sex, clinical symptoms or duration of untreated psychosis, but are influenced by age. Changes in the ventricles and sulcal size are unlikely to be progressive, suggesting a neurodevelopmental origin, whereas changes in the area of the sylvian fissure may be of a more degenerative nature.     

Prolactin bioassay in schizophrenia before and after neuroleptics.

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.     

A DSM-III family study of the nonschizophrenic psychotic disorders

The authors conducted a blind DSM-III family study based on probands diagnosed from long-term follow-up information as having schizophreniform disorder, schizoaffective disorder, or psychotic affective illness. The pattern of psychopathology in relatives of schizophreniform probands closely resembled that found previously in relatives of schizophrenic probands. Relatives of schizoaffective probands had an excess risk for schizophrenia, other psychoses, and bipolar illness. The pattern of illness found in relatives of the probands meeting Research Diagnostic Criteria for mainly schizophrenic schizoaffective disorder appeared indistinguishable from that of relatives of schizophrenic probands. Relatives of probands with psychotic affective disorder had an excess risk for schizophrenia and for unipolar and bipolar affective disorder.     

Sleep in schizophrenic patients on and off haloperidol therapy. Clinically stable vs relapsed patients.

We examined the state-dependent contribution of neuroleptic withdrawal and psychotic relapse in influencing sleep measures. Eighteen clinically stable male schizophrenic patients taking haloperidol were studied with 3 nights of polysomnography for baseline measures and again after neuroleptic withdrawal. Sleep measures were also obtained at the point of relapse (n = 9) or after a 6-week drug-free period if the patient remained clinically stable (n = 9). Neuroleptic withdrawal led to a global deterioration of rapid eye movement and non-rapid eye movement sleep and a reduction of rapid eye movement latency in both groups. Relapsers differed from nonrelapsers in that they had a larger decrease in total sleep time, sleep efficiency, total non-rapid eye movement sleep, and stage 2 sleep. The level of psychosis was inversely correlated with sleep efficiency, total sleep time, and stage 4 sleep in the drug-free patients. Our data suggest that clinical state needs to be identified in sleep studies of drug-free patients.     

Dexamethasone suppression test in schizophrenic patients before and during neuroleptic treatment

The dexamethasone suppression test (DST) was performed in 21 drug-free schizophrenic patients. The patients satisfied DSM-III and Research Diagnostic Criteria for schizophrenia and were in an acute phase of the disease. In 15 of the patients the DST was repeated after about 5 weeks of treatment with neuroleptics. DST compliance was checked by analysis of dexamethasone concentrations in plasma. In the acute phase 71% (at 04 p.m.) of the patients were nonsuppressors. After neuroleptic treatment the frequency of abnormal responders had decreased to 20%. The decrease in nonsuppressors was not due to alteration of the dexamethasone concentration between the two test occasions. Prolactin levels were markedly increased at the second test occasion compared with the first. There were no significant relationships between cortisol levels, cortisol suppression and prolactin levels. The high frequency of nonsuppressors among schizophrenic patients in the acute phase of the disease indicates that acute stress may be a confounding factor in the outcome of DST.     

精神分裂症帕罗西汀激发试验及其与疗效的关系

目的探讨精神分裂症中枢5-羟色胺（5－HT）、多巴胺（DA）功能,以及非典型、典型抗精神病药对它们的影响。方法采用随机、双盲法应用固定剂量利培酮6mg/d、氟哌啶醇20mg／d治疗78例精神分裂症患者,共12周。治疗前后测定皮质醇、催乳素对帕罗西汀激发试验的反应,并以18名正常人为对照组。结果治疗前患者组基础皮质醇[（106±41）μg/L]、皮质醇对帕罗西汀激发试验的反应（曲线下面积AUC为717±229）高于对照组[（73±25）μg／L及AUC585±163],而基础催乳素[（5±7）μg/L]低于对照组[（9±5）μg／L]、催乳素对帕罗西汀激发试验的应答比对照组呈降低趋势（AUC49±41对68±43,P＞0．05）。治疗后,两组患者的催乳素基础值比治疗前均增高（P均＜0.05）;两组之间帕罗西汀介导的催乳素反应差异无显著性。治疗后,两组皮质醇的基础值[（74±32）μg/L及（82±27）μg/L]均较治疗前降低,其中利培酮治疗后降低更为明显。利培酮治疗后皮质醇对帕罗西汀激发试验的反应（AUC518±213）降低,并与对照组差异无显著性,而氟哌啶醇组皮质醇反应与治疗前差异光显著性（P＞0．05）。结论精神分裂症患者治疗前可能有中枢DA功能亢进和5－HT功能增高。利培酮治疗使患者原来过高的中枢5－HT功能接近正常,而氟哌啶醇     

Prolactin response to single and multiple doses of haloperidol in schizophrenic patients

Serum prolactin and blood levels of haloperidol were assessed in schizophrenic patients after single acute oral doses of haloperidol and during fixed dose treatment with this medication. Although significant intrapatient correlations between prolactin responses to different doses of haloperidol were found, no statistically significant interpatient relationship between haloperidol dose and prolactin response emerged. There were statistically significant relationships between steady-state plasma and red cell haloperidol levels (measured by radio- receptor or gas liquid chromatographic techniques) and serum prolactin response, but not between blood levels after the acute haloperidol dose and prolactin response.     

Elevated prolactin in pediatric patients on typical and atypical antipsychotics

As part of systematic treatment trials of haloperidol, clozapine, and olanzapine with a total of 35 children and adolescents with early onset psychosis, prolactin was measured at baseline and week 6 of treatment. The National Institute of Mental Health patients--13 females, 22 males (mean age, 14.1+/-2.3 years; range, 9.1-19 years) with childhood onset schizophrenia (n = 32), or Psychotic Disorder not otherwise specified (NOS) (n = 3) with onset of psychosis before age 13--were recruited for open or double-blind trials of haloperidol, clozapine, or olanzapine. Baseline serum prolactin was measured after a 3-week washout period and after 6 weeks of treatment. Mean prolactin concentration after 6 weeks of treatment was significantly elevated on all three drugs; however, on clozapine, mean prolactin remained within the normal range. Prolactin was increased above the upper limit of normal for 100% of 10 patients on haloperidol, 70% of 10 patients on olanzapine, and 0% of 15 patients on clozapine (chi2 analyses: H > C, p = 0.004; O > C, p = 0.001). Given the potential endocrine and possible cardiac correlates of hyperprolactinemia, these more robust prolactin elevations in pediatric patients after short-term exposure to olanzapine than those reported for adults justify longer observation intervals with bigger samples to establish treatment safety of atypical antipsychotics in adolescents.