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Drug Discovery for Psychiatric Disorders
By Zoran Rankovic, Matilda Bingham, Eric J. Nestler, Richard Hargreaves
The Royal Society of ChemistryCopyright © 2012 The Royal Society of Chemistry
All rights reserved.
Psychiatric Disorders – an Overview
KATHRYN M. CONNOR AND DAVID MICHELSON
Merck Research Laboratories, UG4C-018, Box 1000, North Wales, PA 19454, USA
The psychiatric illnesses represent, collectively, a group of brain disorders characterized by behavioural and cognitive abnormalities and dysfunction. That psychiatric disorders exist and are abnormal states has been recognized throughout history, though, as with the history of illness generally, the meanings attributed to them have varied considerably across cultures and eras. Today psychiatric disorders are understood as behavioural and cognitive syndromes that reflect specific alterations or abnormalities in brain function, and comprise several distinct categories. Some of the more common psychiatric disorders include the psychotic illnesses, which are associated with gross disruptions of normal cognitive functioning such as hallucinations, thought disorders and delusions; affective disorders, which are characterized by marked extremes of mood states such as severe depressed mood or mania and/or disruptive oscillations between different mood states; anxiety disorders, characterized by hypervigilance, arousal or fear out of proportion to external stimuli, as well as disorders of impulse control such as ADHD, substance use disorders and eating disorders.
It is important to recognize that even within a given diagnostic category, psychiatric disorders generally are classified on the basis of observed signs and symptoms – these are syndromal diagnoses. The Diagnostic and Statistical Manual for Mental Disorders, 4th edition Text Revision (DSM-IV-TR) states:
[In DSM-IV] there is no assumption that all individuals having the same mental disorder are alike in all important ways. The clinician using DSM-IV should therefore consider that individuals sharing a diagnosis are likely to be heterogeneous ... (p. xxxi).
This heterogeneity means that two individuals with, for example, schizophrenia can present with quite different sets of signs and symptoms: one patient may experience paranoid delusions and auditory hallucinations, while another may present with disorganized thinking and loose associations. To complicate matters further, this heterogeneity is not confined to disease phenotype – it may also be that the pathogenesis and pathophysiology of a given psychiatric disorder vary among different individuals who share that diagnosis. From the perspective of drug discovery and drug development this is of particular importance, as it suggests that different patients with the same diagnosis may have quite different responses to a particular intervention.
Our current understanding of the etiology of most psychiatric disorders is imperfect. Characteristic alterations in certain laboratory or other biological measures have been shown is some disorders, but few psychiatric disorders have been associated with broadly reproducible pathophysiological findings that suggest a clear link to disease pathogenesis and etiology. With respect to the genetic bases of disease, many psychiatric disorders have been shown to have high heritability, and studies have suggested that some specific gene polymorphisms appear to be associated with increased risk for particular disorders. However, even for the genes with the strongest evidence of association to particular illnesses, the contribution to the overall observed phenotype attributable is likely to be small, suggesting that most psychiatric illness are the product of a complex interaction of genetic and environmental factors. Finally, most psychiatric disorders appear to have important developmental components in which experience and gene-environment interactions act together in disease pathogenesis.
1.2 Diagnostic Considerations
As noted above, and in contrast to other fields of medicine where diagnosis is based on pathophysiology or etiology, psychiatric diagnoses or diseases are predominantly syndromes. While the psychiatric research community continues to work toward defining specific mental illnesses based on pathophysiology and etiology, this goal has only been achieved for a limited number of disorders, such as many of the dementias (e.g., Alzheimer's, multi-infarct or those due to other general medical conditions), delirium and substance-induced syndromes.
The process of diagnosis in psychiatry has been formalized through the development of structured classification systems. The most widely used classification systems are those based on the DSM-IV-TR and the International Classification of Diseases (ICD-10) Classification of Mental and Behavioural Disorders, both of which are currently under revision. These systems enable a consistent and comprehensive approach for diagnosing psychiatric disorders. Within each system, the psychiatric diagnoses are categorized based on the most salient features, with further summary of each diagnosis including specification of the symptoms required to make a given diagnosis. Using these frameworks for psychiatric diagnosis serves several functions, notably reducing the complexity of these clinical phenomena, facilitating communication between clinicians and researchers, assisting in prediction of outcome and determination of appropriate treatment alternatives. Table 1.1 provides a listing of the various categories of psychiatric disorders as described in DSM-IV-TR.
1.3 Treatment Options
At the present time, pharmacologically based approaches are considered the foundation of treatment for most psychiatric disorders. Developments in the field of psychopharmacology since the 1950s have provided considerable advances for the treatment of psychiatric illness. These developments have also served as tools for expanding our understanding of neurochemistry and for developing new disease classifications based on responses to specific drugs manipulating specific neurochemical targets in brain. Pharmacologic treatment considerations for some of the more common psychiatric disorders are as follows.
Antipsychotics have been the mainstay of treatment for schizophrenia since the development of chlorpromazine in the 1950s and the recognition of the role of dopamine in this chronic and debilitating disorder. Working primarily through dopamine receptor blockade, the first-generation antipsychotics represented an important advance in the treatment of schizophrenia, improving the positive symptoms which are hallmarks of the disorder (i.e. delusions, disordered thought and speech and perceptual disturbances), with benefits observed within one to two weeks. However, these drugs have little impact on the negative symptoms (i.e. blunted affect, alogia, anhedonia, asociality and avoliton) and cognitive dysfunction, which are also characteristic of the disorder. The newer, "atypical" antipsychotics also demonstrate serotonergic acitivity, with less dopaminergic activity and, arguably, improved tolerability. Nonetheless, all antipsychotics have significant and unpleasant side-effects which can limit their utility, including the following: extra-pyramidal symptoms and risk of tardive dyskinesia; weight gain, diabetes, dyslipidemia and risk of metabolic syndrome; galactorhea and sexual dysfunction; haematologic effects (e.g., agranulocytosis); and neuroleptic malignant syndrome. Clearly, alternative treatments with better tolerability and a broader spectrum of activity, improving both positive and negative symptoms as well as cognition, are needed. In recent years, considerable research interest has focused on the development of drugs targeting glutamatergic pathways; however, no successful development programs have emerged to date.
1.3.2 Major Depression
Approved pharmacologic treatments for depression act primarily through increasing synaptic availability of monoamines and/or direct interaction with monoaminergic receptors. In comparison to older generation tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors, the selective serotonin reuptake and serotonin norepinephrine reuptake inhibitors (SSRI and SNRI, respectively) and other newer antidepressants have broader therapeutic indices, thereby allowing for marked expansion of psychiatric treatment into primary care settings. The full benefit of treatment may take 6 to 12 weeks, with initial improvement generally reported within 2 weeks. While awaiting the antidepressant response, short-term anxiolytic treatment may be co-administered. For patients who fail to respond to an optimal dose of an antidepressant, another class of antidepressant may be tried or the antidepressant can be augmented with another drug. As with anti-psychotics, antidepressants are also associated with a number of treatment-limiting side-effects including sexual dysfunction, weight gain, insomnia, sedation, other psychiatric and neurologic symptoms, dietary restrictions (MAO inhibitors), lethality in overdose (TCAs and MAO inhibitors), increased risk of suicidal ideation and behaviour and discontinuation symptoms with abrupt discontinuation. Preclinical and clinical observations over the last several decades have implicated other neurochemical systems as therapeutic targets for depression, with potential roles for the following: hippocampal neurogenesis (neurotrophins); hypothalamic-pituitary axis dysfunction (CRF antagonists); immunologic dysfunction, with activation of pro-inflammatory cytokines; circadian dysfunction; and the role of oestrogen, given the increased prevalence of depression in women and alterations in mood that are observed during the reproductive years.
1.3.3 Anxiety Disorders
Pharmacologic treatment of anxiety primarily targets reducing the increased arousal and fear associated with the various anxiety disorders. Available pharmacologic agents that have demonstrated efficacy for anxiety disorders work primarily through increasing GABAergic tone and/or modulating serotonergic and noradrenergic transmission. Benzodiazepines have rapid onset of action, an important attribute for an anxiolytic, with variable duration of effect based on a given drug's half-life and metabolic profile (e.g., presence of active metabolites), and many of these drugs need to be taken several times a day. Benzodiazepines can be associated with the development of tolerance, which, in turn, can lead to the need for dose escalation. When administered chronically, benzodiazepines are associated with withdrawal phenomena upon abrupt discontinuation and, therefore, tapering over time may be required for patients who wish to discontinue these medications. Other untoward effects include residual sedation, cognitive impairment, increased risk of falls in the elderly and respiratory depression and potential lethality in overdose. With the development of the TCA and SSRI/SNRI antidepressants, clinicians noted that patients also reported improvement in symptoms of anxiety. Efficacy of several antidepressants has subsequently been demonstrated for treating a variety of anxiety disorders, including panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder and generalized anxiety disorder. Unlike the benzodiazepines, however, SSRI/SNRIs can be anxiogenic upon initiation and onset of an anxiolytic effect may takes several weeks. The other side-effects for SSRI and SNRI antidepressants described above are frequently even less well tolerated in patients with anxiety disorders. For more refractory cases, atypical antipsychotics or MAO inhibitors may be indicated. The future of drug development for the treatment of anxiety disorders is challenged by the absence of well-defined, novel targets.
Insomnia may be viewed as a primary disorder of sleep or, alternatively, as a condition secondary to another underlying illness, such as sleep apnoea, major depression or substance abuse or dependence, for example. Secondary insomnias are best treated by addressing the underlying condition. In contrast, pharmacological treatment of primary insomnia is currently dominated by benzodiazepines (BZD), non-BZD hypnotics acting at the benzodiazepine site, sedating antidepressants such as trazodone and sedating non-prescription medications which are readily available over the counter (e.g. sedating anti-histamines). As noted above, benzodiazepines have a number of properties and side-effects that have limited their use. In addition, the non-BZD treatments also have issues with tolerability, including next-day cognitive impairment related to residual effects of treatment. Recognizing the potential role of melatonin in regulation of sleep/wake cycle, recent work with melatonin agonists has shown benefit in treating transient circadian disturbances (e.g., jet lag), but appear less promising for insomnia. Recent identification of novel compounds targeting orexigenic pathways directly linked to circadian biology offers promise for future therapies that overcome the limitations and disadvantages of those affecting the GABAA receptor system.
1.3.5 Bipolar Disorder
Bipolar disorder is characterized by periodic alterations in mood states, cycling between extremes of mood elevation and arousal, often accompanied by psychosis and depression. Pharmacologic treatment targets stabilization of mood and reducing the likelihood of cycling between mood states. The most widely prescribed mood stabilizers are lithium and various anticonvulants (e.g., lamotrigine and sodium valproate). Atypical antipsychotics have also demonstrated efficacy in treating mania. Antidepressants may be used in this population in conjunction with mood stabilizers, but with caution, due to the risk of precipitating mania.
1.3.6 Other Psychiatric Disorders
The development of pharmacologic treatments for other common psychiatric disorders has been hampered by our limited understanding of the underlying neurobiology and pathophysiology of these conditions and, thereby, inability to identify neurochemical targets for drug development. For example:
Attention-deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in childhood, often manifesting during the early school years and adversely impacting academic performance and normal psychosocial development and may persist into adulthood. The underlying pathophysiology for ADHD is unknown, but currently approved pharmacologic treatments include stimulants and, more recently, the selective norepinephrine reuptake inhibitor atomoxetine. While limited data are available regarding long-term outcomes associated with atomoxetine, stimulants are controlled substances with potential for abuse and the safety of their use in the long term continues to be a topic of debate and investigation.
Autism is a pervasive neurodevelopmental disorder manifesting within the first three years of life and affecting the brain's normal development of social and communication skills. Research suggests a complex etiology, with contributions from genetic, neurophysiologic and environmental influences. There are currently no medications approved for treating patients with autism. Thus, medications are prescribed primarily for the symptomatic treatment of disruptive behaviours.
Excerpted from Drug Discovery for Psychiatric Disorders by Zoran Rankovic, Matilda Bingham, Eric J. Nestler, Richard Hargreaves. Copyright © 2012 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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