Cecilio Álamo

Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

Long-Acting Injectable Risperidone Compared with Zuclopenthixol in the Treatment of Schizophrenia with Substance Abuse Comorbidity

Objective: This study aimed to compare the efficacy of long-acting risperidone and zuclopenthixol in subjects with schizophrenia and substance abuse. Method: A total of 115 subjects with schizophrenia and substance use disorders were enrolled for an open, randomized, controlled, 6-month follow-up study. Fifty-seven subjects were selected for treatment with long-acting injectable risperidone, while another 58 were treated with zuclopenthixol-depot. Results: Long-acting risperidone patients presented fewer positive urine tests (8.67 compared with 10.36, P = 0.005), showed improved scores on the Positive and Negative Syndrome Scale, and showed better compliance with the Substance Abuse Management program. The use of long-acting risperidone and less severe dependence explained the outcome at the end of the follow-up. Conclusions: Long-acting injectable risperidone was more effective than zuclopenthixol-depot in improving substance abuse and schizophrenia symptoms in subjects with dual diagnosis.

The consolidation of neuroleptic therapy : Janssen, the discovery of haloperidol and its introduction into clinical practice

The discovery of haloperidol at the end of the 1950s constitutes one of the greatest advances of 20th century psychiatry. This antipsychotic drug has their origin in the research process of central analgesic molecules derived from pethidine and methadone, carried out by the Belgian company Janssen Phamaceutica. After the synthesis of phenoperidine, numerous analogues of this compound were studied, and chemists at Janssen took the decision to substitute the propiophenone group for a butyrophenone group. One of these compounds went the R-1625, a stronger agent with specifically neuroleptic properties but lacking morphine-like activity. This substance was synthesized on the 11th February 1958 and received the generic name of haloperidol because of the two halogenated substitutes incorporated into the molecule. Clinical development of haloperidol was conducted, primarily, by psychiatric research team at the University of Liège that confirmed its efficacy in the treatment of various psychiatric disorders such as acute and chronic paranoid psychosis, mania, or chronic treatment-resistant schizophrenia. Under the brand name Haldol((R)), haloperidol was licensed and marketed in Belgium in October 1959. The direct and differed consequences of its introduction into the psychiatric practice have been multiple, involving different areas of socio-sanitary reality. Moreover, haloperidol has contributed substantially to the development of biological psychiatry and currently neuroscience, because it made possible the development of new experimental models for predicting the effects of antipsychotics, and allowed the postulate of the firsts biological hypotheses about the schizophrenia etiology. Haloperidol has been included in the World Health Organisations list of essential medicines.

Effects of yohimbine on morphine analgesia and physical dependence in the rat.

The effects of yohimbine on morphine analgesia and on the development of opiate physical dependence were studied to find out more about the involvement of alpha 2-adrenergic mechanisms in opioid actions. Male Sprague-Dawley rats (250-300 g) were used. The acute effect of morphine (5 mg/kg i.p.) in the tail-flick test was reduced significantly by pretreatment with a single dose of yohimbine (2 mg/kg i.p.). Alone yohimbine, produced a slight hyperalgesia. Animals treated with a sustained-release preparation of morphine (300 mg/kg s.c.) showed the same sensitivity to opiate analgesia 72 h later whether they were treated concomitantly with yohimbine or not, but they exhibited fewer withdrawal symptoms upon naloxone injection after yohimbine (2 or 4 mg/kg i.p. 24, 28, 48 and 52 h after the start of systemic morphine treatment). The results obtained confirm previous data on the effects of yohimbine on morphine analgesia and reveal the importance of alpha 2-adrenergic activation in the development of opioid physical dependence.

Naltrexone improves outcome of a controlled drinking program

Naltrexone is widely used in therapeutic programs with abstinence as a goal. However, it has been used in only a few studies aimed at reducing alcohol consumption. The purpose of this study was to evaluate the efficacy of naltrexone as an adjunct in controlled drinking programs. This was an open randomized study of 12 weeks duration that compared two therapeutic strategies: use of naltrexone in a controlled drinking program (NTX+CD) and the controlled drinking program alone (CD), without NTX. Each group comprised 30 male patients with mild alcohol dependence. During treatment, there were no differences between groups in drinking behavior, though the NTX+CD group showed significantly less craving. In the 12-month follow-up period, the NTX+CD group showed significantly fewer drinking days and heavy drinking days and less craving than the CD group. The results of this study suggest a role for naltrexone in controlled drinking programs.

A Bibliometric Study of the Use of the Classification and Diagnostic Systems in Psychiatry over the Last 25 Years

Background: Our purpose was to examine the use of classification and diagnostic systems in the field of psychiatry (CDSP) from a bibliometric perspective, over the period 1980–2005. Methods: We selected (in EMBASE and MEDLINE databases) documents that contained, in any of their sections, the descriptors ‘psychiatr*’, ‘DSM*’, ‘ICD*’, or ‘diagnostic criteria’,as well as other more specific descriptors. As a bibliometric indicator of production we applied Price’s law. We also calculated the national participation index (PI) and correlated it with overall PI in biomedical and health sciences, and with PI in the discipline of psychiatry. Results: We obtained 20,564 original documents; 15,743 referred to the Diagnostic and Statistical Manual of Mental Disorders (DSM) and 3,106 to the International Classification of Diseases (ICD). Our results indicate non-fulfilment of Price’s law, since scientific production on CDSP does not undergo exponential growth (correlation coefficient r = 0.9651, vs. r = 0.9927 after linear adjustment). Of the 10 journals with the highest impact factor in the field of psychiatry, the Journal of Clinical Psychiatry has the highest PI in the DSM subgroup (PI = 14.77), and the British Journal of Psychiatry in the ICD subgroup (PI = 1.54). The principal producer country is the United States (PI = 37.9), though in proportion to its production in the psychiatric field the ranking is headed by Finland. Only 10 countries, of the 20 major producers in health sciences, surpass their own PI in the field of psychiatry (Brazil, Italy, Japan, Austria, Spain, Germany, France, India, Switzerland, and China). Conclusions: Over recent years, the use of CDSP (basically the DSM or ICD) in the scientific literature has increased. Nevertheless, the abstracts to these studies, included in the principal databases, should always specify the diagnostic criteria employed, with a view to increasing information levels and reliability for the reader.

Historical evolution of the neurotransmission concept

In this review we analyse the evolution of the neurotransmission phenomenon, whose nature have had three basic historical interpretations; a first, of an humoral nature, formulated by the classical Greeks (Alexandrian School), and which lasted, thanks to the work of Galen, until the sixteenth century (the theory of spiritus animalis); a second, purely mechanical one, developed on the basis of Cartesian conceptions, and which dominated in the seventeenth and eighteenth centuries; and finally, the electrochemical interpretation, which emerged in the nineteenth century, coinciding with the coming of age of numerous scientific disciplines, such as microscopic anatomy (Cajal), physiology (Sherrington), pharmacology (Bernard, Schmiedeberg) or experimental chemistry (Hensing). This latest interpretation can be broken down into an electrical hypothesis, dominant in the nineteenth century (Galvani, Du Bois-Reymond), and the current chemical hypothesis, which can be dated back to 1904, thanks to the research and the research by Elliott (chemical mediators) and Langley (receptive substances) on sympathetic stimulation. Finally, we describe the process of the discovery of the different neurotransmitters and neuroreceptors, and analyse the new interpretations postulated in relation to the neurotransmission concept at the dawn of the twenty-first century.

Antipsychotic switching in bipolar disorders: a systematic review

With the increasingly widespread use of antipsychotics in bipolar disorder (BD), switching among these agents and between antipsychotics and mood stabilizers has become more common, in particular, since the introduction of the novel atypical antipsychotics with mood stabilizer properties. This systematic review aims to provide a comprehensive update of the current literature in BD about the switching of antipsychotics, among them and between them and mood stabilizers, in acute and maintenance treatment. We conducted a comprehensive, computerized literature search using terms related to antipsychotic switching in BD in the PubMed/Medline, PsycINFO, CINAHL database; the Cochrane Library and; the Clinicaltrials.gov web up to January 9th, 2013 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search returned 4160 articles. After excluding duplications, reviews, case reports and studies that did not fulfil the selection criteria, 8 studies were included. Not only have few articles on antipsychotic switching been published but also recruitment in most studies included mixed samples of patients. In general, antipsychotic switching, regardless of the route of drug administration, was well tolerated and no interference was shown in antipsychotic effectiveness during the interchange of drugs. Metabolic improvement was perceived when the switch involved antipsychotics with a low metabolic risk profile. The evidence-base for antipsychotic switching in BD is scant, and little controlled data is available. Switch from quetiapine to lithium and from risperidone to olanzapine has proven successful. Switching to antipsychotics with low metabolic risk had some positive impact on several safety measures. In stabilized patients, the plateau cross-taper switch may be preferred.

Effects of zonisamide in the treatment of alcohol dependence.

Objective:Anticonvulsant drugs have been used in the treatment of alcohol dependence. The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence. Methods:Open-label zonisamide was examined in 22 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence. Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d. Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the Severity of Alcohol Dependence Scale. Alcohol craving and alcohol consumption were assessed at weeks 2, 4, 6, 8, 10, and 12. The concentration of &ggr;-glutamyltransferase was used as an indirect measure of alcohol consumption. Results:Significant improvement was observed in visual analog scale for craving severity scores, weekly drink consumption, and &ggr;-glutamyltransferase. Zonisamide was well tolerated, with only a dropout due to adverse events. Conclusions:Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption. A placebo-controlled study would be of interest.

Active Metabolites as Antidepressant Drugs: The Role of Norquetiapine in the Mechanism of Action of Quetiapine in the Treatment of Mood Disorders

Active metabolites of some antipsychotic drugs exhibit pharmacodynamic and pharmacokinetic properties that may be similar to or differ from the original compound and that can be translated by a different profile of responses and interactions to clinical level. Some of these antipsychotics’ active metabolites might participate in mechanisms of antidepressant activity, as m-chlorophenylpiperazine (aripiprazole), 9-OH-risperidone and norquetiapine. Norquetiapine exhibits distinct pharmacological activity from quetiapine and plays a fundamental role in its antidepressant efficacy. In this review, we analyze the differential pharmacological aspects between quetiapine and norquetiapine, both from the pharmacokinetic and pharmacodynamic perspectives (affinity for dopaminergic, noradrenegic, and/or serotonergic receptors, etc.), as well as differential neuroprotective role. The pharmacological differences between the two drugs could explain the differential clinical effect, as well as some differences in tolerability profile and drug interactions. The available data are sufficient to arrive at the conclusion that antidepressant activity of quetiapine is mediated, at least in part, by the active metabolite norquetiapine, which selectively inhibits noradrenaline reuptake, is a partial 5-HT1A receptor agonist, and acts as an antagonist at presynaptic α2, 5-HT2C, and 5-HT7 receptors.