Anticholinergic medication for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with serious mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many people treated with antipsychotic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects. However, there is also a suggestion from animal experiments that the chronic administration of anticholinergics could cause tardive dyskinesia. OBJECTIVES: To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol, benztropine, biperiden, orphenadrine, procyclidine, scopolamine, or trihexylphenidyl) are clinically effective for the treatment of people with both antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illnesses. SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (16 July 2015 and 26 April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports identified in the search if they were controlled trials dealing with people with antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illness who had been randomly allocated to (a) anticholinergic medication versus placebo (or no intervention), (b) anticholinergic medication versus any other intervention for the treatment of tardive dyskinesia, or (c) withdrawal of anticholinergic medication versus continuation of anticholinergic medication. DATA COLLECTION AND ANALYSIS: We independently extracted data from included trials and we estimated risk ratios (RR) with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The previous version of this review included no trials. We identified two trials that could be included from the 2015 and 2017 searches. They randomised 30 in- and outpatients with schizophrenia in the USA and Germany. Overall, the risk of bias was unclear, mainly due to poor reporting: allocation concealment was not described; generation of the sequence was not explicit; studies were not clearly blinded; and outcome data were not fully reported.Findings were sparse. One study reported on the primary outcomes and found that significantly more participants allocated to procyclidine (anticholinergic) had not improved to a clinically important extent compared with those allocated to isocarboxazid (MAO-inhibitor) after 40 weeks' treatment (1 RCT, n = 20; RR 4.20, 95% CI 1.40 to 12.58; very low quality evidence); that there was no evidence of a difference in the incidence of any adverse effects (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence); or acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence). The other trial compared anticholinergic withdrawal with anticholinergic continuation and found no evidence of a difference in the incidence of acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 10; RR 2.14, 95% CI 0.11 to 42.52; very low quality evidence).No trials reported on social confidence, social inclusion, social networks, or personalised quality of life - outcomes designated important to patients. No studies comparing either i. anticholinergics with placebo or no treatment, or ii. studies of anticholinergic withdrawal, were found that reported on the primary outcome 'no clinically important improvement in TD symptoms and adverse events'. AUTHORS' CONCLUSIONS: Based on currently available evidence, no confident statement can be made about the effectiveness of anticholinergics to treat people with antipsychotic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with antipsychotic-induced TD should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow-up.

[The use of the monoamine oxidase inhibitor isocarboxazide in treatment-resistant depression]. / Anvendelse af monoaminooksidasehæmmeren isocarboxazid ved behandlingsresistent depression

The antidepressant efficacy of isocarboxazide is well established; however, the clinical use early became restricted and today the use of isocarboxazide in Denmark is very limited. Isocarboxazide is safe when keeping a low tyramine-containing diet and avoiding concomitant treatment with certain drugs. The risk of developing oedema can be reduced by vitamin B6 treatment. Normal dosage isocarboxazide may be prescribed for all patients because isocarboxazide is not metabolized through the CYP2D6 enzyme complex like most other antidepressants. It is recommended to include isocarboxazide in the official treatment algorithms for patients who are resistant to conventional antidepressant therapy and electroconvulsive therapy.

The Major Depression Rating Scale (MDS). Inter-rater reliability and validity across different settings in randomized moclobemide trials. Danish University Antidepressant Group.

The Major Depression Rating Scale (MDS) has been derived from the Hamilton Depression Scale and the Melancholia Scale. The MDS contains the nine DSM-IV items for major depression which all have anchoring scores from 0 to 4; hence, the theoretical score range is up to 36. The Major Depression Rating Scale has in this study been psychometrically analysed in randomized moclobemide trials. The results showed that the MDS had higher internal validity than the Hamilton Depression Scale. Thus, the homogeneity of the items was higher; factor analysis identified only one general depression factor (after 4 weeks of treatment explaining more than 50% of the variance). The inter-rater reliability of the two scales was of the same high level. The ability to measure changes (external validity) was tested in randomized clinical trials with moclobemide versus tricyclics (clomipramine and notriptyline) performed in Denmark in the psychiatric setting as well as in the general practice. The results showed that in the psychiatric setting tricyclics were superior to moclobemide with effect sizes ranging between 0.43 and 0.53. The highest effect size was obtained with the Melancholia Scale and the Major Depression Rating Scale, while the Hamilton Depression Scale was below 0.50. In the general practice setting no difference was found between moclobemide and clomipramine. In conclusion, the Major Depression Rating Scale has been found to have a more homogeneous factor structure than the Hamilton Depression Scale, but still with the same level of reliability and external validity. However, studies are needed to standardize the scale, especially in the general practice setting.

A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination.

Treatment-resistant depression is a clinical complication that not infrequently affects a certain number of patients. Within the treatment strategies proposed for this condition, the association of a MAO inhibitor (MAOI) with a tricyclic antidepressant has gained reputation both for its unusual efficacy, as for its potential toxicity. However, when cautions are taken, it may be safely administered. Most reports on this combination have been carried in nonresistant patients and, when resistant patients are included, only the acute phase of the treatment is reported. In this study, a group of well-defined resistant patients received an open trial with the association of isocarboxazide and amitryptiline (n = 25). Those who responded were followed during the next 3 years (n = 12) and every 6 months an attempt was made to discontinue the MAOI and continue only with amitryptiline. At the end of the study, 4 patients maintained response with single medication, 6 still required both drugs and 2 relapsed. No clinical differences were apparent between the outcome groups, except that those who maintained their response only with the 2 combined drugs had more previous depressive episodes than the others. The isocarboxazide/amitryptiline combination may be a good treatment option for at least some forms of resistant depression. The safety of this treatment modality is confirmed, even when given for long periods of time. The study also suggest that there are no clinical characteristics in resistant depression that may predict the treatment outcome but, perhaps in some patients, a combined treatment is required to obtain a broader biochemical effect that could convert them from nonresponders to responders.

MAOIs in the contemporary treatment of depression.

We review the literature on the effectiveness of the monoamine oxidase inhibitors (MAOIs) and present metaanalyses of controlled trials comparing the FDA-approved MAOIs with both placebo and comparator tricyclic antidepressants. For outpatients, metaanalyses with intent-to-treat samples revealed generally comparable overall efficacy for phenelzine, isocarboxazid, and tranylcypromine. Drug-placebo differences were 29.5% (+/- 11.1%) (phenelzine; nine studies), 41.3% (+/- 18.0%) (isocarboxazid; three studies), and 22.1% (+/- 25.4%) (tranylcypromine; three studies). For inpatients, phenelzine was 22.3% (+/- 30.7%) (five studies) more effective than placebo, whereas the isocarboxazid-placebo difference was lower (15.3%) (+/- 12.6%). Both phenelzine and isocarboxazid were significantly less effective than comparator tricyclics for inpatients, whereas tranylcypromine has not been adequately studied. Both phenelzine and tranylcypromine appear to be more effective than tricyclics in depressed outpatients with atypical features. Monoamine oxidase inhibitors are also effective treatments for outpatients who have failed to respond to tricyclic antidepressants. Our review also suggests (1) the FDA-approved MAOIs treat a somewhat different group of patients than tricyclics; (2) more severely depressed inpatients may not respond as well to MAOIs as to tricyclics; and (3) because of preferential MAOI responsivity, atypical or anergic depressions may be biologically different than classical depressions.

Serotonin syndrome.

We describe a patient treated with trazodone, isocarboxazid, and methylphenidate hydrochloride who developed confusion, agitation, poor concentration, rigidity, myoclonus, involuntary movements, orthostatic hypotension, and hyperreflexia. CK was normal, and the syndrome resolved spontaneously over 12 hours. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4-methylenedioxy-methamphetamine, dextromethorphan, meperidine, S-adenosylmethionine) alone or in combination with monoamine oxidase inhibitors. It is characterized by various combinations of myoclonus, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, autonomic instability, low-grade fever, nausea, diarrhea, diaphoresis, flushing, and rarely, rhabdomyolysis and death.

Pathologic hair-pulling: a review of the literature and case reports.

Pathologic hair-pulling (trichotillomania) has been described in the dermatologic and psychiatric literature for the last century, but has become the focus of increased attention in the last few years. Once thought to be either a wholly benign condition or a symptom of obsessive-compulsive disorder, more recently hair-pulling has been noted in the context of numerous types of psychopathology, and has been reported to respond to several different types of intervention, both psychological and somatic. Estimates of its prevalence have varied widely. Because of the disparate conclusions of the literature on this condition, a more careful assessment of diagnostic validity is recommended.

Moclobemide in depression: a randomized, multicentre trial against isocarboxazide and clomipramine emphasizing atypical depression.

Moclobemide was compared with isocarboxazide and clomipramine in patients with depression. A total of 167 outpatients were allocated to daily treatment with 300 mg moclobemide, 30 mg isocarboxazide or 150 mg clomipramine for 6 weeks. Moclobemide was slightly inferior to clomipramine, whereas isocarboxazide had an intermediate position. There was no interaction between treatment and atypical or nonatypical depression. Anticholinergic symptoms and orthostatic hypotension were most pronounced in the clomipramine group.

Predictors of response to monoamine oxidase inhibitors: do they exist?

Multiple regression analysis was conducted on potential response predictors in a double-blind study of monoamine oxidase inhibitors (MAOI) and placebo treatment in 130 depressed outpatients. Positive main effects were found for sex (female), lack of prior hospitalization, presence of precipitating events. A negative main effect was found for concurrent physical illness. Treatment x predictor effects were found for distinct quality and non-reactivity. Non-reactivity was associated with positive outcome in the active drug group, but with negative outcome in the placebo group [corrected]. Distinct quality demonstrated a more complex effect, its presence being associated with decreased improvement in the treatment group and greater improvement in the control group. No atypical depressive symptoms predicted MAOI response, and we were unable to characterize a specifically responsive MAOI syndrome.

Anorexia nervosa in the elderly: a case report and review of the literature.

Anorexia nervosa is a rare disorder in the elderly but should be thought of in the differential diagnosis of extreme weight loss, especially if there are accompanying psychological features and normal baseline investigations. Psychiatric opinion should be obtained and treatment, although of unproven value, considered, since improvement may increase mobility and reduce morbidity and mortality.

Classification of depression by grade of membership: a confirmation study.

One hundred and thirty out-patients with depression were studied by grade of membership multivariate (GOM) analysis. Five depressive types were generated. Pure Type I represented a mild form of melancholia in older, stable males, who showed a modest drug response. Pure Type II included obsessive-anxious symptoms in older patients who responded well to an MAOI drug, but poorly to placebo. Pure Type III was a mildly symptomatic form of depression which responded well to placebo. Pure Type IV included features of agitation, mood worsening later in the day, anorexia and depersonalization; it was commonly precipitated by external stress and MAOI treatment was more effective than placebo. In Pure Type V depression, patients were mostly younger females with high levels of symptomatology, atypical vegetative symptoms, unstable life-styles, disadvantaged backgrounds and a poor response to MAOI and placebo. These results resemble in many ways our earlier GOM study of depression, as well as other multivariate studies of depression in the literature.

Symptoms of interpersonal sensitivity in depression.

Six self-rated items of interpersonal sensitivity (IPS) were examined in 174 depressed outpatients. These items were "feeling critical of others," "your feelings being easily hurt," "feeling others do not understand you or are unsympathetic," "feeling others are unfriendly," "feeling inferior to others," "feeling shy or uneasy with the opposite sex." The population was grouped into tertiles based on their pretreatment IPS score. High levels of IPS were associated with earlier onset and greater chronicity of depression, higher Hamilton Rating Scale for Depression (HRSD) score, more severe depressed mood, guilt, suicidality, impaired work and interest, retardation, depersonalization, paranoia, and cognitive symptoms of depression. More frequent atypical features were found, e.g., overeating/weight gain, self-pity, phobic avoidance, and panic attacks. Response to a monoamine oxidase (MAO) inhibitor drug increased at higher levels of IPS, while the response to a placebo decreased.

A trial of isocarboxazid in the treatment of bulimia nervosa.

Eighteen women completed a double-blind, placebo-controlled crossover study designed to investigate the effects of isocarboxazid in the treatment of bulimia nervosa. There was a significant reduction in binge eating and vomiting during isocarboxazid treatment. Response was not influenced by either the presence or absence of current major depression or personality disorder. There were no serious adverse effects from this monoamine oxidase inhibitor therapy, although over 50% of patients elected to discontinue isocarboxazid 1 year after the study.

The response of depressed inpatients to isocarboxazid.

Fifty-six inpatients with unipolar depression completed treatment with isocarboxazid. In comparing the differences between responders and nonresponders, it was found that psychomotor retardation, pathological guilt, daily persistence of unremitting symptoms, phobic anxiety, dexamethasone suppression test nonsuppression, and neuroticism were significantly more common among nonresponders. Reactivity of mood, blaming others, and extraversion were more common in responders. Total endogenous depression scores on the Newcastle 1, Newcastle 2, and Michigan scales were also significantly higher in nonresponders. Attained platelet monoamine oxidase inhibition was similar in both groups.

MAOI treatment response: multiaxial assessment.

While studying the effectiveness of the MAOI isocarboxazid for the treatment of depression, we noted that many patients experienced a reduction of symptoms without equivalent improvement in other areas of their lives. We evaluated four outcome areas: symptoms, work, family functioning and social functioning. After 6 weeks on medication, symptoms improved the most, significantly more so than the other three areas. For the group of patients who completed 24 weeks on medication, all four outcome areas were further improved compared to the 6-week levels, with the improvement in work functioning reaching statistical significance. We conclude that the assessment of treatment outcome is more complex than the simple measurement of symptom reduction, and that different outcome areas are likely to improve at different rates and to different extents.

An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology.

Isocarboxazid and placebo were evaluated in 130 anxious depressives. Drug was superior to placebo on depression, anxiety, interpersonal sensitivity, and global measures, and on symptoms of hostility, anxiety, obsessiveness, and psychological-cognitive components of depression. There were no significant differences between treatment effects on psychomotor and typical vegetative symptoms. Isocarboxazid was more effective than placebo in major, but not in minor, depression. It was significantly more effective in depression classified as endogenous depression or melancholia by various diagnostic criteria. Drug was more effective than placebo in atypical depression with vegetative reversal and in Brief Psychiatric Rating Scale (BPRS)-derived profiles of anxious and hostile depression; there were no drug-placebo differences in atypical depression without vegetative reversal, or in BPRS retarded and agitated/excited depression. Interpersonal sensitivity emerged as an important drug-responsive dimension.

A comparative evaluation of three discriminant scales for endogenous depression.

Three discriminant scales for diagnosing endogenous depression were examined in 56 depressed inpatients. These scales were the Newcastle 1 (N1), Newcastle 2 (N2), and Michigan Index (MI). The scales agreed on diagnosis in 17 (30%) patients; respective frequencies of endogenous depression were 23%, 57%, and 78% for the N2, N1, and MI scales. Relationships were examined between treatment response to isocarboxazid, drug dose, and diagnostic type for each scale. Significant dose X diagnosis interactions were noted for N1 and N2, but not for MI. A correlational within-dose analysis of all three scales revealed that actual diagnostic score was related to outcome only for high-dose patients on the Newcastle-1 scale; no other significant correlations emerged.