Pharmacotherapy of depression: a historical analysis.

Iproniazid and imipramine, the prototypes of monoamine oxidase inhibitor (MAOI) and monoamine (re)uptake inhibitor (MAUI) antidepressants, were introduced in 1957. The relationship between iproniazid's antidepressant effect and its MAO inhibiting property was tenuous. Because of the potential drug-drug interactions and the need for dietary restrictions, the use of MAOIs became restricted to atypical depression. The confounding of reserpine reversal with antidepressant effect led to the theory that MAU inhibition is responsible for imipramine's antidepressant effect. Driven by neuropharmacological theory, non-selective reuptake inhibitors were replaced first by selective norepinephrine reuptake inhibitors, then by selective serotonin reuptake inhibitors, and more recently, by a series of new antidepressants to relieve the stimulation of serotonin-5HT2A receptors and the compensatory decline of dopamine in the brain. Each antidepressant has its own identity, but meta-analyses indicate a widening of the antidepressant response range from 65-70% to 45-79%, and a lowering of the antidepressant threshold from 65% to 45%. Although one can no longer expect that 2 of 3 depressed patients will respond to treatment, the newer antidepressants are better tolerated, because they produce less anticholinergic side effects.

Pharmacotherapy of mental illness--a historical analysis.

The history of pharmacotherapy of mental illness can be divided into three periods. Introduction of morphine, potassium bromide, chloral hydrate, hyoscine, paraldehyde, etc., during the second half of the 19th century (first period), led to the replacement of physical restraint by pharmacological means in behavior control. Introduction of nicotinic acid, penicillin, thiamine, etc., during the first half of the 20th century (second period), led to significant changes in the diagnostic distribution of psychiatric patients; psychoses due to cerebral pellagra, and dementia due to syphilitic general paralysis virtually disappeared from psychiatric hospitals, and the prevalence of dysmnesias markedly decreased. Treatment with therapeutically effective drugs of mania, schizophrenia, depression, bipolar disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, Alzheimer's disease, etc., during the second half of the 20th century (third period), brought to attention the heterogeneity of the populations within the diagnostic categories of schizophrenia and depression. Introduction of the first set of psychotropics and the spectrophotofluorimeter during the 1950s triggered the development of neuropsychopharmacology. Introduction of genetic technology for the separation of receptor subtypes in the 1980s opened the path for the "tailoring" of psychotropic drugs by the dawn of the 21st century, to receptor affinities.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.

Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half-lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.

Selective drugs versus heterogeneous diagnoses towards a new methodology in psychopharmacologic research

In this presentation the history of modern neuropsychopharmacology was reviewed with special reference to the impasse in pharmaco-therapeutic progress. It was postulated that a methodology for the delineation of the therapeutic profile of psychotropic drugs and identification of the treatment responsive form(s) of illness is an essential prerequisite for progress in the pharmacotherapy of mental illness. It is reasonable to assume that the information generated by the methodology will provide the necessary orientation points for devoloping therapeutically more effective and clinically more selective psychotropic drugs. It should also open up the possility to complement the current capability of tailoring grugs to receptor profiles with the capability of tailoring drugs to the different forms and suborms of mental illness

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997.

OBJECTIVE: To assemble expert clinical experience and judgment regarding the treatment of anxiety disorders in a systematic, quantitative manner, particularly with respect to changes during the preceding five years. METHOD: A panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options relevant to seven vignettes describing typical cases of different anxiety disorders. RESULTS: The preferred initial treatment strategy in 1992 was a combination of medication with a psychological therapy for all vignettes except simple phobia, where a psychological procedure alone was favored. There was little change in 1997, primarily some decrease in the choice of psychological therapy and some increase in the choice of medication for social phobia. Experts recommending a medication in 1992 most often chose as first-line treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA) for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's most frequent recommendation for agoraphobia, PD, and OCD changed to a specific serotonin reuptake inhibitor (SSRI); and they also recommended these compounds more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or TCAs. However, in 1997 many again chose a combination of medications, often a BZ plus a SSRI, so that, overall, there was only a small decline in recommendations for BZs. As second-line medications (1997 only), the experts recommended SSRIs most often for most vignettes, but a TCA for PD and GAD. Recommendations for a combination of medications rose substantially for most vignettes, usually a BZ plus an antidepressant. CONCLUSIONS: Combined cognitive-behavioral therapy plus medication was highly favored by the experts as the initial treatment strategy for anxiety disorders. During the preceding five years, SSRIs displaced older antidepressants as the experts' first-line choices for the pharmacotherapy of anxiety disorders. In case of an unsatisfactory response, the experts' second-line choices more often were an older antidepressant or a combination of an antidepressant plus a BZ. According to the experts' judgements, the BZs, especially combined with an antidepressant, remain mainstays of pharmacotherapy for anxiety disorders.

Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997.

A follow-up survey in 1997 to a 1992 study of the recommendations of an international expert panel on the use of benzodiazepines (BZDs) and other psychotherapeutic medications in the treatment of anxiety disorders suggests that the BZDs remain a mainstay of pharmacotherapy for most of these conditions. BZDs were mentioned more often than any other class of drugs as preferred first-line therapy for anxiety disorders, except obsessive compulsive disorder. The introduction of the selective serotonin reuptake inhibitors (SSRIs) did not significantly affect the experts' recommendations for the use of BZDs as first-line pharmacotherapy. Rather, the SSRIs displaced the tricyclic antidepressants. Some implications of the continuing recommendations for the use of BZDs in anxiety disorders are discussed.

International Study of Expert Judgement on Therapeutic Use of Benzodiazepines and Other Psychotherapeutic Medications: V. Treatment strategies in panic disorder, 1992-1997.

The objective of this study was to assemble expert clinical experience and judgment regarding the treatment of panic disorder in a systematic, quantitative manner, particularly with respect to changes during the past 5 years. A panel of 73 internationally recognized experts in the field of pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six experts completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options as they relate to a vignette describing a typical case of panic disorder. The preferred initial treatment strategy in 1992 (59%) and in 1997 (55%) was a combination of medication with cognitive behavioral therapy. The vast majority of the expert panel included a medication in their recommendations--91% in 1992 and 90% in 1997. Experts recommending a medication for panic in 1992 chose as first-line treatment a benzodiazepine (35%), a selective serotonin reuptake inhibitor (SSRI, 7%), an older antidepressant (33%), or a combination of medications (25%), principally a benzodiazepine plus an older antidepressant (19%). In 1997, fewer chose a benzodiazepine (15%) or an older antidepressant (11%) alone, whereas 33% chose an SSRI alone. More experts chose a combination of medications in 1997 (39%), and the increase was attributable mainly to the choice of a benzodiazepine plus an SSRI (17%). Overall, there was only a small decline in recommendations for benzodiazepines, whereas the increased choice of SSRIs came largely at the expense of the older antidepressants. As second-line medications for panic should their first-line choice fail, the experts in 1997 recommended a benzodiazepine (7%), an SSRI (15%), an older antidepressant (28%), or a combination of medications (50%), most often a benzodiazepine plus an older antidepressant (21%) or a benzodiazepine plus an SSRI (17%). (Experts were not asked to recommend second-line treatment in 1992). Thus, in case of unsatisfactory response, the experts' choices shifted from benzodiazepines and SSRIs alone toward the older antidepressants alone or combinations of an antidepressant plus a benzodiazepine. This report concluded that combined cognitive behavioral therapy plus medication was highly favored by the experts as the initial treatment strategy for panic disorder. Over the past 5 years, SSRIs displaced older antidepressants as the experts' choice for first-line pharmacotherapy of panic disorder. In case of an unsatisfactory response, the experts more often recommended an older antidepressant or a combination of an antidepressant plus a benzodiazepine. According to the experts' judgments, the benzodiazepines, especially combined with an antidepressant, remain mainstays of pharmacotherapy for panic disorder.

The history of the psychopharmacology of schizophrenia.

OBJECTIVE: To review the historical development of the psychopharmacological treatment of schizophrenia. METHOD: A chronological literature review of the clinical practices and theoretical models that have controlled drug treatment of schizophrenia at different times. RESULTS: Effective treatment of schizophrenia was achieved only after the introduction of antipsychotic drugs, in the 1950s, and is still progressing. CONCLUSION: Close collaboration between basic neuroscience and careful and informed clinical practice are likely to lead to continued progress.

International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications: II. Pharmacotherapy of anxiety disorders.

OBJECTIVE: To assemble expert clinical experience and judgement in the treatment of anxiety and related disorders in a systematic, quantitative manner. METHODS: A panel of internationally recognized Experts in treating anxiety and depression was constituted by multistage peer nomination. 90% completed a questionnaire. This report focuses on case vignettes of 7 anxiety disorders followed by questions about relevant therapeutic options. RESULTS: Panelists usually recommended both psychological and pharmacological interventions. Most favored antidepressants, usually tricyclic, for agoraphobia, panic and OCD; beta-blockers for specific social phobia; and benzodiazepines for GAD and adjustment disorder. Some Experts favored polypharmacy, usually an antidepressant and a benzodiazepine. The majority usually advocated pharmacotherapy for 6 months or more. They recommended the same duration of treatment with benzodiazepines and other medications, except for GAD. CONCLUSIONS: The responses of the Expert Panel imply that; (1) most anxiety disorders are serious and merit vigorous, prolonged pharmacotherapy; and (2) antidepressants and benzodiazepines are effective and safe for long-term treatment of these conditions. This outcome contrasts with the widespread apprehension about long-term pharmacotherapy, especially with benzodiazepines, and some regulatory views.

Psychopharmacology and successful cerebral aging.

1. Aging is characterized by a progressive loss of coordinated functions with a loss of complexity in all physiologic systems and a gradual decrease in the adaptability to the environment. A number of different theories of aging are briefly reviewed and pharmacologic intervention with, or rate control of the aging process is entertained. 2. Dementia is characterized by a progressive, non-specific disintegration of personality with cognitive decline. The distinctiveness of the disease process which underlies dementing illness from the aging process is emphasized. A number of different pharmacologic treatment modalities with a potential for interfering with cognitive decline and for providing disease control in dementing illness are considered. 3. Nootropics are defined as substances which facilitate integration through activation of physiologic adaptation. The possibility is entertained that nootropics through their particular action mechanisms might interfere with both the dementing process (i.e., disintegration of personality) and the aging process (i.e., loss of coordinated functions).

Glycosaminoglycan polysulfate in primary degenerative dementia. Pilot study of biologic and clinical effects.

To test the hypothesis that the therapeutic effects of glycosaminoglycan polysulfate (GAP) in primary degenerative dementia of the Alzheimer type (PDD) is associated with a reversal of biochemical changes seen in PDD, a two-phase, clinical-biochemical study was conducted. In the first phase of this study a number of biochemical parameters were compared in 12 patients with PDD and their sex- and age-matched controls, and it was found that platelet monamine oxidase B activity was significantly higher and cerebrospinal fluid (CSF) homovanillic acid levels significantly lower in the PDD than in the normal control group. In the second phase of this study the same 12 PDD patients were treated with GAP at a daily dosage of 250 lipasemic-releasing units for a period of 1 month and it was found that all four biochemical parameters shifted towards normal values during therapy with the changes in CSF 5-hydroxy-indole acetic acid levels attaining statistical significance. Although clinical changes were minimal, in light of prior clinical findings in studies conducted with GAP in similar populations, the possibility was entertained that clinical improvement with GAP in PDD patients is preceded by biochemical changes.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: III. Clinical features affecting experts' therapeutic recommendations in anxiety disorders.

Our objective was to assemble expert clinical experience and judgment in the treatment of anxiety and related disorders in a systematic, quantitative manner. This article reports on some clinical features apart from diagnosis that may affect choice of strategy in the pharmacotherapy of anxiety disorders. A panel of internationally recognized experts in treating anxiety and depression was constituted by multistage peer nomination. Ninety percent (66 of 73) completed an extensive questionnaire. This report focuses on the expert panel's responses to questions on therapeutic options, based on multi-part case vignettes of several anxiety disorders presenting clinical variations within the same diagnosis. In the presence of higher levels of functional impairment, the experts more often recommended formal psychosocial procedures for adjustment disorder; medication for agoraphobia, social phobia, obsessive-compulsive disorder, and adjustment disorder; and polypharmacy for agoraphobia. Their therapeutic recommendations were not materially affected by chronicity in the case of panic disorder. Under the condition of heavy use of alcohol in the case of generalized anxiety disorder, the experts avoided benzodiazepines in favor of various other medications. In the presence of a serious cardiac conduction defect in the case of obsessive-compulsive disorder, they less often recommended medication. Those who did recommend medication changed their preference from tricyclic antidepressants (clomipramine) to selective serotonin reuptake inhibitors. Under the condition of a more severe precipitating event in the case of adjustment disorder, the experts were more likely to recommend both formal psychosocial intervention and medication.(ABSTRACT TRUNCATED AT 250 WORDS)

[Nosology, genetics, neurobiology, and psychopharmacology of schizophrenia]. / Aspectos nosológicos, genéticos, neurobiológicos y psicofarmacológicos de la esquizofrenia.

The development of psychiatric nosology is outlined, and five principles responsible for the organization of psychopathologic symptoms into psychiatric disorders are proposed. Within the frame of reference of the nosologic organizing principles, the evolution and dissolution of the unitary concept of schizophrenia are reviewed, and some of the findings in neurobiologic, genetic and psychopharmacologic validation studies are discussed. It is suggested that findings in family genetic studies and in clinical psychopharmacologic investigations are supportive of Leonhard's (1957) contention that systematic and unsystematic schizophrenia are two distinct populations.

Early manifestations of dementing illness: treatment with glycosaminoglycan polysulfate.

1. In a multicenter, placebo-controlled, double-blind clinical trial in 156 elderly patients with psychopathologic symptoms, glycosaminoglycan polysulfate was found to be a therapeutically effective agent in the treatment of the earliest manifestations of a dementing process. 2. Treatment with glycosaminoglycan polysulfate in the daily dosage of 600 LRU, administered on the basis of a divided dosage schedule for 24 weeks, was significantly superior to an inactive placebo on several outcome measures including the SCAG Total and factor scores (i.e., Cognitive Dysfunction, Withdrawal, Agitation/Irritability and Depression), the NOWLIS Total and Fatiguability factor scores, the MMSE, the HAM-D Total and Vegetative Symptoms factor score and the CGI Severity of Illness and Global Improvement. 3. The drug was well tolerated; vital signs and laboratory measures did not show clinically significant changes within the experimental period.

Aspectos nosológicos, genéticos, neurobiológicos y psicofarmacológicos de la esquizofrenia. / [Nosology, genetics, neurobiology, and psychopharmacology of schizophrenia]

The development of psychiatric nosology is outlined, and five principles responsible for the organization of psychopathologic symptoms into psychiatric disorders are proposed. Within the frame of reference of the nosologic organizing principles, the evolution and dissolution of the unitary concept of schizophrenia are reviewed, and some of the findings in neurobiologic, genetic and psychopharmacologic validation studies are discussed. It is suggested that findings in family genetic studies and in clinical psychopharmacologic investigations are supportive of Leonhards (1957) contention that systematic and unsystematic schizophrenia are two distinct populations.

Aspectos nosológicos, genéticos, neurobiológicos y psicofarmacológicos de la esquizofrenia. / [Nosology, genetics, neurobiology, and psychopharmacology of schizophrenia]

The development of psychiatric nosology is outlined, and five principles responsible for the organization of psychopathologic symptoms into psychiatric disorders are proposed. Within the frame of reference of the nosologic organizing principles, the evolution and dissolution of the unitary concept of schizophrenia are reviewed, and some of the findings in neurobiologic, genetic and psychopharmacologic validation studies are discussed. It is suggested that findings in family genetic studies and in clinical psychopharmacologic investigations are supportive of Leonhards (1957) contention that systematic and unsystematic schizophrenia are two distinct populations.

Glycosaminoglycan polysulfate in the treatment of old age dementias.

1. In a multicenter, placebo-controlled, double-blind clinical trial in 155 elderly patients with cognitive decline, glycosaminoglycan polysulfate was found to be a therapeutically effective agent in the treatment of old age dementias. 2. Treatment with glycosaminoglycan polysulfate in the daily dosage of 600 LRU, administered on the basis of a divided dosage schedule for 12 weeks, was significantly superior to an inactive placebo on several outcome measures including the Wechsler Memory Scale-Russell Revision (Easy Paired Associates Learning and Immediate Visual Reproduction), Mini Mental State Examination, the Sandoz Clinical Assessment Geriatric (Cognitive Dysfunction and Depression), Hachinski Dementia Scale, Brief Psychiatric Rating Scale (Confusion and Depressive Withdrawal) and Global Improvement Scale of the Clinical Global Impression. 3. Adverse effects with glycosaminoglycan polysulfate were few and mild. The drug was equally well tolerated and equally effective in the two major dementias of old age, i.e., primary degenerative and multi-infarct. The number of abnormal laboratory test readings remained essentially unchanged from pre-treatment to post-treatment.

Nimodipine in the treatment of old age dementias.

1. In a multicenter, placebo-controlled, double-blind clinical study in 178 elderly patients with cognitive decline, nimodipine, a calcium antagonist was found to be a therapeutically effective agent in the treatment of old age dementias. 2. Treatment with 90 mg of nimodipine administered orally in divided doses for 12 weeks was significantly superior to an inactive placebo on all outcome measures including the Wechsler Memory Scale, the Mini Mental State Examination, the Global Deterioration Scale, the Sandoz Clinical Assessment Geriatric Scale, the Plutchik Geriatric Rating Scale, the Severity of Illness and Global Improvement Scales of Clinical Global Impression, and the Hamilton Psychiatric Rating Scale for Depression. 3. Adverse effects with nimodipine were few and mild. The drug was equally well tolerated and equally effective in the two major dementias of old age, i.e., primary degenerative and multi-infarct. The number of abnormal laboratory test readings remained essentially unchanged from pre-treatment to post-treatment.