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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 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) 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.

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.

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.

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 (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 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.

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 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.

The newcastle Endogenous Depression Diagnostic Index of Carney et al. was studied for reliability and validity. Good inter-rater reliability was obtained for diagnostic category and for item scores in 36 patients. The scale showed construct validity with reference to the Hamilton and Montgomery-Asberg rating scales. Concurrent validity was shown relative to other diagnostic scales of endogenous depression. Predictive validity was demonstrated in that endogenous and nonendogenous depressive responded differently to isocarboxazid. The continued use of 5 as the point of separation between endogenous and nonendogenous depression is questionable.

Trichotillomania may sometimes be an atypical variant of depressive illness. A case is reported in which the MAO inhibitor isocarboxazid was successfully used to treat both depression and associated trichotillomania. The symptoms recurred upon discontinuation of the drug and were ameliorated by reintroduction of isocarboxazid .

The authors report a case of grave orthostatic hypotension (Shy-Drager's syndrome) with major postural disturbances. The biological test confirmed a catecholaminergic deficiency. After several drugs were tried unsucessfully, an association of L-Dopa and fractionated doses of mono-amine-oxydase inhibitor was proposed. The increase blood pressure was sufficient to block the diturbances of postural adaptation, without inducing hypertensive jerks. The functionnal result have been stable for three years, while the parkinsonian syndrome have shown little progression.

Double-blind, placebo-controlled trials have documented the efficacy of some monoamine oxidase (MAO) inhibitors in treating certain depressed patients. This preliminary report of a 6-week, double-blind, placebo-controlled study of the MAO inhibitor isocarboxazid (Marplan) examines the time course of platelet MAO inhibition and treatment response, and describes symptoms that distinguish markedly improved from slightly improved responders. Thirty male outpatients, ages 28-64, randomly divided into placebo (n = 15) and active medication (n = 15) groups, were followed weekly. Medication was started at 20 mg daily and increased to achieve 90% platelet MAO inhibition. Data were analyzed for 24 patients who completed at least 3 weeks of the study. A clinician's global change rating at the study's conclusion showed that 12 of 13 patients (92%) in the active medication group improved, while 3 of 11 (27%) patients in the placebo group improved. Significant symptomatic improvement occurred in the active treatment group by week 3. Trends suggest that anxiety improved first (week 2), followed by depression (week 3), and finally cognitive outlook (week 6). Only minimal difficulties were observed with orthostatic hypotension, hypertensive crises, or other side effects. At baseline, the only significant difference between the markedly improved and slightly improved groups was greater psychomotor retardation in the markedly improved group. Trends suggest that the markedly improved group showed less depression, anxiety, sleep disturbance, and weight loss, fewer gastrointestinal complaints, and more helplessness and worthlessness.

The monoamine oxidase inhibitors are at present being used relatively infrequently in my opinion because of reports of severe and dangerous side effects such as toxic hepatocellular damage and hypertensive crises and also on account of several studies which have not given a very encouraging picture regarding the efficacy of this group of drugs. The purpose of this article is to demonstrate that this group of antidepressant drugs is very useful when the proper indications for their employment are observed and are relatively safe provided that appropriate precautions such as the avoidance of cheese and other foods high in tyramine content are taken by the patients being treated with these compounds. The history, pharmacology, side effects, and indications for their use are reviewed, and it is indicated that the MAO inhibitors are the therapeutic agents of choice in atypical depressions associated with anxiety, phobic and hysterical symptoms, and depressive illnesses (including endogenous depressions) which have failed to respond satisfactorily to tricyclic antidepressants. It is then demonstrated both from a review of the literature relating to these drugs and also from my own clinical experience that these compounds are very effective when used in the treatment of the psychiatric conditions for which they are indicated and are also relatively safe when the appropriate precautions are conscienciously observed.

In a fixed-dose inpatient study, isocarboxazid produced a dose-related lowering of systolic blood pressure at weeks 2 and 4. Systolic blood pressure was also lowered by the drug in a placebo-controlled outpatient study. The magnitude of these reductions was considerable, reaching an average of 14.6 mm in inpatients who received a 50-mg dose, and 18.7 mm in outpatients. There was no evidence for a dose-related orthostatic effect, and greater orthostasis relative to placebo was found only at week 3 in the outpatient study. Significant bradycardia was produced by isocarboxazid in outpatients at weeks 2, 3, and 4 relative to placebo, but no dose-related effect was found among inpatients. Inpatients with a baseline systolic orthostatic drop of greater than or equal to 10 mm showed a significantly better response to isocarboxazid than did those with an orthostasis of less than 10 mm. The theoretical significance of these findings is discussed.

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.

Appetite, weight, and preference for carbohydrate-containing food were followed in patients treated in double-blind trials of seven antidepressant regimes. Trimipramine and isocarboxazid combined had a significant effect in increasing appetite, carbohydrate preference, and weight; in patients who had lost appetite at presentation and were on this treatment, improvement in Hamilton score was linked to increase in weight--a finding not true of the other treatments.

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.

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.

Fifteen patients with a variety of myoclonic syndromes were studied clinically, pharmacologically, and physiologically. CSF tryptophan, 5HIAA, and HVA were also measured. Of these patients, 8 were improved to varying degrees by therapy with 5HTP, tryptophan in combination with MAOI (but not tryptophan alone), and clonazepam. This group included 6 cases of post-anoxic myoclonus, one case of post-traumatic myoclonus and one undiagnosed case of non-progressive focal myoclonus and epilepsy. In this group low levels of CSF 5HIAA were found compared to non-responsive cases and controls. Two cases of dysynergia cerebellaris myoclonica, 2 cases of undiagnosed aetiology, 2 cases of essential myoclonus, and one case of palatal myoclonus failed to respond to drug therapy. However, even amongst the responsive group the improvement varied. The most dramatic responses were seen in those patients in whom physiological study suggested that myoclonus was mediated by brain-stem structures. Less dramatic responses were seen in patients in whom the myoclonus appeared to originate from cortical structures. The neurochemical basis of myoclonus responding to 5HT precursors and clonazepam is discussed. It is suggested that such myoclonus arises from a relative hypoactivity of the 5HT neuronal system which results in a release of abnormal responses to sensory stimuli which characterize this type of myoclonus.

In a double-blind study, isocarboxazid was found to have greater efficacy than placebo. Patients with weight gain, increased appetite, and increased sleep responded particularly well, with a rapid onset of improvement that was apparent by one week. Their response to placebo was poor. Using a flexible dose, the modal range was 30-60 mg per day. Higher doses were poorly tolerated. At the doses used, side effects were generally mild, the most common being dizziness and myoclonus.

The author reports on studies of the comparative efficacy of ECT, the newer psychotropic drugs, and combinations of both in the treatment of depression and schizophrenia. He concludes that ECT is indicated for acutely suicidal and other severely impaired depressive patients but not necessarily for schizophrenic patients, although ECT has been successful with some schizophrenic patients for whom drugs were ineffective.

In an open prospective clinical study, 14 female outpatients with anorexia nervosa or bulimia completed a 6-week trial of isocarboxazid, with a mean dose of 34 mg. The eight bulimic and six restrictive anorexic subjects did not show any significant differences in medication response. Ratings of depression and anxiety showed significant improvement after the fourth week. Significant improvement in eating behavior, as measured by the number of meals missed per day, was noted. For the bulimic subgroup, bingeing and vomiting showed a nonsignificant reduction, while the urge to binge was significantly reduced. There was no significant weight change in either group during the study, although the restrictive group had gained substantially at 6-month follow-up.

The Montgomery-Asberg Depression Scale was evaluated in 44 depressed inpatients. All items of the scale occurred frequently in the sample; the scale exhibited construct validity (internal homogeneity) and concurrent validity relative to the Hamilton Depression Scale and the concepts of endogenous and nonendogenous depression. Sleep disturbance, reduced appetite, and suicidal thoughts, correlated poorly with the remainder of the scale. Reasons for this finding are discussed. Inter-rater reliability was demonstrated between a psychiatrist and a nurse on individual item and total scale scores.

In a 6-week, double-blind study outpatients diagnosed as suffering from atypical depression were treated with either isocarboxazid or placebo. Selection criteria were purposely broad so as to capture the entire range of patients so diagnosed. Patients were then subclassified along several symptomatic, syndromal, phenomenological, and diagnostic categories in order to identify clinical characteristics specifically responsive to isocarboxazid. Although isocarboxazid was clearly superior to placebo for the overall group of atypical depressives, the authors were by and large unable to identify subgroups specifically responsive to the monoamine oxidase inhibitor. A few factors correlated with better response to both isocarboxazid and placebo: no family history of alcoholism or sociopathy, lack of self-pity, and not meeting Research Diagnostic Criteria for major depressive disorder. The single item that was associated with a statistically significant advantage of isocarboxazid over placebo was loss of anticipatory pleasure. Clinical implications and suggestions for further research are discussed.

CSF 5-HT and 5-HIAA were measured in endogenously depressed patients (ICD-9) (n = 23) and controls (n = 11). Distribution of sex, age and body height was similar in the two groups. Non-parametric statistics were used. In depressed patients CSF 5-HT concentrations were found to be higher (P less than or equal to 0.01) than in controls. A further classification of the depressed patients by the Newcastle Scale showed that the highest values were found in the endogenous group compared to the non-endogenous group (P less than or equal to 0.02). CSF 5-HIAA was found to be equal in the two groups, even when pairs matched for height were compared. No relation between clinical recovery due to drug treatment and changes in CSF 5-HT was seen. Our data support a possible involvement of 5-HT in the biology of depression, but the anatomical and functional levels of a serotonin derangement are still unknown.

Three definitions of atypical depression are evaluated with respect to the effects of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) on the basis of pooled data from several double-blind studies. Those three definitions of atypical depression are depression with associated panic, depression secondary to a diagnosis of anxiety, and depression with reversed vegetative change. In none of these forms was a drug difference observed. However, when gender was taken into account, MAOIs were superior to TCAs in depressed women with panic attacks, whereas TCAs were superior to MAOIs in depressed men with panic attacks.

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.

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.

Isocarboxazide has been used as long-term treatment for a selected group of 20 depressive patients, of whom some 90% (17/19) were non-responders to treatment with tricyclic antidepressants. At the follow-up the median duration of illness was 162 months, and the median duration of treatment was 42 months. Side-effects and interactions were moderate thus legitimating a treatment procedure on which all the patients of the material responded better than on any other antidepressive treatment. Treatment with monoamine-oxidase-inhibitors, like isocarboxazide, should not be left untried in the case of therapy-resistant 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.

This paper reports combined antidepressant treatment with isocarboxazid /mianserin in 60 patients with endogenous depression/melancholia. The combination was used as the first drug treatment choice in 33 cases. Thirty-two patients obtained complete remission and one responded only incompletely. The depression improved after a few days' treatment, and full recovery was obtained after approximately 2 weeks. There were no serious side-effects or interactions, but weight gain was a common problem.

Of 50 outpatients with nonpsychotic, nonmelancholic, anxious depression, the 24 patients taking isocarboxazid had better scores on all outcome measures than the 26 patients taking placebo. Differences on several variables reached statistical significance by weeks 4-6.

The response to the MAOI isocarboxazid was investigated in a two-phase protocol. Phase 1 was a double-blind, placebo-controlled study; Phase 2 was an open active medication trial for Phase 1 placebo patients who still met symptom criteria. In Phase 1, 60 male outpatients were randomly divided into placebo or active medication groups. Mean platelet MAO inhibition was 86% by Week 1, while significant symptomatic improvement was not seen until Week 3. In Phase 2, 16 of the symptomatic placebo patients were given an open trial on isocarboxazid; thus, 43 patients received a trial of active medication. Separation of responders (N = 26) from nonresponders (N = 17) by discriminant function analysis using 3 entry variables (platelet MAO activity, standing diastolic blood pressure, and psychomotor irregularity) accounted for 28% of the variance, with correct classification of 32 of the 43 patients.

This study was aimed at the assessment of therapeutic and side effects of simultaneous administration of tricyclic antidepressants and MAOI. The sample consisted of 122 patients with depressive syndromes, treated at the "Centro de Psicología Médica San Martín de Tours" (period 1970/1973), with Isocarboxazide and Trimiprimine. All patients received both drugs three times a day. The average daily dose was 20 mg of Isocarboxazide together with 125 mg of Trimiprimine. The average treatment was 70 days long. The study lead to the following conclusions: 1. There were no serious side effects. 2. The scarce side effects registered were not very different from those of the other anti-depressants. 3. The therapeutic doses were lower than those required when each drug is used alone. 4. The speed of action was higher than for each drug separately. 5. The overall percentage of improvement in patients was higher than the percentage obtained for each drug alone. 6. The lack of side effects for a theoretically risky combination of drugs is likely to be attributed to the neuroleptic action of Trimipramine.

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.