LIST REFERENCES LIST REFERENCES A) ANTIDEPRESSANT... 4256 H) *SUM FG 38592 B) ANTIDEPRESSIVE AGENTS 8273 I) *ON E&H 95 C) ANTIDEPRESSIVE AGEN... 3098 J) ABSTRACT ONLINE 2640208 D) MONOAMINE OXIDASE I... 4464 K) *ON I&J 47 E) *SUM ABCD 20091 L) DEPRESSION 27793 F) RESISTANCE 27119 M) *ON G&J&L 33 G) DRUG RESISTANCE 11473 *** *** *****AMERICAN JOURNAL OF PSYCHIATRY***** (REFERENCE 1 OF 45) 81157679 Paul SM Extein I Calil HM Potter WZ Chodoff P Goodwin FK Use of ECT with treatment-resistant depressed patients at the National Institute of Mental Health. Am J Psychiatry 1981 Apr;138(4):486-9 The authors review the use of ECT with nine seriously depressed patients at the National Institute of Mental Health over the past 8 years. Despite the patients' poor prior response to a variety of pharmacological treatments, only one patient failed to show a complete response to ECT. With most patients, improvement was quite rapid and dramatic, and all of the ECT responders were free of depression for at least 1 year after treatment. These results are consistent with previous studies; they deserve reemphasis now in light of recent controversies over ECT, including legislative and judicial attempts to restrict its use. (REFERENCE 2 OF 45) 86266099 Garbutt JC Mayo JP Jr Gillette GM Little KY Mason GA Lithium potentiation of tricyclic antidepressants following lack of T3 potentiation. Am J Psychiatry 1986 Aug;143(8):1038-9 Four patients whose depressions were failing to respond to administration of tricyclic antidepressants were given separate trials of T3 and lithium. In all four cases, T3 failed to potentiate the antidepressant, whereas the lithium did. *****BRITISH JOURNAL OF PSYCHIATRY***** (REFERENCE 3 OF 45) 82001235 De Montigny C Grunberg F Mayer A Deschenes JP Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry 1981 Mar;138:252-6 Eight patients suffering from a major unipolar depression and having field to respond to treatment for three weeks or more with tricyclic antidepressants were given lithium. All eight patients experienced a remarkable relief of their depression within 48 hours. This rapid antidepressant effect of lithium in "treatment-resistant' patients might be due to the enhancement of the efficacy of the central serotoninergic system, unveiling the tricyclic antidepressant-induced sensitization of the serotoninergic postsynaptic receptors. (REFERENCE 4 OF 45) 88078682 Hale AS Procter AW Bridges PK Clomipramine, tryptophan and lithium in combination for resistant endogenous depression: seven case studies. Br J Psychiatry 1987 Aug;151:213-7 Seven patients suffering from severe endogenous depression who had proven resistant to lengthy trials of treatment with tricyclic and other antidepressants are described. Their successful treatment with a combination of clomipramine, L-tryptophan and lithium is discussed in the context of other strategies for the treatment of resistant depression. Institutional address: Brook General Hospital London. (REFERENCE 5 OF 45) 86052100 Nolen WA van de Putte JJ Dijken WA Kamp JS L-5HTP in depression resistant to re-uptake inhibitors. An open comparative study with tranylcypromine. Br J Psychiatry 1985 Jul;147:16-22 L-5HTP and tranylcypromine were compared in an open, but controlled and cross-over study, in patients suffering from major depression; all were non-responders to several reuptake inhibitors, including oxaprotiline and fluvoxamine. After four unsuccessful sleep- deprivations, L-5HTP or tranylcypromine were given during four weeks in a crossover design. Of 17 patients given L-5HTP during both treatment periods, none responded, whereas of 26 patients treated with tranylcypromine, 15 responded. Thus, L-5HTP is not a therapeutically effective alternative in depressed patients who have not responded to reuptake inhibitors. *****JOURNAL OF THE AMERICAN GERIATRICS SOCIETY***** (REFERENCE 6 OF 45) 86141387 Borson S Raskind M Antidepressant-resistant depression in the elderly [editorial] J Am Geriatr Soc 1986 Mar;34(3):245-7 [No Abstract Available] *****JOURNAL OF CLINICAL PSYCHIATRY***** (REFERENCE 7 OF 45) 78129956 Ananth J Pecknold JC Prediction of lithium response in affective disorders. J Clin Psychiatry 1978 Feb;39(2):95-100 Lithium carbonate has established itself as an effective therapeutic agent in primary affective disorders. As not all the patients with primary ffective disorders respond to lithium therapy, it is necessary to identify responders prior to treatment. The important indicators of favourable lithium response include a definitive diagnosis of primary affective disorder, occurrence of less than four episodes of mania and depression within one year, psychotic features during both manic as well as depressive episodes, "grandiose-elated" picture during manic episodes; a family history of bipolar illness and response of affected family members to lithium treatment. While those with more than four episodes are not likely to respond to lithium therapy, those with episodes less frequent than once a year or two may not need prophylactic lithium. Among the depressed, hypersomnic depressed patients respond to lithium combined with a monoamine oxidase inhibitor. In addition to clinical predictors of response to lithium treatment, there are a number of pharmacokinetic, neurophysiological and biochemical indices which have been employed as supplementary predictors of response to lithium therapy. (REFERENCE 8 OF 45) 86008109 Lydiard RB Tricyclic-resistant depression: treatment resistance or inadequate treatment? J Clin Psychiatry 1985 Oct;46(10):412-7 The apparent resistance to tricyclic antidepressant treatment of many depressed patients often may be a result of an inadequate therapeutic trial. Several potentially important variables which may contribute to apparent treatment resistance are discussed, including interpatient pharmacokinetic variability, noncompliance, and inadequate duration of treatment. The current status of the relationship of clinical response and plasma levels of tricyclics and the use of therapeutic blood monitoring to reduce the failure rate in tricyclic antidepressant treatment are also discussed. *****LANCET***** (REFERENCE 9 OF 45) 79155677 Schlesser MA Winokur G Sherman BM Genetic subtypes of unipolar primary depressive illness distinguished by hypothalamic-pituitary-adrenal axis activity. Lancet 1979 Apr 7;1(8119):739-41 Serum-cortisol response to the 1 mg overnight dexamethasone suppression test was investigated in 86 patients with unipolar primary depressive illness and 80 non-depressed controls (45 with mania and 35 with schizophrenia). The depressed patients were assigned to one of three genetic subtypes according to the family psychiatric history. Resistance to suppression of serum-cortisol by dexamethasone was found in 37 of 86 (43%) depressives and none of the 80 controls. Non-suppression distinguished the three genetic subtypes of depression, being found in 23 of 28 (82%) patients with familial pure depressive disease (F.P.D.D.), 13 of 35 (37%) patients with sporadic depressive disease (S.D.D.), and 1 of 23 (4%) patients with depression spectrum disease (D.S.D.). The three genetic subtypes were further distinguished by the age of onset, with S.D.D. the oldest, and by the number of previous depressive episodes, with F.P.D.D. the most. Severity of depression did not separate the three subtypes. This is the first report of a distinct neuroendocrine abnormality which supports an objectively defined classification of unipolar primary depressive illness. It is suggested that unipolar primary depressive illness is three or more separate illnesses, each with a potentially distinctive mode of inheritance, pathophysiology, neurochemistry, clinical course, and treatment response. (REFERENCE 10 OF 45) 78198550 Robinson DS Nies A Antidepressant drug levels and clinical response [letter] Lancet 1978 Jul 8;2(8080):100 [No Abstract Available] *****MEDICAL CLINICS OF NORTH AMERICA***** (REFERENCE 11 OF 45) 88231905 Laage TA Recognizing the drug-resistant patient in anxiety and depression. Med Clin North Am 1988 Jul;72(4):897-909 The number and variety of anxiolytic and antidepressant medications available to the modern clinician lend an unparalleled efficacy to the outpatient treatment of anxiety disorders and depression. Where diagnosis is precise and complicating organic factors have been excluded, true treatment resistance in either anxiety disorders or depression is rare. Proper patient education to assist compliance, adequate dosage of individual agents, patience to give the medication time to work, overcoming the reluctance to attribute the patient's problem to a medically treatable disorder rather than to moral or characterologic defect, and the flexibility to shift to other or to additional medications on encountering initial treatment resistance are the keystones to the successful management of more than 90 per cent of all cases. Institutional address: Harvard Medical School Boston Massachusetts. *****MEDICAL JOURNAL OF AUSTRALIA***** (REFERENCE 12 OF 45) 80077465 Urinary MHPG: improved tricyclic antidepressant drug selection in clinical practice [editorial] Med J Aust 1979 Sep 8;2(5):233-4 [No Abstract Available] *** *** *****ACTIVITAS NERVOSA SUPERIOR***** (REFERENCE 13 OF 45) 75105787 Lapin IP Proceedings: Antagonism of nicotinic acid and other kynurenines to antidepressants: one of the probable reasons of the therapy- resistance in depression? Act Nerv Super (Praha) 1974;16(4):260-1 [No Abstract Available] *****ACTAS LUSO-ESPANOLAS DE NEUROLOGIA, PSIQUIATRIA Y CIENCIAS AFINES***** (REFERENCE 14 OF 45) 90022768 Lopez-Ibor Alino JJ Chinchilla A Vega M Sanchez P Camarero M Jorda L Vinas R Moreno I [Refractory depression: therapeutic alternatives] Depresiones resistentes: alternativas terapeuticas. Actas Luso Esp Neurol Psiquiatr Cienc Afines 1989 Jul-Aug;17(4):223-30 (Published in Spanish) A group of 89 patients admitted to the Psychiatric Unit of a General Hospital, with diagnosis of depression according to ICD-9 criteria and randomly chosen were studied. 26 of them (29.2%) were resistant depressions and 63 (7.82%) responded to treatment. Both groups were composed retrospectively in order to analyse resistance or lack of response to a first treatment with tricyclic or tetracyclic antidepressants in effective dosages. We considered: the personality type; the associated somatic pathology; prolonged social stress; period of evolution of the disorder; previous treatments; type of disorder uni or bipolar; familial morbidity; diagnosis reconsideration; analysis of therapeutic compliance; side effects and intolerance. We observed a statistically significant difference with regard to prophylactic treatment (38.4% resistant versus 98.3% non- resistant, p less than 0.0001); a greater suspicion of psycho- organicity in the resistant group (p less than 0.05); a longer interval of time for the resistant group between the beginning of the disorder and the beginning of treatment in our service (F: 1.45, t: 2.58, p less than 0.01). The alternatives used with our patients are analysed and we propose schedules for tackling this kind of problem. *****ANNALES DE MEDECINE INTERNE***** (REFERENCE 15 OF 45) 87211511 Des Lauriers A Baruch P Vindreau C Jouvent R Widlocher D [Depressions resistant to tricyclic antidepressive treatment and hypothyroidism] Depressins resistant aux traitements antidepresseurs tricycliques et hypothyroidie. Ann Med Interne (Paris) 1987;138(2):119-22 (Published in French) The relationship between thyroid disorders and depression is well known. This type of endocrine disease is mainly observed in patients with depression resistant to appropriate antidepressor therapy. Three clinical forms of this association may be distinguished: hypothyroidism in a patient with depression but without a previous psychiatric history; a relapse of depression in a manico depressive patient who has developed hypothyroidism; the finding of slight thyroid dysfunction (increased TSH response after injection of TRH) in a patient with depression. The frequency of the association of hypothyroidism and resistant depression underlines the need to perform thyroid function tests in all depressed patients who do not respond normally to appropriate antidepressor therapy. The precise mechanism of the resistance of depressive symptoms to tricyclic antidepressors is unclear. Several arguments point to an effect of triiodothyronine on central noradrenergic receptors. In practice, significant hypothyroidism implies substitute therapy. Minor thyroid dysfunction (abnormal TRH test alone) may require the association of tricyclic antidepressors and thyroid hormone although the indications and precise dosages of this drug association have not been established. *****ANNALES MEDICO-PSYCHOLOGIQUES***** (REFERENCE 16 OF 45) 77264981 Oules J [Drug-resistant depressive states] Les etats depressifs chimioresistants. Ann Med Psychol (Paris) 1977 Mar;1(3):463-6 (Published in French) [No Abstract Available] *****BIOLOGICAL PSYCHIATRY***** (REFERENCE 17 OF 45) 76161566 Deberdt R Van Hooren J Biesbrouck M Amery W Antinuclear factor-positive mental depression: a single disease entity? Biol Psychiatry 1976 Feb;11(1):69-74 Antinuclear factor (ANF) was present in the serum of about 30% of 53 patients newly admitted to the psychiatric hospital because of mental depression. Clinically, ANF-positive depression closely resembles manic-depressive psychosis but tends to be more resistant to treatment. It is suggested that ANF-positive depression may be a quite distinctive disease. (REFERENCE 18 OF 45) 86188034 Ries RK Wittkowsky AK Synergistic action of alprazolam with tranylcypromine in drug- resistant atypical depression with panic attacks. Biol Psychiatry 1986 May;21(5-6):522-6 [No Abstract Available] *****CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE***** (REFERENCE 19 OF 45) 85073946 Kwamie Y Persad E Stancer H The use of carbamazepine as an adjunctive medication in the treatment of affective disorders: a clinical report. Can J Psychiatry 1984 Nov;29(7):605-8 This is a report of an open clinical trial of Carbamazepine in the treatment of patients who suffered from affective disorders and who did not have an adequate response to Lithium or other medications. Our findings suggest that Carbamazepine can be a useful adjunctive medication when used in combination with Lithium and other psychotropic medications. The characteristics of the patients who responded were examined. The clinical state of the patients at the point of intervention varied; eight patients were manic and four patients were depressed. Four patients were judged to have had markedly effective responses, four showed an effective response and in four there was a slightly effective response. From the duration of the trials it was evident that in cases where Carbamazepine produced a good response its effect was seen as early as two weeks. The mean daily dose used varied from 300-1300 mgs. Because of the open nature of this trial, Carbamazepine was not withdrawn except in one instance. (REFERENCE 20 OF 45) 89106045 MacEwan GW Remick RA Treatment resistant depression: a clinical perspective [see comments] Can J Psychiatry 1988 Dec;33(9):788-92 One hundred and fourteen patients with a diagnosis of "treatment resistant depression" (TRD) were assessed and treated at a Mood Disorders Clinic. Diagnostically, 52 (45.6%) subjects met criteria for bipolar disorder, 49 (42.9%) for recurrent depression, and 13 (11.4%) patients did not fulfill diagnostic criteria for affective disorder which explained their treatment resistance. With appropriate, individualized treatment, 59 of 98 (60.2%) patients had complete symptom remission based on clinical and psychometric ratings (initial Ham-D 26.7, final Ham-D 5.9). Eighteen of 98 patients had partial remission (final Ham-D 15.9) with vigorous pharmacological interventions, and 8 subjects exhibited "absolute" TRD (final Ham-D 23.4). The results suggest the value of specialized mood disorder services. The partial and absolute TRD's were more likely to be older, received more Axis II diagnoses, and had previous histories of drug or alcohol abuse. Institutional address: Department of Psychiatry University of British Columbia Vancouver. *****CLINICAL NEUROPHARMACOLOGY***** (REFERENCE 21 OF 45) 91004097 Hermesh H Aizenberg D Munitz H Trazodone treatment in clomipramine-resistant obsessive-compulsive disorder. Clin Neuropharmacol 1990 Aug;13(4):322-8 Trazodone (TZ) was administered to nine patients suffering from obsessive-compulsive disorder (OCD), who failed to respond to either clomipramine (CMI) or to CMI plus lithium carbonate. The group, as a whole, showed significant but mild improvement. Three patients responded very favorably to TZ. In these three responders, efficacy was substantiated by the return of the original obsessive-compulsive (OC) symptoms following TZ withdrawal and their amelioration after its readministration. Interestingly, the aggravation of OCD symptomatology that has been associated with a specific TZ metabolite was not observed. This study is consistent with previous reports of the anti-OC efficacy of TZ and suggests the involvement of complex serotonergic mechanisms in the pathophysiology of this disorder. Institutional address: Gehah Psychiatric Hospital Beilinson Medical Center Petah Tikva Israel. (REFERENCE 22 OF 45) 90335840 Potter WZ Manji HK Antidepressants, metabolites, and apparent drug resistance. Clin Neuropharmacol 1990;13 Suppl 1:S45-53 Antidepressant drugs are extensively metabolized prior to elimination from the body. These metabolites usually have biological and chemical properties different from those of the parent drug. This article explores the pharmacodynamic consequences of such metabolism as possibly contributing to failure to respond to or tolerate a drug. Differential side effects, especially of tricyclic antidepressant metabolites, are considered. Next, shifts in effects of presumed serotonin uptake inhibitors are described. Problems involving active metabolites of more novel compounds such as bupropion, amoxapine and trazodone range from possible reversal of response to prohibitive side effects. Finally, principles are deduced for identifying those cases in which metabolic consideratios are most likely to be relevant to observed drug resistance. Institutional address: Section on Clinical Pharmacology National Institute of Mental Health Bethesda MD 20892. (REFERENCE 23 OF 45) 90335839 Gram LF Inadequate dosing and pharmacokinetic variability as confounding factors in assessment of efficacy of antidepressants. Clin Neuropharmacol 1990;13 Suppl 1:S35-44 The scientific literature on tricyclic antidepressants contains few studies on the dose-effect relationship, and this aspect of the treatment has for many years been given little attention. However, recent reviews point out inadequate dosing as an important factor in "drug resistant depressions." Tricyclic antidepressants have a narrow therapeutic range and standard doses, which are frequently recommended, will not be therapeutic in some patients and toxic in other patients. Use of flexible dose schemes, which has been customary in clinical trials, carry a considerable risk of underdosing because common side effects occur at subtherapeutic doses. Dosing according to therapeutic effect is not feasible in light of the slow and variable rate of response. Much of the difficulties in establishing a dose-effect relationship appears to be related to the considerable pharmacokinetic variability. The major source of this variability is the genetic polymorphism related to the sparteine/debrisoquine oxygenase. For some of the tricyclic antidepressants, a concentration effect relationship has been established, but almost exclusively on the basis of retrospective studies. The dose-response problem is particularly important in clinical trials. Apparent differences or equivalence between a new drug and the control therapy thus may entirely be related to differences in doses of the two drugs. For tricyclic antidepressants, the use of flexible dose schedules and poor control of compliance may often lead to underdosing and a response rate below the real potentials of these drugs. Underdosing combined with a high rate of placebo response will increase the type 2 error risk considerably and may ultimately lead to the introduction of drugs that are less effective than the classical drugs. Institutional address: Department of Clinical Pharmacology Odense University School of Medicine Denmark. (REFERENCE 24 OF 45) 90335835 Altamura AC Drug-resistance phenomena in major psychoses: their discrimination and causal mechanisms. Clin Neuropharmacol 1990;13 Suppl 1:S1-15 Drug-resistance phenomena are commonly encountered in psychiatric practice and are of particular concern in the treatment of major psychoses. Of paramount importance is the need to discriminate between drug-resistance problems due to pharmacodynamic factors (i.e., receptor sensitivity) or pharmacokinetic factors (inadequate plasma concentration of the drugs at receptor sites). To exclude the former, plasma level measurements of antidepressant and neuroleptic compounds are desirable. Actually, lack of or poor compliance is a peculiarity (often underestimated) when treating psychotic patients, and the use of the drug plasma level/dose ratio (L/D) approach is useful, particularly with outpatients. Another source of drug resistance stems from the inter-individual metabolic variability, as with haloperidol or anticholinergic drugs, which are used to counteract neuroleptic-induced extrapyramidal side effects. In general, plasma-level measurement is advisable whenever no or poor response is obtained during standard treatments with neuroleptic, antidepressant, or anticholinergic drugs. Finally, this author suggests a four-level discrimination process to determine drug resistance in major psychoses, which includes clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors. Institutional address: Department of Clinical Psychiatry University of Milan Italy. *****COMPREHENSIVE PSYCHIATRY***** (REFERENCE 25 OF 45) 78126227 Freyhan RA Treatment-resistant or untreatable? Compr Psychiatry 1978 Mar-Apr;19(2):97-101 [No Abstract Available] *****ENCEPHALE***** (REFERENCE 26 OF 45) 87133330 Vandel B Vandel S [Pharmacokinetic factors and resistance to antidepressant treatment] Facteurs pharmacocinetiques et resistance aux traitements antidepresseurs. Encephale 1986 Oct;12 Spec No:217-22 (Published in French) A number of treatment failures occurring during antidepressant treatment may be related to the pharmacokinetics of the drug used. In fact, numerous factors are able to modify the fate of the antidepressant in the body. These factors may involve the absorption, distribution, biotransformation or elimination of the drug. The reality of these problems is illustrated by a number of clinical case reports. Such modifications lead to a variation in the quantity of drug available to exert its antidepressant action at the sites responsible for the pharmacodynamic effects. This raises the possible value of defining, and then using in practice, the therapeutic zone of the plasma concentrations of the antidepressant used, below and above which a poor therapeutic response is likely. Modern analytical techniques actually allow the routine analysis of plasma concentrations of a number of antidepressants, resulting in a more rational approach to drug therapy and a decrease in the number of depressions resistant to antidepressant treatments. (REFERENCE 27 OF 45) 87133329 Petit M Dollfus S [Biochemical factors of resistance to antidepressants] Facteurs biochimiques de resistance aux antidepresseurs. Encephale 1986 Oct;12 Spec No:207-15 (Published in French) This review of the literature concerning the biochemical factors of resistance to antidepressants is essentially based on the anomalies of neurotransmitters and the enzymes which regulate them. In the case of 5HIAA, because of the bimodal distribution in depressed patients, it appears to be generally accepted that when a low level of this catabolite is found in the cerebrospinal fluid, this may represent a factor of resistance to noradrenergic antidepressants, or even to all antidepressants. In contrast, a high level of this catabolite represents a factor of poor response to serotoninergic antidepressants. Low levels of urinary MHPG predict a poor response to serotoninergic antidepressants, while high levels are observed in cases of depression resistant to noradrenergic antidepressants. MAO activity, evaluated after two weeks' treatment with MAOI, is considered to be a biochemical factor of resistance when it is inhibited by less than 80%. High levels of COMT (related to the degree of anxiety and agitation) reflect a poor response to noradrenergic antidepressants. Finally, a number of strategies designed to control resistant depression (reserpine, lithium carbonate, ...) could, in certain cases, suggest the existence of a functional defect in the serotoninergic systems. (REFERENCE 28 OF 45) 87133328 Olivier-Martin R [Psychological factors, compliance and resistance to antidepressant treatment] Facteurs psychologiques, observance et resistance aux traitements antidepresseurs. Encephale 1986 Oct;12 Spec No:197-203 (Published in French) The compliance, or the degree of adhesion of the patient to the doctor's prescription, is a variable which must be taken into account in the interpretation of the results of a given treatment. It is generally estimated that the level of non-compliance with psychotropic or other classes of drugs is between 20 and 50% of cases. Among the factors favouring non-compliance, the authors initially discuss those related to the drug and to the modalities of prescription: severity of side effects, quality of clinical improvement obtained, complexity and duration of treatment. However, many other factors also appear to be involved, particularly related to the patient: personal beliefs and the attitude towards the disease and the drug can constitute important factors of resistance, and to the psychiatrist, whose attitude can never be considered to be neutral in relation to a particular drug or to a particular patient. The capacity of the therapist to manage and control the treatment is an essential part of the therapeutic relationship between the doctor and his patient. *****INTERNATIONAL JOURNAL OF PSYCHIATRY IN MEDICINE***** (REFERENCE 29 OF 45) 76189504 van Praag HM Therapy-resistant depressions: biochemical and pharmacological considerations. Int J Psychiatry Med 1975;6(1-2):99-111 Two statements are presented here: 1) antidepressants increase the amount of MA at the central receptors, and 2) antidepressants are effective in some, but quite ineffective in other patients, even if they belong to the same diagnostic category. Three questions result from these statements: 1) Does a central MA deficiency occur in depressive patients? 2) If so, is this disorder present in only a proportion of the patients? 3) If so, can this explain the apparent selectivity of antidepressants in the sense that particularly MA- deficient patients benefit from this type of therapy? A tentative answer is given to these three questions. In depressive patients the cerebral MA turnover can be diminished. These disorders do not occur in all patients but seem to be confined to certain categories of depression. Diminution or non-diminution of the central MA turnover is a (not the) factor which determines whether antidepressant medication will succeed or fail. The theoretical and practical implications of these answers are discussed. *****INTERNATIONAL PHARMACOPSYCHIATRY***** (REFERENCE 30 OF 45) 80136630 Laux G Reimer F [Treatment of therapy resistant depressions with high dose clomipramine] Behandlung therapieresistenter Depressionen mit hochdosierten Clomipramin-Infusionen. Int Pharmacopsychiatry 1979;14(5):294-9 (Published in German) 50 so-called therapy-resistant depressed inpatients have been treated with daily i.v. infusions of Clomipramine in a high dosage, using a fixed therapy schedule with increasing and decreasing dosage ranging from 250 to 500 mg. The majority of the inpatients showed sufficient or good therapeutic effects, notable side effects were rare. The therapeutic possibilities of so-called therapy-resistant depressions are discussed. (REFERENCE 31 OF 45) 80093815 Pare CM Monoamine oxidase inhibitors in resistant depression. Int Pharmacopsychiatry 1979;14(2):101-9 [No Abstract Available] *****JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY***** (REFERENCE 32 OF 45) 88228464 Zusky PM Biederman J Rosenbaum JF Manschreck TC Gross CC Weilberg JB Gastfriend DR Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study. J Clin Psychopharmacol 1988 Apr;8(2):120-4 Resistance to antidepressant therapy is a common clinical problem in the treatment of affective disorders. Adjunctive low dose lithium is a promising strategy based on biochemical models and encouraging clinical trials. After a mean duration of 9.2 months of conventional therapy, 16 healthy patients with treatment-resistant depression were treated for a minimum of 2 weeks with either adjunctive lithium or placebo using a double-blind design. We found no difference between the two groups in rate or degree of response. The two most dramatic responses occurred in patients treated with placebo, although 50% of patients treated with lithium had at least a partial response. The number of patients studied was clearly inadequate to avoid a type 2 error. The cumulative response rate reported in the literature of greater than 60%, however, suggests that lithium is indeed an effective adjunct in some patients with treatment-resistant depression. Our patients differed from those in other studies in that they were treated with a lower dose of lithium, the duration of conventional antidepressant therapy was longer, and, finally, they were less depressed and possibly depressed for a longer period. These differences may explain the comparable lithium and placebo responses in this study. Institutional address: Department of Psychiatry Harvard Medical School Massachusetts General Hospital Boston 02114. (REFERENCE 33 OF 45) 87308902 Amsterdam JD Berwish N Treatment of refractory depression with combination reserpine and tricyclic antidepressant therapy. J Clin Psychopharmacol 1987 Aug;7(4):238-42 Chronic reserpine use has been reported to precipitate severe depression in some individuals as a result of its amine-depleting action. However, early clinical studies demonstrated that acute administration of high doses of parenteral reserpine in combination with a tricyclic antidepressant could produce rapid improvement in depressive symptoms. Because these early studies defined treatment resistance as failure to respond to a brief course of treatment with a single tricyclic antidepressant, we performed a more stringent, placebo-controlled evaluation of high dose reserpine in nine depressives refractory to at least six previous drug treatments. Overall, neither reserpine nor placebo produced a meaningful decrease in depression ratings within 1 week of treatment; however, one patient did respond to a second course of reserpine. Side effects were mild to moderate in severity, and there were no cases of profound hypotension. Although the efficacy of this drug combination in severely refractory depressives was not confirmed, reserpine may still prove a useful adjunctive agent in some tricyclic-resistant depressed patients. *****JOURNAL OF THE INDIAN MEDICAL ASSOCIATION***** (REFERENCE 34 OF 45) 86113495 Prasad AJ Efficacy of carbamazepine as an antidepressant in chronic resistant depressives. J Indian Med Assoc 1985 Jul;83(7):235-7 [No Abstract Available] *****NEUROPSYCHOBIOLOGY***** (REFERENCE 35 OF 45) 86014812 Dessauer M Goetze U Tolle R Periodic sleep deprivation in drug-refractory depression. Neuropsychobiology 1985;13(3):111-6 For some time it has been known that total and partial sleep deprivation (in the second half of the night) produces an immediate antidepressive effect and a short-term effect of approximately 1-week duration. A 25-day trial is discussed here. 18 endogenous depressives who proved to be refractory to tricyclic antidepressive therapy were treated with periodic sleep deprivation (5 sleep deprivation treatments in the second half of the night at 5-day intervals) under continued drug therapy. The combined treatment led to a better result than would have been expected from drug therapy alone. Some of the sleep deprivation treatments effected an accelerated remission without the efficacy of treatment subsiding. In individual cases recovery occurred after one or a few partial sleep deprivation sessions. Whether in other respects sleep deprivation shortens the course of depressive phases is still unproven. *****PHARMACOPSYCHIATRY***** (REFERENCE 36 OF 45) 89221254 Amsterdam JD Berwish NJ High dose tranylcypromine therapy for refractory depression. Pharmacopsychiatry 1989 Jan;22(1):21-5 A substantial number of depressed patients will experience a chronic, treatment-resistant affective disorder. Aggressive treatment of these patients with various drug combinations, unconventional antidepressants, or electroconvulsive therapy has met with only partial success. There remains a pressing need to identify more effective methods of utilizing "first-line" antidepressant agents to achieve a more rapid therapeutic action. To this end, we initiated a study using high doses of the MAO inhibitor tranylcypromine, at a range of 90 mg to 170 mg daily, in seven refractory depressed patients who had failed to respond to at least three prior treatments regimens. Four out of seven subjects (57%), who had failed to respond to a mean of 8 +/- 5 prior treatment, had a complete response, and one patient had a partial response to high dose tranylcypromine. The mean SD maximum tranylcypromine dose for the responders was 112 +/- 16 mg daily (range 90 mg to 130 mg). Response did not appear to be a function of severity of illness, duration of present episode, or the number of prior treatment failures. Overall, the side effect profile was favorable, and no "cheese reactions" were encountered. These observations are of clinical significance and suggest the need for further controlled studies using high doses of tranylcypromine. Institutional address: Department of Psychiatry School of Medicine University of Pennsylvania Philadelphia. (REFERENCE 37 OF 45) 89221171 Moller HJ Kissling W Baumann P Breyer-Pfaff U Delini-Stula A Holsboer F Jungkunz G Kuhs H Laux G Muller WE et al Baumann W Non-response to antidepressants: risk factors and therapeutic possibilities [published erratum appears in Pharmacopsychiatry 1989 Mar;22(2):92] Pharmacopsychiatry 1988 Nov;21(6):285-7 [No Abstract Available] Institutional address: Psychiatrische Klinik der Technischen Universitat Munchen FRG. *****PSYCHIATRIA CLINICA***** (REFERENCE 38 OF 45) 76079697 Hopkinson G Kenny F Treatment with reserpine of patients resistant to tricyclic antidepressants. A double-blind trial. Psychiatr Clin (Basel) 1975;8(3):109-14 The literature concerning the therapeutic effects of the administration of reserpine to patients who fail to respond satisfactorily is discussed briefly. A double-blind study was conducted on 14 patients; eight were given 5 mg of reserpine i.m. and six were given 2 ml of normal saline on 2 successive days. The administration of the tricyclic antidepressants the patients had been taking, was continued. The Hamilton Depressive Rating Scale was administered on the day before treatment was commenced, and repeated on the fourth day. Statistical analysis revealed that the patients who received reserpine showed a highly significant improvement of a good quality. The mean fall in the Hamilton rating for the placebo group was 6 points, and in the reserpine group it was 18.87. The therapeutic significance of the findings is discussed. *****PSYCHOPATHOLOGY***** (REFERENCE 39 OF 45) 87290400 Farid BT Irritability and resistance in obsessional neurosis. Psychopathology 1986;19(6):289-93 Eleven patients with primary obsessional neurosis were followed up after successful treatment. There was a significant association between reduction of interference of obsessions and anxiety. A stronger significant association was found between reduction of resistance to obsessions and irritability. These findings are discussed in the light of the current concepts of the phenomenology of obsessional neurosis. *****PSYCHOPHARMACOLOGY BULLETIN***** (REFERENCE 40 OF 45) 91204933 Nierenberg AA Methodological problems in treatment resistant depression research. Psychopharmacol Bull 1990;26(4):461-4 To better understand why treatment resistant depression (TRD) has been resistant to systematic study, the author analyzes methodologic problems facing TRD researchers with a focus on the difficulty of defining TRD. Then approaches for clinicians to interpret limited and potentially biased TRD data are suggested. Institutional address: Treatment Resistant Depression Program McLean Hospital Harvard Medical School Belmont MA 02178. *****PSYCHOPHARMACOLOGY SERIES***** (REFERENCE 41 OF 45) 88320298 Shaw DM Pharmacological management of treatment-resistant depression. Psychopharmacol Ser 1988;5:118-29 Treatment-resistant depression might be considered as the failure of two families of antidepressant therapy given sequentially at sufficient dosage, for an adequate length of time and with continuous compliance. Patients with treatment-resistant depression should be assessed as though they were new referrals, and factors which may be contributing should be dealt with whenever possible. A sequence of therapies based on a tricyclic antidepressant and a monoamine oxidase inhibitor, each combined with putative adjuvant therapies, is proposed as a working model pending further studies and developments. Institutional address: Department of Psychological Medicine University of Wales College of Medicine Whitchurch Hospital Cardiff UK. *****PSYCHOPHARMACOLOGY***** (REFERENCE 42 OF 45) 90018080 Cowen PJ McCance SL Cohen PR Julier DL Lithium increases 5-HT-mediated neuroendocrine responses in tricyclic resistant depression. Psychopharmacology (Berlin) 1989;99(2):230-2 The addition of lithium to the tricyclic antidepressant medication of 11 depressed patients resulted in an increase in the prolactin response to L-tryptophan after both 4 days and 4 weeks of lithium treatment. There was also a significant fall in Hamilton Depression scores. The results suggest that lithium and tricyclic antidepressants may act synergistically to enhance certain aspects of brain 5-HT function in depressed patients. Institutional address: MRC Unit of Clinical Pharmacology Littlemore Hospital Oxford UK. (REFERENCE 43 OF 45) 87318393 Price LH Charney DS Heninger GR Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects. Psychopharmacology (Berlin) 1987;92(4):431-7 Early studies showed dramatic improvement in some depressed patients when a brief course of parenteral reserpine was added to ineffective tricyclic antidepressant (TCA) treatment. We treated eight patients with DSM-III melancholic major depression with desipramine (DMI) greater than or equal to 2.5 mg/kg/day (plasma levels greater than 125 ng/ml) for at least 4 weeks. All patients failed to respond and received reserpine 5 mg IM b.i.d. over 2 days, in seven cases as a placebo-controlled, double-blind trial. One patient had dramatic resolution of depressive and psychotic symptoms within 48 h, but relapsed within 2 weeks; two other patients had transient hypomanic symptoms. Depression ratings did not significantly change for the sample as a whole, but plasma and cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) decreased and CSF levels of homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5- HIAA) increased. Despite robust effects on central monoamine metabolism, reserpine augmentation appears insufficiently effective for routine use in managing refractory depression. *****ZHURNAL NEVROPATOLOGII I PSIKHIATRII IMENI S. S. KORSAKOVA***** (REFERENCE 44 OF 45) 91143274 Sonnik GT Shul'ga AI Ivanishchenko GE Kovachev VI [Mechanism of the development of drug resistance in protracted depressive conditions (morphometric study of the hypothalamus)] Mekhanizm vozniknoveniia terapevticheskoi rezistentnosti pri zatiazhnykh depressivnykh sostoianiiakh (morfometricheskoe issledovanie gipotalamusa. Zh Nevropatol Psikhiatr 1990;90(10):71-3 (Published in Russian) A polynomial approximation of the relationship between the age and the nucleus volume of the hypothalamic neurosecretory cells was made. This parameter increased approximately 150 times from the neonatal period to 4 years of age and subsequently it remained practically unchanged. In manic-depressive psychosis (depressive phase), it was 1.4 times and in involutional depression 2 times lower than in healthy adults. This fact indicates the secretion lowering which supports desynchronism. A conclusion is drawn that the low efficiency of the therapy of lingering depressions could be accounted for by the insufficiently intense and oriented influence on their pathogenetic substrate--the neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus. (REFERENCE 45 OF 45) 89046301 Kushner SG Koliaskina GI Tsutsul'kovskaia MIa Fomenko AM Vladimirova TV [Imipramine antibodies in endogenous depression in young people] Antitela k imipraminu pri endogennykh depressiiakh iunosheskogo vozrasta. Zh Nevropatol Psikhiatr 1988;88(7):89-90 (Published in Russian) The drug antibodies were radioimmunologically detected in 58.3% of depressive patients treated with Imipramine. A group of patients with the antibodies permanently present either proved fully resistant or showed a minor effect. A group with antibodies arising just at the start of the treatment displayed either complete remission or substantial improvement. Antibodies were not found in patients exhibiting full recovery or considerable improvement.