Long-term Neuroleptic Therapy Research Articles

CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects.

Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time.

Modulatory effect of neurosteroids in haloperidol-induced vacuous chewing movements and related behaviors

Tardive dyskinesia is a syndrome of abnormal and involuntary movements which occurs as a complication of long-term neuroleptic therapy especially classical neuroleptics such as haloperidol and chlorpromazine. Dysfunction of GABA receptor mediated inhibition, and increased glutamatergic neurotransmission has been implicated in the development of orofacial dyskinesia in rats and tardive dyskinesia in humans. Neurosteroids modulate both GABAergic as well as glutamatergic neurotransmission in various brain areas. The objective of the present study was to elucidate the role of various neurosteroids in neuroleptic-induced vacuous chewing movements and related behaviors in rats by using behavioral, biochemical, and neurochemical parameters. Animals chronically treated with haloperidol (1 mg/kg i.p.) for a period of 21 days exhibited marked increase in vacuous chewing movements, tongue protrusions, and facial jerkings as compared to vehicle-treated controls. It also resulted in increased superoxide anion levels and lipid peroxidation, whereas decreased levels of endogenous antioxidant enzymes (catalase and superoxide dismutase) in rat brain striatum homogenates. Neurochemical studies revealed that chronic administration of haloperidol resulted in significant decrease in the levels of dopamine, serotonin, and norepinephrine in rat brain striatum homogenates, whereas urine biogenic amines metabolite levels were increased. In a series of experiments, rats co-administered with allopregnanolone (0.5, 1, and 2 mg/kg i.p.) and progesterone (5, 10, and 20 mg/kg i.p.), both positive GABA-modulating [negative N-methyl-D-aspartate (NMDA)-modulating] neurosteroids prevented, whereas pregnenolone (0.5, 1, and 2 mg/kg i.p.) and dihydroxyepiandrosterone sulfate (0.5, 1, and 2 mg/kg i.p.) both negative GABA-modulating (positive NMDA-modulating) neurosteroids aggravated all the behavioral, biochemical, and neurochemical parameters. These results suggest that neurosteroids may play a significant role in the pathophysiology of vacuous chewing movements and related behaviors by virtue of their action on either the GABA or NMDA modulation. Furthermore, neurosteroids showing selectivity for positive GABA modulation and/or negative NMDA modulation may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further evaluation.

Neuroleptic Malignant Syndrome Associated with Colon-Cancer

Neuroleptic malignant syndrome (NMS), a potentially hazardous side effect of antipsychotic agents, usually develops within 10 days after receiving these agents. We describe a 65-year-old male who developed NMS after taking neuroleptics for alcohol dependence syndrome for several years. He was successfully treated by stopping these agents but three months later, an advanced sigmoid colon cancer was detected. He underwent surgery and the clinical course was uneventful. The present case is rare in that he developed NMS after long-term neuroleptic therapy and concurrent alimentary tract malignancy can be a risk factor for the development of NMS.

Effects of N-methyl-d-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias

Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma. The objective of the present study was to elucidate the role of N-methyl-D-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats. Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit. All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05). These results suggest that NMDA receptors may play a significant role in the pathophysiology of tardive dyskinesia. Furthermore, antagonists showing selectivity for NMDA receptors containing the NR2B subunit may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further testing.

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT 3 receptor antagonists

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT 3 receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT 3 receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT 3 receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.

The role of glutamate receptors in antipsychotic drug action.

It has recently been postulated that disturbances in glutamatergic neurotransmission may contribute to the pathophysiology of schizophrenia. Therefore the aim of the present study was to evaluate the role of glutamate NMDA and group II metabotropic receptors in the antipsychotic drug action. To this aim the influence of some well-known neuroleptics on cortical NMDA receptors was examined. Furthermore, their behavioral effects were compared with those of the novel agonist of group II glutamate metabotropic receptors, LY 354740, in some animal models of schizophrenic deficits. We found that long-term administration of the typical neuroleptic haloperidol and the atypical one clozapine increased the number of NMDA receptors labelled with [3H]CGP 39653 in different cortical areas. Long-, but not short-term, treatment with haloperidol and raclopride diminished the deficit of prepulse inhibition produced by phencyclidine, which is a model of sensorimotor gating deficit in schizophrenia. In contrast, neither short- nor long-term treatment with clozapine influenced the phencyclidine effect in that model. Acute treatment with LY 354740 reversed neither (1) the deficit of prepulse inhibition produced by phencyclidine or apomorphine, nor (2) the impairment in a delayed alternation task induced by MK-801, which is commonly used to model the frontal lobe deficits associated with schizophrenia. The present study suggests that an increase in the density of cortical NMDA receptors may be important to a longterm neuroleptic therapy. Conversely, the results do not support the role of group II metabotropic glutamate receptors in the antipsychotic drug action.

Can chronic neuroleptic treatment promote sleep disturbances in elderly schizophrenic patients?

It has been proposed that sleep disturbances, especially reduced delta sleep, are related to a poor outcome in schizophrenia. To determine whether long-term treatment with neuroleptics can promote sleep disturbances by increasing the risk of a nocturnal myoclonus syndrome (NMS) (=periodic movements in sleep) related insomnia, we performed all-night polysomnography in 10 chronically ill schizophrenic patients who had been under neuroleptic therapy for a mean of 27 years. NMS-related insomnia was detected in all 10 patients. Potential pathophysiological relationships between long-term neuroleptic therapy and NMS occurrence are discussed. Our findings suggest that long-term administration of neuroleptics favours the appearance of insomnia.

Bone mineral density, sex hormones, and long-term use of neuroleptic agents in men.

To study the prevalence and severity of bone mineral loss and its relationship to sex hormone levels in men on long-term neuroleptic therapy. Sixteen men with schizophrenia who were from 19 to 62 years old and had taken neuroleptic medication for 1 to 30 years had bone mineral density (BMD) of the lumbar spine and proximal femur measured by dual-energy x-ray absorptiometry. Results were compared with those from 16 age-matched control subjects. Serum testosterone, sex hormone-binding globulin, free testosterone index (FTI), prolactin, and pituitary gonadotropins were assayed and compared with age-matched Red Cross blood donor controls (N = 23 to 90 for the various assays). At the lumbar spine and at two of the three sites in the proximal femur (trochanter and Ward's triangle but not femoral neck), the BMD was lower in patients than in controls. A statistically significant increase in prolactin and sex hormone-binding globulin and a significantly decreased luteinizing hormone and FTI were found in the treated versus the control group. In the patient group, a significant inverse relationship existed between age and BMD at all sites. Lumbar spine density was related directly to FTI (r = 0.607; P=0.05) and inversely to duration of treatment (r = -0.767; P<0.001), although both correlations were accounted for mainly by age associations in multiple stepwise linear regression. Prolactin values did not correlate with either BMD or FTI. BMD was significantly lower with long-term neuroleptic use. In the lumbar spine, these changes may be related to the associated findings of decreased free testosterone and hyperprolactinemia, although the significance of other factors such as an independent drug effect, the psychiatric disease itself, and lifestyle cannot be excluded.

Bone Mineral Density, Sex Hormones, and Long-Term Use of Neuroleptic Agents in Men

Objective To study the prevalence and severity of bone mineral loss and its relationship to sex hormone levels in men on long-term neuroleptic therapy. Methods Sixteen men with schizophrenia who were from 19 to 62 years old and had taken neuroleptic medication for 1 to 30 years had bone mineral density (BMD) of the lumbar spine and proximal femur measured by dualenergy x-ray absorptiometry. Results were compared with those from 16 age-matched control subjects. Serum testosterone, sex hormone-binding globulin, free testosterone index (FTI), prolactin, and pituitary gonadotropins were assayed and compared with age-matched Red Cross blood donor controls (N = 23 to 90 for the various assays). Results At the lumbar spine and at two of the three sites in the proximal femur (trochanter and Ward’s triangle but not femoral neck), the BMD was lower in patients than in controls. A statistically significant increase in prolactin and sex hormone-binding globulin and a significantly decreased luteinizing hormone and FTI were found in the treated versus the control group. In the patient group, a significant inverse relationship existed between age and BMD at all sites. Lumbar spine density was related directly to FTI (r = 0.607; P≤0.05) and inversely to duration of treatment (r = –0.767; P<0.001), although both correlations were accounted for mainly by age associations in multiple stepwise linear regression. Prolactin values did not correlate with either BMD or FTI. Conclusion BMD was significantly lower with longterm neuroleptic use. In the lumbar spine, these changes may be related to the associated findings of decreased free testosterone and hyperprolactinemia, although the significance of other factors such as an independent drug effect, the psychiatric disease itself, and lifestyle cannot be excluded. (Endocr Pract. 1997; 3:209-213)

Absence of parkinsonism among patients in long-term neuroleptic therapy who abuse cocaine.

The study used the United Parkinson's Disease Scale to compare parkinsonian signs and symptoms among 19 patients in long-term neuroleptic therapy who had a history of cocaine abuse with those among 24 similar patients with no history of cocaine use. There was no significant difference between the two groups' scores. The results suggest that chronic cocaine abuse is not a risk factor for parkinsonism among subjects in long-term neuroleptic therapy.

Recurrent mandibular dislocation under neuroleptic drug therapy, treated by bilateral eminectomy

Acute mandibular dislocations caused by extrapyramidal syndromes under neuroleptic therapy have often been reported in the literature. However, the success of surgical therapy for recurrent mandibular dislocation in patients under long-term neuroleptic therapy has been discussed controversially. In our opinion, modifications in drug therapy--including the administration of so-called atypical neuroleptics--should be considered before advocating surgery. If the revised therapeutic approach proves to be unsuccessful because of psychotic relapse or persistence of extrapyramidal symptoms, good operative results may be achieved by bilateral eminectomy as reported on three psychiatric patients in this paper. In order to avoid postoperative subluxation and internal derangement due to increased muscular tension under chronic neuroleptic therapy, as much bone as possible should be removed when performing eminectomy.

Usage and Side Effects of Neuroleptics in Elderly Japanese Patients

The authors assessed the use and side effects of neuroleptics (especially tardive dyskinesia [TD]) in elderly patients in Japan (N = 73; mean age 76 years, 32 men and 41 women) admitted for the first time to six psychiatric hospitals. The comparison group was 74 elderly patients with dementia admitted to nursing homes or psychiatric hospitals and not treated with neuroleptics. The mean dose of neuroleptics in the Japanese elderly patients was lower than that in Western countries; however, the prevalence of side effects was higher, possibly because of polypharmacy. The total number of psychotropic drugs correlated significantly with the number of side effects. Incidence of dyskinesia in the patients treated with neuroleptics (for a mean of 20 months) was significantly greater (44%) than that in non-neuroleptic-treated patients (14%). A significant risk factor for TD was long-term neuroleptic therapy, whereas age, gender, psychiatric diagnosis, neuroleptic dose, and antiparkinsonian drug use were not risk factors.

Expression of Glutamic Acid Decarboxylase mRNA in Striatum and Pallidum in an Animal Model of Tardive Dyskinesia

Long-term administration of neuroleptics can induce tardive dyskinesia in humans. Oral movements with the same distinctive form observed in humans with tardive dyskinesia are observed in rats treated with haloperidol for 8 and 12 months but not 28 days. We have examined the effects of these long-term haloperidol treatments on the levels of mRNA encoding glutamic acid decarboxylase (GAD, Mr 67,000), the rate-limiting enzyme of GABA synthesis, in the striatum and pallidum of adult rats. Despite the differences in behavior, GAD67 mRNA was increased in the striatum and entopeduncular nucleus (internal pallidum) after both 28 days and 8 months of haloperidol administration. In contrast, only long-term haloperidol treatments (8 and 12 months) decreased GAD67 mRNA in globus pallidus (external pallidum). This effect contrasted with the increased level of GAD67 mRNA we have previously observed in the globus pallidus after short-term haloperidol treatment (3-14 days), a regimen that induces catalepsy. Together with data indicating a loss of GAD activity in target areas of the globus pallidus in humans with tardive dyskinesia, the results suggest that decreased GABAergic transmission in the projection neurons of the external pallidum may play a critical role in the motor side effects associated with long-term neuroleptic therapy.

Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis

1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D 2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D 2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.

Treatment of Acute Neuroleptic‐Induced Movement Disorders

Acute extrapyramidal syndromes (EPS), including dystonia, parkinsonism, and akathisia, are associated with the use of virtually all neuroleptic agents. They may be alleviated by reducing the neuroleptic dosage, switching to a lower-potency drug, or administering an adjunctive agent such as an anticholinergic, amantadine, benzodiazepine, or beta-blocker. Akathisia may be only partly dispelled by anticholinergics; alternatives are beta-blockers, benzodiazepines, and clonidine. In patients receiving long-term neuroleptic therapy, both the prophylactic use and the duration of treatment with concomitant anti-EPS drugs are controversial. Administration of prophylactic anti-EPS drugs should be based on the likelihood that the patient will develop EPS, as well as the risk of adverse reactions resulting from extended use of the agents in a specific patient. The decision to continue anti-EPS therapy should be reevaluated frequently, especially in elderly patients.

Effects of calcium channel blockers on tardive dyskinesia

Tardive dyskinesia (TD) is a serious iatrogenic disorder that is induced by long-term neuroleptic therapy. There are no well-established treatments for TD but a number of agents, such as calcium channel blockers and vitamin E, have shown some promise in decreasing the symptoms of TD. We reviewed the treatment outcome literature on the efficacy of the three prototypic calcium channel blockers, verapamil, diltiazem, and nifedipine, on TD. Although the outcome data were equivocal, when taken in their best light, they suggested that calcium channel blockers may be effective in decreasing the symptoms of TD. However, the studies were methodologically flawed in many respects and future research must ensure that the basic requirements for scientific validity are incorporated in the experimental design. Further, there is a need for dose-response studies of the three prototypic calcium channel blockers, as well as investigations of their comparative effects.

Anticardiolipin antibodies in a sample of chronic schizophrenics receiving neuroleptic therapy.

Drug-induced antiphospholipid antibodies have been considered insignificant, a belief that has recently been questioned. Previous studies noted an association between chlorpromazine treatment and the presence of anticardiolipin antibodies (ACA), especially IgM ACA, and have suggested that thrombosis might be more likely in the presence of IgG ACA. We studied the cases of 27 patients receiving long-term neuroleptic therapy who had no history of cerebrovascular disease. IgG ACA was present in 7 (26%) of the 27, and IgM ACA was present in 5 (19%), yet none had shown any manifestations of cerebrovascular disease since initiation of neuroleptic therapy. These data suggest that drug-induced ACA do not predispose to cerebrovascular disease, even when IgG ACA is predominant.

Cocaine Use by Schizophrenic Outpatients Who Receive Depot Neuroleptic Medication

Back to table of contents Previous article Next article ArticleNo AccessCocaine Use by Schizophrenic Outpatients Who Receive Depot Neuroleptic MedicationAndrew M. Stone, Robert A. Greenstein, Geraldine Gamble, and A. Thomas McLellanAndrew M. StoneSearch for more papers by this author, Robert A. GreensteinSearch for more papers by this author, Geraldine GambleSearch for more papers by this author, and A. Thomas McLellanSearch for more papers by this authorPublished Online:1 Apr 2006https://doi.org/10.1176/ps.44.2.176AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail "Cocaine Use by Schizophrenic Outpatients Who Receive Depot Neuroleptic Medication." Psychiatric Services, 44(2), pp. 176–177 Access content To read the fulltext, please use one of the options below to sign in or purchase access. Personal login Institutional Login Sign in via OpenAthens Purchase Save for later Item saved, go to cart PPV Articles - Psychiatric Services $35.00 Add to cart PPV Articles - Psychiatric Services Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? Subscribe Now / Learn More PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development. Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.). FiguresReferencesCited byDetailsCited byAre Patients with Schizophrenia Reliably Reporting their Cannabis Use? An African Cross-sectional StudyCentral Nervous System Agents in Medicinal Chemistry, Vol. 22, No. 3Patterns of Justice Involvement Among Adults With Schizophrenia and Bipolar Disorder: Key Risk FactorsAllison G. Robertson, Ph.D., M.P.H., Jeffrey W. Swanson, Ph.D., Linda K. Frisman, Ph.D., Hsiuju Lin, Ph.D., and Marvin S. Swartz, M.D.1 July 2014 | Psychiatric Services, Vol. 65, No. 7Dartmouth Assessment of Lifestyle Instrument (DALI): A Substance Use Disorder Screen for People With Severe Mental IllnessStanley D. Rosenberg, Ph.D., Robert E. Drake, M.D., Ph.D., George L. Wolford, Ph.D., Kim T. Mueser, Ph.D., Thomas E. Oxman, M.D., Robert M. Vidaver, M.D., Karen L. Carrieri, R.N., M.A., and Ravindra Luckoor, M.D.1 February 1998 | American Journal of Psychiatry, Vol. 155, No. 2Validity of Substance Use Self-Reports in Dually Diagnosed OutpatientsRoger D. Weiss, M.D., Lisa M. Najavits, Ph.D., Shelly F. Greenfield, M.D., M.P.H., Jose A. Soto, B.A., Sarah R. Shaw, B.A., and Dana Wyner, B.A.1 January 1998 | American Journal of Psychiatry, Vol. 155, No. 1Absence of parkinsonism among patients in long-term neuroleptic therapy who abuse cocaine1 April 2006 | Psychiatric Services, Vol. 48, No. 1 Volume 44Issue 2 February 1993Pages 176-177 Metrics PDF download History Published online 1 April 2006 Published in print 1 February 1993

Effects of neuroleptic treatments on peripheral opioid secretion.

The effects of short- and long-term neuroleptic therapy on peripheral secretion of beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) were examined in 25 chronic schizophrenic patients. Haloperidol was given to 8 patients for 10 days (group A: 0.1 mg/kg b.w./day) and to another group of 8 patients for 30 days (group B: 10-18 mg/day). The other 9 patients were given a combination of haloperidol (6-30 mg/day) with either chlorpromazine (25-75 mg/day), clotiapine (40-60 mg/day), or fluphenazine decanoate (25-75 mg/month) for 14-18 months (group C). beta-EP and beta-LPH levels were assayed before and after each treatment. Haloperidol plasma levels were assayed in group B patients at the end of treatment. beta-EP mean basal levels were higher in patients than in controls; however, beta-LPH mean basal levels were higher only for group A patients. After treatment, the mean levels did not differ from those prior to therapy in groups A and B, while beta-LPH levels were significantly higher in group C. Level increases or decreases in single patients did not correlate with drug dose or duration of treatment, with baseline peptide levels or with the clinical effects of the various treatments.

Neuroendocrine effects of clonidine in chronic schizophrenic patients under long-term neuroleptic therapy and after drug withdrawal: relations to psychopathology.

The sensitivity of the alpha-adrenergic hypothalamic pituitary system, as indicated by growth hormone (GH) release after clonidine (0.15 mg i.v.), was studied in nine chronic schizophrenic in-patients (study 1) under long-term neuroleptic (NL) therapy and after 5 days' drug withdrawal and in 17 chronic schizophrenic in-patients (study 2) under long-term NL therapy and after 12 days' drug withdrawal. GH response after 5- and 12-day drug-free periods did not differ significantly from that under NL treatment; however, it was significantly lower after 12 days' drug withdrawal (AUC: 319.9 +/- 445.5 ng/ml X min) compared to age- and sex-matched normal controls (579 +/- 611 ng/ml X min). The basal norepinephrine (NE) plasma levels under long-term NL therapy were significantly elevated in both studies (study 1:894 +/- 553 pg/ml; study 2:432 +/- 268 pg/ml) compared to controls (study 1:253 +/- 55 pg/ml, study 2:234 +/- 126 pg/ml), and were decreased significantly after 5 days' drug withdrawal compared to NL treatment. There was no significant correlation between age, duration of NL therapy, last daily dosage, psychopathology, and NE plasma levels and GH response. The data presented suggest hyposensitivity of alpha-adrenergic receptor function in the hypothalamic-pituitary axis after 12 days' drug withdrawal in chronic schizophrenics. The significantly elevated NE plasma levels under NL therapy indicate that there is no adaption mechanism, even after long-term treatment.