Drug research: from the idea to the product

The path of a new drug from the idea to product may be divided into 2 phases, namely drug discovery and drug development. In drug discovery a dramatic change is taking place. Due to a remarkable progress in understanding and explaining the underlying cause of many diseases by identifying and sequencing the genes encoded within DNA, it has become possible with new methods, like molecular biology or gene technology, to develop simple test assays by which a large number of compounds may be tested in regard to their biological efficacy. Automation of these test systems utilizing computer-controlled robotic systems has made it possible to evaluate up to 1 million substances per robot per year on their biological effect. While the classical medicinal chemistry cannot produce such a large number of new compounds, combinatorial chemistry may offer the opportunity to screen large numbers of novel compounds rapidly and to reduce the time taken to identify drug candidates substantially. Overall, it is estimated that combinatorial chemistry techniques have resulted in a reduction in the time taken to identify drug candidates of between 18-24 months. In drug development 2 partly overlapping phases can be differentiated, namely the preclinical and clinical phase. During the first part of drug development necessary requirements for first use in man are met by performing preclinical pharmacological, toxicological, and pharmacokinetic investigations in the animal and in in vitro testing. These investigations are playing a central part for the benefit/risk evaluation of new drugs. Only if the risks connected to the clinical study are medically justifiable in relation to the likely therapeutic benefit of the compound, the clinical trial may basically take place under consideration of the legal requirements of the country in which the study is carried out. In drug research clinical pharmacology is the connecting link between preclinical and clinical research. Clinical pharmacology produces the necessary basis for the clinical trial of a new substance in the patient with the target indication. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial and the probable effective dose range and dosing interval is made, the aim of phase II-IV is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Only with a very careful drug investigation during phase I-IV it is really possible to register the therapeutic risk and benefit of a new drug and to control resulting serious problems. An analysis of registered drugs during the last years shows that despite enhanced efforts and dramatically rising development costs the innovation potential of the classical approach is steadily decreasing. Therefore, it is absolutely necessary to develop new innovative drugs with the help of new technologies like molecular and cell biology, gene technology, or immunology as well as combinatorial chemistry and robot supported substance screening.     

Diurnal variation in serum remnant-like lipoproteins, platelet aggregation and fibrinolysis in healthy volunteers

The linkage of cobalamin and folate deficiency to psychiatric illness has been studied and debated since these vitamins were first discovered in the 1940s. The clinical relevance of these deficiencies remains the subject of investigation and scholarly discussion. This article reviews case reports and studies derived from a MEDLINE search for English-language articles related to folate, cobalamin, and psychiatric illness. Emphasis is given to clinical research and recent developments. Preclinical evidence for direct effects of folate and cobalamin on brain functioning is compelling, and numerous associations of their deficiencies to psychiatric illness are evident. These vitamin deficiencies may typically present initially with psychiatric symptoms, but any direct causal relationship to specific neuropsychiatric illnesses are not well defined. The relationship of these vitamins in dementia is significant, but they may only rarely be a cause of truly reversible dementia. Folate deficiency appears most tightly connected with depressive disorders, and cobalamin deficiency with psychosis. Contrary to intuition, vitamin deficiencies appear to occur infrequently with eating disorders. Other diagnoses have been investigated much less extensively. The diagnosis and management of these deficiencies in the context of neuropsychiatric illness is still a matter of discussion. The quality of clinical research in this area is improving, but there are many unanswered questions that affect clinical practice. Clinicians should remain vigilant to the possibility of deficiencies of folate and cobalamin in diverse psychiatric populations. Normal hematological indices do not rule out the deficiencies. Further study is needed to refine the detection and clinical management of these vitamin deficiencies in psychiatric populations.     

Self-medication of the common cold

Assessment of psychiatric disorders encounters unique complexities in homeless populations. Although the use of structured diagnostic instruments has significantly improved research methodology in this area, questions remain about the validity of using cross-sectional diagnostic methods derived from studies of more general populations. In particular, the validity of structured diagnostic instruments in the assessment of schizophrenia, depression, drug use disorder, and antisocial personality disorder (ASPD) in homeless populations has been questioned. The purpose of this study was to examine the association of psychiatric diagnoses with the weather. It was hypothesized that self-report of psychiatric illness may be affected by prevailing weather conditions. Nine hundred homeless subjects randomly sampled from St. Louis shelters, day centers, and unsheltered locations were interviewed over a 1-year period. Official average daily temperature and amount of precipitation on the day of each subject's interview were compared with lifetime and current psychiatric diagnoses ascertained by the Diagnostic Interview Schedule. Similar analyses were performed in general population data from the Epidemiologic Catchment Area study. The study found that among homeless men, inclement weather on the day of interview was associated with lifetime and current diagnoses of major depression, lifetime drug use disorder, lifetime diagnosis of ASPD, and current alcohol use disorder. These findings, however, were not present in homeless women and not reflected in the general population. The results, although limited, suggest that weather may confound cross-sectional, standardized methods of psychiatric diagnosis in homeless men. Weather-related factors among homeless men are associated with ascertainment of both lifetime and current diagnosis of major depression, as well as lifetime drug use disorder and ASPD and current alcohol use disorder. Possible interpretations of these findings are discussed, with implications for intervention strategies for psychiatric disorders in the larger context of homelessness and social problems.     

Spouse similarity for lifetime psychiatric history in the general population

BACKGROUND: Most studies of spouse similarity for psychiatric disorders have focused on clinical samples and are thus limited by selection bias. This study is, to our knowledge, the first comprehensive investigation of spouse similarity for lifetime psychiatric history in a general population sample using standardized diagnostic criteria. METHODS: We studied 519 pairs of spouses residing in Edmonton, Canada who completed the Diagnostic Interview Schedule psychiatric interview. In each pair, one spouse belonged to a random subsample of persons who had participated in a large population survey and was re-interviewed. Association between spouses for lifetime DSM-III psychiatric disorders was analysed with bivariate and multivariate logistic regression analyses. RESULTS: We observed significant spousal association for lifetime presence of affective disorders and for the spectrum of antisocial personality and addiction disorders. Antisocial personality in one spouse was also associated with anxiety disorders in the other spouse, namely post-traumatic stress disorder in wives and phobia in husbands; similarly, drug abuse/dependence in wives was associated with generalized anxiety in husbands and male drug abuse/dependence was associated with female post-traumatic stress disorder. Dysthymia in wives was associated with generalized anxiety and post-traumatic stress disorder in husbands. CONCLUSIONS: The existence of associations between spouses for the presence of psychiatric disorders, either similar or different, has significant implications for both clinicians and researchers. Future research should aim at exploring the aetiological mechanisms of these associations.     

Statistical methods in psychiatric genetics

Most psychiatric disorders are determined by the complex interplay between genetic and environmental factors. Aetiological research into these complex disorders raises many different questions which require a variety of statistical methods. These include survival analysis for the estimation of morbid risk, structural equation models for the partitioning of phenotypic variances and covariances into genetic and other components, complex segregation analysis to detect loci of major effect, and linkage and association analysis for the localisation and identification of susceptibility genes. Future developments in psychiatric genetics will involve the integration of genetic and epidemiological statistics in order to study the interplay between genetic and environmental factors in the complex pathways which lead to mental disorders.     

Integrative concepts in modern forensic psychiatry

Forensic psychiatric diagnosis and treatment should be guided by juridical goals and never be an end in itself. As a whole it is a public service concerning the interests of the perpetrators and the security of the entire population as well. Recent progress in forensic psychiatry is based on integral and comprehensive concepts. In the evaluation of criminal responsibility the new approaches of psychiatric diagnosis like operationalism, application of quantificating instruments and multiaxial diagnostic systems are of considerable importance. The ICD-10 classification of WHO can now be regarded as our reference system. To be acceptable for juridical purposes the evaluation of criminal responsibility has to be based on a systematical analysis of all important factors like actual situation of crime, environment, influence of psychotropic substances, psychosocial stressors, influences of biography and mental disorders. Assessment of prognosis is obligatory by law in many cases. These are juridical decisions, which have to be prepared by the psychiatric experts in the form of risk evaluations considering factors like development of delinquency, analysis of crime, kind of mental disturbance, insight of the perpetrator in his disorder, social competence, selfexamination of the perpetrator of his crime, possible therapies and social circumstances after discharge. Only an integral multiprofessional approach can be regarded as successful in the therapy of forensic high risk patients with paraphilas and aggressive impulse-control disorders. In Switzerland there is still a considerable lack of appropriate institutions for these patients. The vast amount of data accumulated during forensic psychiatric routine should be analysed in multicenter studies with scientific documentation systems to achieve progress in forensic risk calculation and efficiency of therapies.     

The dissociative disorders. Rarely considered and underdiagnosed

A wide variety of dissociative disorders, including dissociative amnesia, dissociative fugue, depersonalization disorder, dissociative identity disorder, and various forms of dissociative disorder not otherwise specified. In many instances, these disorders are either underdiagnosed or misdiagnosed secondary to the clinician's mistaken belief that dissociative disorders are rare. Recent research shows that dissociative disorders may comprise 5% to 10% of psychiatric populations. This article reviews the epidemiology and clinical symptomatology of these disorders. In addition, various screening and diagnostic instruments, such as the DES, Structured Clinical Interview for Dissociative Disorders, and MMPI, are discussed.     

Sleep disorders in neurology. Hypersomnia

Hypersomnia (excessive sleepiness) accompanies many diseases. 14% of the total Austrian population regularly have problems staying awake during the day or are prone to taking spontaneous naps. Hypersomnia is a symptom of the sleep apnea syndrome, which is a risk factor for cerebrovascular disorders. Daytime sleepiness is also a characteristic symptom of narcolepsy, idiopathic hypersomnia, episodic hypersomnia, and many more neurological or psychiatric disorders; it can also be drug induced. Involvement of brain structures which are essential for the regulation of the sleep wake cycle as a result of neurological disorders can likewise lead to hypersomnia. Symptomatic treatment is necessary when treatment of the causal factors is not possible or no improvement has been achieved.     

An overview of mental health services for the elderly

Psychiatric distress is substantially prevalent among elderly individuals, particularly in the primary care and institutional settings, where most older persons receive mental health care. Barriers to care from providers include negative attitudes and stigmatization and poor recognition by general health care professionals. When psychiatric disorders are recognized, the intensity and duration of treatment provided is generally below standards for adequacy. Further research can determine the impact of patient, caregiver, and provider factors on treatment provision and on patient adherence to treatment. Assessment of factors influencing the treatment process are needed to ensure that treatments provided in the real world approximate the efficacy established in controlled clinical trials.     

New drug treatments for alcohol problems: a critical appraisal

This review considers the novel drug treatments that have been suggested to help prevent relapse or attenuate drinking in people with alcohol problems. The evidence from randomized controlled trials for the efficacy of some of the main candidates: acamprosate, naltrexone, bromocriptine, selective serotonin re-uptake inhibitors and buspirone, was examined. Important methodological problems which may have introduced bias were detected in many of the trials. These included failure to test the integrity of the double blind, excluding or estimating outcome in early withdrawals and the comparison of groups on multiple outcome measures with selective reporting of results. In addition, the generalizability of some studies was limited by the procedures used for sample selection. In view of the potential adverse effects of drug treatment it is concluded that the evidence is not strong enough to support the introduction of any of these substances into routine clinical practice at present. The review also emphasizes the importance of methodological rigour to maximize objectivity in treatment evaluation research.     

Magnetic resonance spectroscopy in psychiatry: basic principles and applications

In vivo magnetic resonance spectroscopy (MRS) is a safe and non-invasive tool which can be used to study aspects of brain chemistry and metabolism. Although a relatively recent technique in the field of psychiatric research, it has already been used in the study of anxiety and affective disorders, dementia, schizophrenia, and neurodevelopmental disorders. This review outlines the basic principles of MRS and summarises the research findings in psychiatric disorders. Although mostly preliminary, these findings highlight the capacity of MRS to detect subtle neurobiological abnormalities in mental disorders. They also suggest a future role for MRS in differential diagnosis and monitoring illness progression. Initial MRS studies have also focused on the metabolic effects of psychiatric treatments and could provide information about their relationship to clinical variables.     

What is the psychiatrist's role in drugs and alcohol?

OBJECTIVE: This article describes a consensus view of the role of psychiatrists in respect of alcohol and other drug (AOD) problems, in response to the view expressed by Wodak [1]. METHOD: The data were selected on the basis of the knowledge and experience of the authors. RESULTS: Psychiatrists have made major contributions in the primary, secondary and tertiary prevention of AOD problems over many years in Australia and New Zealand. In recent years there has been an explosion of new knowledge in the AOD area and a shift from mental health to primary and public health care for these patients. Substance use disorders (SUD) are highly prevalent in all areas of psychiatric practice, requiring treatment in their own right as well as complicating the treatment of coexisting psychiatric illness. CONCLUSION: It is argued that psychiatrists have important roles in harm reduction, prevention and policy development; brief and early intervention in SUD in liaison and child psychiatry; and systematic treatment for those with dependence and other psychiatric comorbidity. A research and collaborative approach to AOD services and patients should be encouraged, rather than engaging in divisive debate over "ownership' of this area of clinical practice.     

On a premenstrual psychiatric diagnosis: What's in a name?

A new diagnosis has been approved for inclusion in a special appendix of the revised catalog of psychiatric disorders, the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.). This diagnosis, "Late Luteal Phase Dysphoric Disorder," is gender specific, insofar as only women have the potential for menstrual cycles. Because it pertains to only one gender, this diagnosis should be carefully scrutinized for potential bias. To aid in evaluating the diagnosis, we critically examine research on premenstrual symptoms, the rationale and supporting evidence for the diagnosis, and its potential scientific, clinical, and social ramifications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Investigating the pharmacological and nonpharmacological factors that modulate drug reinforcement.

Drug use is driven by principles of reinforcement and is sensitive to influences in the environmental context in which it occurs. Although a wide range of factors has been shown to directly influence the reinforcing effects of commonly abused drugs, 2 general types include pharmacological and nonpharmacological factors. Both can assert a powerful impact on a drug's reinforcing effects and, therefore, the degree to which a particular drug comes to be used and abused. This invited review seeks to briefly describe some of the current psychopharmacology research on the interactions between these factors and drug abuse. Several pharmacological influences on drug use will be discussed, including the interactions between psychomotor stimulants and recent advances in the development of pharmacotherapies for opioid abuse. With regard to nonpharmacological factors, there is a large body of research demonstrating that nondrug reinforcers can exert a powerful influence on the reinforcing effects of commonly abused drugs. More specifically, identifying alternative nondrug sources of reinforcement can, if made available contingent on drug abstinence, produce robust decreases in drug self-administration. Presented here is a very brief review of some recent scientific efforts to develop and extend behavioral interventions targeting drug use across a wide range of clinical populations. In summary, understanding the interactions among the variables present in the context of drug use is critical to understanding risk factors for substance use disorders as well as developing efficacious treatments for drug dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experimental therapeutics of neurodegenerative disorders: unmet needs

Viewpoint The experimental therapeutics of neurodegenerative disorders is in its infancy, but neuroprotective strategies are already being applied in healthy persons at high risk of developing disease as well as in patients with manifest illness. Knowledge of etiology and pathogenesis, improved design of clinical trials, the development of biological markers, the advent of genetic animal models, the enhanced identification of susceptibility factors, and more effective drug delivery-such advances have improved the prospects for forestalling onset of illness and clinical decline in the growing numbers of people affected by neurodegenerative disorders.     

The risk of suicide

HISTORICAL PERSPECTIVE: A certain number of historical elements including the progressive loss of religious values and the fact that suicide is considered to be an integral part of medical knowledge must be taken into consideration when assessing the risk of suicide. The sociological and psychoanalytical approaches attempt to help draw the suicidal subject out of the his/her personal implication by affecting the social and subconscious aspects of the problem respectively. Other elements such as psychiatric, sociocultural, biological and psychopathological factors are also involved in evaluating the risk of suicide. RISK FACTORS: Durkheim's analysis of the social, familial and occupational factors observed in suicide remains pertinent for assessing risk. Psychiatric disorders are also highly significant risk factors since some type of disorder is found in approximately 90% of all suicide victims. Affective disorders including rapidly alternating bipolar behavior, psychoses, particularly schizophrenia, and borderline personality are the most frequently observed, especially when associated with certain types of behavior such as drug or alcohol abuse. The risk related to other factors such as suicidal behavior (attempts or ideation) is independent of the psychiatric illness. For example, the risk of successful suicide is 30 greater the year after an attempted suicide than in the normal population. ASSESSING RISK: There are no known clinical means, notably psychometric, which can successfully predict the imminence of suicide. Recent studies on brain monoamine levels have shown that a lower 5-HIAA level does play some role in suicidal behavior, particularly violent suicide, although there is no predictive power for normality. It is important to recall that certain advances in the field of psychopathic illnesses offer new insight into concepts such as the death instinct and the suicidal act itself.     

Introduction to the featured section: Genetic research on smoking.

Presents an overview of the featured section concerning genetic research and smoking. A better understanding of the genetics of smoking should lead to more precise identification of individuals at risk and also greatly facilitate drug discovery programs, to identify novel agents that can mimic or antagonize nicotine effects. Developments in genetic research have considerable potential for enhancing smoking prevention and treatment in the future. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Perception of natural fluctuations in peak flow in asthma: clinical severity and psychological correlates

OBJECTIVE: This review focused on empirical research that addressed the effectiveness of service models for the care of patients with personality disorders. METHOD: Services discussed included those delivering acute care, such as crisis and emergency services and acute psychiatric hospitalization; continuing care, such as outpatient services, day hospital treatment, and assertive community treatment programs; and other community programming, such as integrated treatment for comorbid substance abuse and psychoeducational interventions for families of patients with personality disorders. The review focused on studies that included patients with personality disorders, and it measured outcomes relevant to patients with personality disorders. Evidence from randomized controlled trials was highlighted. RESULTS: Few systematic studies of acute services were available. Community programming can decrease the risk of suicide attempts and reliance on inpatient admissions. Services must develop methods of ensuring compliance with treatment. Assertive community treatment for Axis II patients should be developed, implemented, and tested. Comprehensive programming for patients with personality disorders must include integrated treatment for substance abuse and family psychoeducational programs. CONCLUSION: Promising new models of care for patients with personality disorders are ready for testing and wider application.     

Effects of free radical production and scavengers on occlusion-reperfusion induced arrhythmias

The DSM-IV section of the DSM-IV and ICD-10 Personality Questionnaire (DIP-Q) was used to screen for personality disorders in 448 subjects from three clinical samples (general and forensic psychiatric patients and candidates for psychotherapy) and a sample of 139 healthy volunteers. Differences between the samples with regard to patterns of personality pathology in relation to concurrent Axis I disorders and sociodemographic variables were analysed. The prevalence of personality disorders according to DIP-Q was 14% among the healthy volunteers, compared to 59% in the general psychiatric sample, 68% in the forensic psychiatric sample and up to 90% among psychotherapy candidates. Moreover, from a dimensional perspective (i.e. the number of fulfilled Axis II criteria), all clinical groups differed significantly from the control group in all specified personality dimensions and clusters. Dimensional DIP-Q cluster scores also discriminated significantly between the three clinical samples. Unexpectedly, the odds ratio for an Axis II disorder was nearly five times higher among psychotherapy applicants than among general psychiatric patients, independent of concomitant Axis I disorders, gender or age. The strongest association between DIP-Q score and Axis I disorders was found for depressive disorders, which more than doubled the odds ratio for a personality disorder diagnosis. This association could result from high true comorbidity, but could also be due to the fact that a concomitant depressive state can increase self-reported personality difficulties. The high prevalence among psychotherapy candidates may to some extent reflect help-seeking exaggeration of problems. These are aspects to consider when using the DIP-Q, which overall appears to discriminate well between different samples.     

The relative roles of bipolar disorder and psychomotor agitation in substance dependence.

Previous studies have shown that both bipolar disorder (BPD) and psychomotor agitation (PMA) are associated with substance dependence. These two findings have yet to be integrated, despite evidence that PMA is closely linked with the bipolar spectrum. Accordingly, the current study examined whether BPD and PMA had unique or overlapping associations with substance dependence disorders. Participants were 2,300 individuals seeking outpatient psychiatric treatment. Before treatment, participants were assessed using structured clinical interviews, which yielded DSM-IV psychiatric diagnoses and clinical ratings of mood symptoms. Current PMA and lifetime BPD were present in 483 and 172 (bipolar I, n = 71; bipolar II, n = 101) participants, respectively. Current PMA and lifetime BPD each were associated with increased prevalence of lifetime nicotine, alcohol, and drug dependence (ORs ≥ 1.52, ps ≤ .0004). These associations remained significant when controlling for demographic characteristics and comorbid psychiatric disorders, except the link between agitation and alcohol dependence, which was reduced to a trend (p = .058). Although BPD and PMA were associated with each other, these two factors demonstrated unique, nonoverlapping relationships to nicotine, alcohol, and drug dependence. Individuals with both PMA and BPD exhibited especially high rates of comorbid substance dependence. The present results replicate and extend previous findings documenting the relations of BPD and PMA to substance dependence. BPD and PMA may represent independent psychopathological correlates of substance dependence. Future research should explore the theoretical and clinical significance of these potentially distinct relations to substance dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)