Psychiatric Disorders 601411 Schizophrenia

Schizophrenia (see 6.02 Schizophrenia) is a complex and debilitating neurodevelopmental psychiatric disorder that affects approximately 1% of the population. It is characterized by diminished drive and emotion during childhood followed by a deviation from reality with hallucinations, and appears to have both genetic and epigenetic causality. Schizophrenia presents with a spectrum of positive, negative, and cognitive symptoms. Positive symptoms include auditory and visual hallucinations, delusions, disorganized thought, and antisocial or violent behavior. Negative symptoms include dissociation, apathy, difficulty or absence of speech, and social withdrawal. Cognitive symptoms

Table 1 DSM-IV-TR major classifications

Disorders usually first diagnosed in infancy, childhood, or adolescence

Delirium, dementia and amnestic and other cognitive disorders

Mental disorders due to a general medical condition not elsewhere classified Substance related disorders

Sedative, hypnotic, or anxiolytic related disorders

Schizophrenia and other psychotic disorders Mood disorders

Depressive disorders Bipolar disorders

Mental retardation Learning disorders Motor skills disorders Communication disorders

Pervasive developmental disorders, e.g., autism Attention deficit and disruptive behavior disorders, e.g., ADHD

Feeding and eating disorders of infancy or early childhood Tic disorders, e.g., Tourette's disorder Elimination disorders Delirium

Dementia, e.g., dementia of the Alzheimer's type, vascular dementia Dementia due to human immnodeficiency virus (HIV) disease, head trauma, Parkinson's disease, Huntington's disease, etc. Amnestic disorders Catatonic disorder

Alcohol related disorders Alcohol induced disorders

Amphetamine (or amphetamine-like) related disorders

Amphetamine induced disorders

Caffeine related disorders

Cannabis related disorders

Cannabis induced disorders

Cocaine related disorders

Cocaine induced disorders

Hallucinogen related disorders

Hallucinogen use disorders

Hallucinogen induced disorders

Inhalant use disorders

Inhalant induced disorders

Nicotine related disorders

Nicotine use disorders

Nicotine induced disorders

Opioid related disorders

Opioid use disorders

Opioid induced disorders

Phencyclidine-related disorders

Phencyclidine use disorders

Phencyclidine induced disorder

Sedative, hypnotic, or anxiolytic use disorders

Sedative, hypnotic, or anxiolytic induced disorders

Polysubstance related disorder

Other (or unknown) substance related disorders

Paranoid, disorganized, catatonic, etc.

Major depressive disorder Bipolar I disorder Bipolar II disorder continued

Table 1 Continued

Anxiety disorders

Panic disorder without agoraphobia Panic disorder with agoraphobia Social phobia

Obsessive compulsive disorder

Posttraumatic stress disorder

Generalized anxiety disorder

Somatization disorder

Pain disorder

Factious disorders

Dissociative amnesia

Dissociative fugue

Sexual desire disorders

Sexual arousal disorders

Orgasmic disorders

Sexual pain disorders

Gender identity disorders

Dyssomnias - primary insomnia, narcolepsy

Parasomnias - nightmare disorder

Somatoform disorders

Factious disorders Dissociative amnesia

Sexual and gender identity differences

Sleep disorders Primary

Related to another mental disorder Other sleep disorders

Impulse control disorders not elsewhere classified

Kleptomania, pathological gambling

Adjustment disorders

Personality disorders

Paranoid personality disorder

Other conditions that may be the focus of clinical attention include disorganized thought, difficulty in attention or concentration, and poor memory. Symptoms usually begin in adolescence or early adulthood, but can occur at any stage of life including childhood. Current diagnostic criteria rely on the DSM-IV-TR classification of schizophrenia. While considerable research has been directed at the genetics of the disorder and significant advances have been made in the development of imaging tools and methods, there is currently no objective clinical test for diagnosis.

Dopamine (DA) and glutamate have been implicated in the molecular pathophysiology of schizophrenia. Thus stimulants that activate brain dopaminergic systems, e.g., cocaine or amphetamine, induce a paranoid psychosis similar to that seen with the positive symptom core of the disease suggesting that overactive DA transmission is a key facet of the disease. Similarly, based on the ability of the psychotomimetics phencyclidine and ketamine to block glutamate receptors (N-methyl-D-aspartate (NMDA)-subtype) the glutamate hypothesis suggests a hypoactivity of excitatory glutamatergic systems.7

Current treatment modalities include typical antipsychotics that act by blocking DA D2 receptors, e.g., haloperidol, thoridazine, and second-generation, atypical antipsychotics that include clozapine, risperidone, olanzepine, quetiapine, and ziprasidone and the partial DA agonist, aripiprazole. These latter agents are all modeled on molecular attributes of clozapine, the only antipsychotic with demonstrated superiority in efficacy to other antipsychotics in treating both positive and negative symptoms. All atypical antipsychotics block 5HT2 receptors in addition to D2 receptors. Their superiority to classical antipsychotics is controversial.8 Thus, the gold standard therapy is clozapine, the use of which is limited due to a rare but fatal occurrence of agranulocytosis associated with treatment. Research efforts over the past 30 years have been focused on understanding the mechanism of action of clozapine, most of which have been highly empirical. Most recently, N-desmethylclozapine, a metabolite of clozapine with potent muscarinic activity, has been identified as another candidate for the mystery factor.9 Novel approaches to therapies for schizophrenia are focused on addressing glutamatergic hypofunction.7

The overall prognosis for schizophrenia is poor. Only 60-70% of patients respond to currently available therapies, and the response is incomplete. In particular, the negative symptoms are usually refractory to treatment with atypical antipsychotics. In addition, there are significant adverse effects associated with prolonged use of antipsychotics including weight gain, increased production of prolactin, and tardive dyskinesia. Affective disorders: depression and bipolar disease

Major depression (see 6.03 Affective Disorders: Depression and Bipolar Disorders) is a chronic disorder that affects 10-25% of females and 5-12% of males. Suicide in 15% of chronic depressives makes it the ninth leading cause of death in the USA. Presenting complaints for depression include: depressed or irritable mood, diminished interest or pleasure in daily activities, weight loss, insomnia or hypersomnia, fatigue, diminished concentration, and recurrent thoughts of death. The World Health Organization (WHO) has estimated that approximately 121 million individuals worldwide suffer from depression and that depression will become the primary disease burden worldwide by 2020. In the majority of individuals episodes of depression are acute and self-limiting. The genetics of major depression are not well understood and have focused on functional polymorphisms related to monoaminergic neurotransmission as the majority of effective antidepressants act by facilitating monoamine availability. Positive associations have been reported between the polymorphism in the serotonin transporter promoter region (5HT TLPR)10 and bipolar disorder, suicidal behavior, and depression-related personality traits but not to major depression. There is preliminary data on the association of polymorphisms in brain-derived neurotrophic factor (BDNF) and depression. However, these are controversial.22

Other mood disorders include bipolar affective disorder (BPAD) and dysthymia. BPAD is diagnosed by discrete periods of abnormal mood and activity that define depressive and manic or hypomanic episodes and occurs in 10% of individuals with major depression. BPAD occurs as two types, I and II, the latter having a familial association and a higher incidence of hypomania. Dysthymia is a chronically depressed mood, usually present for 2 years or more, that does not warrant a diagnosis as major depression.

Depression has traditionally been treated by drugs and electroconvulsive therapy (ECT). The initial drugs to treat depression, the monoamine oxidase inhibitors (MAOIs), e.g., isoniazide, were found by serendipity,11 and from these second-generation MAOIs, e.g., phenelzine, tranylcypromine, and the tricyclic antidepressants (TCAs) were developed and include impramine, desipramine, amitriptyline, etc. The latter are monoamine uptake inhibitors and while highly efficacious, have limiting side effects. Current treatment modalities for depression include more selective monoamine uptake blockers, and include: the SSRIs (selective 5HTuptake blockers), fluoxetine, sertraline, citalopram, paroxetine, etc., the SNRIs (serotonin norepinephrine reuptake inhibitors) that include venlfaxine, nefazodone, and mitrazepine. BPAD is typically treated with mood stabilizers including lithium and valproate, the mechanisms of action of which are currently becoming clearer.

The prognosis for patients diagnosed with major depressive disorders is relatively good with 70-80% of patients exhibiting significant favorable response to treatment. By comparison, the prognosis for bipolar disorder patients is poor. Only 50-60% of BPAD patients gain control of their symptoms with currently available therapies, and a mere 7% become symptom free. Anxiety

Anxiety disorders (see 6.04 Anxiety) are characterized by an abnormal or inappropriate wariness. There are several disorders that fall under the heading of anxiety including panic disorders, phobias, generalized anxiety disorder (GAD), acute stress disorder, and posttraumatic stress disorder (PTSD). Panic disorder is characterized by rapid and unpredictable attacks of intense anxiety that are often without an obvious trigger. Phobias are examples of life-disrupting anxiety or fear associated with an object or situation, including social phobias. GAD develops over time and involves the generalization of fears and anxieties to other, usually inappropriate situations until they ultimately result in an overwhelming anxiety regarding life in general. Acute stress disorder involves the response to a threatened or actual injury or death and is characterized by dissociation, detachment, and depersonalization. Acute stress disorder usually resolves within a few weeks; however it can progress into more severe anxiety disorders such as PTSD. PTSD is characterized by intrusive, anxiety-provoking memories of a stress or trauma (death or injury, terrorist attack, combat experience) that recur and become disruptive to daily function. The symptoms of PTSD include nightmares, obsessive thoughts, flashbacks (re-experiencing the trauma), and avoidance of situations associated with the stressor and a generalization of anxiety.

All of these categories of anxiety can produce crippling and overwhelming emotional and physical symptoms. Anxiety disorders are common with as many as 25% of adults suffering from some form of clinical anxiety at some point in their life with 19 million individuals affected in the USA. Anxiety is estimated to cost worldwide approximately $40 billion annually.

Diagnosis of anxiety disorders is based upon interview with a psychologist or psychiatrist. While a considerable progress has been made in the understanding of the neuronal circuitry underlying fear responses, the biological basis of anxiety disorders is not well understood. Findings of a modest genetic influence including polymorphisms in COMT (catechol O-methyl transferase), the serotonin transporter gene SLC6A4, and 5HT receptors indicate the need for additional genetic linkage studies; however there is a marked environmental/epigenetic component, especially stress in early life, that appears to play a greater role in determining if an individual will develop an anxiety disorder.

Current treatments for anxiety disorders vary depending on the diagnosis. Acute stress disorder can be treated successfully with psychotherapy, and will often resolve itself. Phobias are also successfully treated through behavioral therapy and seldom require medication. The remaining disorders are treated with a combination of therapy and anxiolytic drugs. The earliest anxiolytics were barbiturates, which have now largely been replaced by the benzodiazepines (BZs), e.g., diazepam, clonazepam, etc. While BZs are highly efficacious and have a greater safety margin, there are still significant issues with sedation, withdrawal, dependence liability, and possible overdose. Antidepressants including SSRIs, SNRIs, and 5HT antagonists have also been used with mixed success.

While defined as an anxiety disorder, obsessive compulsive disorder (OCD) has several distinct features that set it apart. It is characterized by an overwhelming sense that negative consequences will arise from the failure to perform a specific ritual. The rituals are repetitive, taking a variety of forms including hand washing, checking to see if the stove is turned off, or the recitation of particular words or phrases. DSM-IV-TR criteria require that the symptoms include obsessions or compulsions that cause marked distress and occupy at least 1 h per day. OCD interferes with normal routine and produces a social impairment equivalent to schizophrenia. In addition to the disabling effect OCD has on the patient, it also produces a significant strain on family relations as relatives become caregivers and are drawn into a routine of providing reassurance and ritual maintenance. OCD becomes apparent at between 22 and 36 years, affecting males and females equally. OCD is highly prevalent, affecting 2-3% of the US population, yet in spite of its clear negative impact on quality of life, OCD is typically underdiagnosed. This is due to a combination of the lack of familiarity of a physician with OCD symptoms and patients tending to be embarrassed and hiding their symptoms.

In contrast to many other psychiatric disorders, OCD patients often have insight into the illogical and extreme nature of their behaviors. Unfortunately there is still reluctance to admit to the symptoms, and it is necessary that the physician probe carefully in order to make an appropriate diagnosis. Positron emission tomography (PET) and single positron emission computed tomography (SPECT) imaging studies suggest a role for increased activity in the orbitofrontal cortex, the cingulated cortex, and the caudate nucleus. Interestingly, these regions have been found to further activate when patients are confronted with a stimulus known to provoke symptoms, and show a decrease activity in response to therapy. While imaging methods are not routinely employed, these studies suggest that an objective diagnostic test is feasible.

Current treatment strategies for OCD include the use of the TCA, clomipramine or the SSRIs, fluoxetine or fluvoxamine at doses higher than those typically used in depressed patients. This approach is effective in 40-60% of patients; however, it only produces a modest 20-40% improvement in symptoms. Therefore, it is critical that patients also undergo behavioral therapy. The pharmacological approach has been found to greatly enhance the success rate of behavioral therapy, and the combined therapies have a much lower relapse rate than either when used alone. For refractory patients, SSRIs can be augmented by the addition of other drugs, e.g., dopamine antagonists. Neurosurgical approaches are available for severely affected patients that do not respond to combined pharmacological and behavioral therapy; however, this approach has not been extensively validated and the overall success rate is less than 50%.

While the prognosis for OCD has improved dramatically with the SSRIs, the overall outlook ranges from moderate to poor. At least 40% of patients are refractory to treatment, and those that respond often experience an incomplete decrease in symptoms and a significant propensity for relapse.

The prognosis for an individual with an anxiety disorder is dependent on the category and severity of the disorder. However, with combined pharmacological and behavioral interventions, the outlook is moderate to good even with the most severe cases of GAD. To satisfy current unmet medical need, efforts are being focused on new chemical entities (NCEs) that have the efficacy of BZs but lack the associated adverse effects. Such agents include g-amino-butyric acid (GABAa) receptor subunit selective 'BZ-like' NCEs12 including neurosteroids (e.g., ganaxolone), direct acting GABAa agonists like gaboxadol, and newer approaches to anxiety including cannabinoids, metabotropic glutamate receptor modulators, nicotinic receptor agonists, and modulators of the corticotrophin-releasing factor (CRF) family of receptors. Attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD (see 6.05 Attention Deficit Hyperactivity Disorder)) is one of the most common childhood psychiatric disorders. An estimated 5-10% of children worldwide are afflicted by ADHD. In addition, there is now increasing acceptance that ADHD occurs in adulthood in approximately 4% of the population. DSM-IV-TR diagnostic criteria classify ADHD symptoms under the headings of inattention or hyperactivity-impulsivity. Symptoms of inattention include lack of attention to detail, carelessness, difficulty in sustaining attention, difficulty in organizing and completing tasks, ease of distraction, and forgetfulness. Hyperactivity-impulsivity includes symptoms such as fidgeting or squirming, excessive and inappropriate running or climbing or a feeling of restlessness, excessive talking, difficulty in awaiting turn, and frequent interruption of others. The subjective nature of these criteria has led to the suggestion that ADHD is simply an extreme in normal behavioral variation that is possibly exacerbated by environmental circumstances. However, there is now a wealth of data clearly demonstrating a genetic inheritance of ADHD, albeit a polygenic disorder, with multiple genes each conferring a small risk. Genes associated with ADHD include: the dopamine transporter (DAT), dopamine receptors (D2, D4, and D5) and dopamine ^-hydroxylase (DBH) gene, the a4 neuronal nicotinic receptor subunit, and the synaptosomal-associated protein, SNAP-25.

Current treatment strategies for ADHD involve the use of classical stimulants such as methylphenidate and amphetamine. These compounds act on DAT and norepinephrine transporters (NET) to enhance monoaminergic transmission in these systems. While effective, methylphenidate has a short half-life and must be administered every 4h producing logistical and social stigma issues when dosing school-aged children, leading to low compliance rates. Long-acting formulations of methylphenidate and the development of atomoxetine, a selective NET inhibitor, have addressed this issue although the use of atomoxetine is confounded by potential hepatotoxicity issues. The atypical stimulant, modafinil, is also effective in treating ADHD without the abuse liability seen with classical stimulants.

While current therapies for ADHD have liabilities such as abuse potential, they produce robust effects on the core symptoms of the disorder. As newer generation formulations and novel targets are evaluated, e.g., histamine H3 receptor antagonists, novel nonstimulant agents that would prove efficacious while avoiding the abuse potential of currently available therapeutics should be feasible. Sleep disorders

Research into sleep disorders (see 6.06 Sleep) has intensified over the last decade given new generations of hypnotics and the success of the novel wake-promoting agent modafinil. The sleep spectrum involves insomnia, narcolepsy, and excessive daytime sleepiness (EDS). Dyssomnias are primary sleep disorders characterized by an abnormal amount, quality, or timing of sleep, and include primary insomnia, narcolepsy, and breathing-related sleep disorder. Primary insomnia is defined as a difficulty in initiating or maintaining sleep, or an inability to obtain restorative sleep. Insomnia is a highly prevalent sleep disorder estimated to affect 35% of the population during the course of a year, with 60% of those afflicted reporting chronic insomnia lasting longer than 1 month. Chronic insomnia is often accompanied by impairments in social and occupational function. Insomnia is roughly twice as common in females as in males, is more frequently observed in patients 60 years and older, and is comorbid with a number of other disorders including depression, Parkinson's disease, and AD. Narcolepsy is a chronic disorder characterized by repeated irresistible sleep attacks, cataplexy, and vivid hallucinations caused by an intrusion of rapid eye movement (REM) sleep into the transitional period between sleep and wake. These attacks typically last from a few seconds to several minutes, and occur at any time without warning. In addition, narcoleptics experience frequent wakening during the night resulting in an overall decrease in night-time sleep duration and quality. Narcolepsy afflicts approximately 200 000 people in the USA and is the third most diagnosed primary sleep disorder in sleep clinics. However, the disorder is believed to be underdiagnosed and actual prevalence may be higher. Of the breathing-related sleep disorders, obstructive sleep apnea (OSA) is the most common, being characterized by repeated obstruction of the upper airway during sleep. These apneic episodes typically last from 20 to 30 s and occur as many as 300 times in a single night. Episodes are typically noted as silent periods that interrupt loud snoring. This disruption in normal breathing leads to frequent awakenings, disruption in sleep architecture, and consequent nonrestorative sleep. In addition, OSA is associated with an increased risk of stroke, heart attack, and high blood pressure. OSA is very common, estimated to affect over 12 million individuals in the USA. The disorder is more common in males than females and is associated with risk factors including obesity and large neck size.

Diagnosis of sleep disorders is usually made by the primary care physician based on patient interview and clinical examination. It is unusual for a patient to be referred to a specialist or sleep clinic for follow-up polysomnography due to the subtle distinctions necessary for accurate diagnosis. For example, the three primary dyssomnias discussed have distinct etiologies and diverse treatments, yet for the most part all three present clinically as EDS. It is therefore not surprising that narcolepsy is not definitively diagnosed in most patients until 10-15 years after the first symptoms become apparent, or that only an estimated 30% of all insomniacs are diagnosed.

From a disease causality perspective, more than 90% of narcoleptic individuals carry the human leukocyte antigen (HLA) gene haplotype, HLA-DR2/DQ1, a reliable genetic marker for narcolepsy with a 100% association of the disease, but this is neither a necessary nor a sufficient causative factor for the disorder. A COMT polymorphism has been associated with the severity of narcolepsy although it may be noted that COMT polymorphisms have also been associated with gender differences in sensitivity to pain, breast cancer, and schizophrenia. Mutations in the orexin/hypoctein systems in both canines and humans have been associated with narcolepsy-cataplexy and numerous genes have been identified in Drosophila melanogaster that affect sleep/wake behaviors including circadian clock genes.

As mentioned above, the choice of treatment for dyssomnia depends upon the diagnosis. Insomnia is typically treated with BZ hypnotics (e.g., triazolam) or more commonly non-BZ hypnotics (e.g., zolpidem). Significant adverse effects are observed with these compounds including a next day 'hangover' effect that can significantly impair function, tolerance, rebound of REM sleep on withdrawal, and addiction. While the non-BZ hypnotics are better tolerated, the same liabilities exist. Patients are occasionally treated with sedating TCAs (e.g., amitriptyline) with mixed results.

Narcoleptic patients are typically treated with stimulant amphetamines or more recently with the novel wake-promoting drug, modafinil. The amphetamines (e.g., methylphenidate) are effective at reducing daytime sleepiness, but carry significant liabilities including irritability, night-time sleep disruption, tolerance, abuse potential, and rebound hypersomnolence. A characteristic of central nervous system (CNS) stimulants like amphetamine is that their positive effects on wake promotion are accompanied by a rebound hypersomnolence following withdrawal, a more profound sleepiness than that which initially led to the use of medication.

Modafinil can alleviate excessive daytime sleepiness without these adverse effects and does not induce tolerance, indicating a lower abuse potential. Both TCAs and SSRIs are effective in treating this aspect of narcolepsy. OSA is typically treated by lifestyle changes such as weight loss and decreased alcohol consumption. Patients may also be placed on a nasal continuous positive airway pressure (CPAP) device. CPAP acts to keep the airway open during the night thus avoiding the apneic episodes. Modafinil is also approved for use in OSA patients with EDS.

Prognosis for these sleep disorders is good for patients with narcolepsy or OSA, and relatively good for patients suffering from insomnia. As discussed above, the currently available treatments for insomnia produce significant adverse effects, so their use is somewhat limited, particularly in the elderly population. Future development of compounds that act outside of the GABA system and restore normal sleep architecture will represent a major breakthrough in the treatment of insomnia and include histamine H receptor agonists, ligands interacting with the orexin/hypocretin system, 5HT2, and melatonin receptor modulators. For wake promotion, there is considerable focus on histamine H3 inverse agonists, modulators of monoamine availability and of the orexin/hypocretin system. It is anticipated that the considerable work ongoing in Drosophilia will aid in identifying new targets for the pharmacotherapy of sleep disorders. An overriding issue however, is the relatively poor diagnosis rate. This is a significant unmet need since these disorders are not only debilitating but in many case life-threatening. Addiction/substance abuse

DSM-IV-TR defines 11 classes of commonly abused substances (see 6.07 Addiction). These include alcohol, amphetamine and amphetamine-like compounds, caffeine, cannabis, hallucinogens, inhalants, nicotine, opioids, phencyclidine, and the class of drugs defined as sedatives, hypnotics, or anxiolytics. Substance dependence is defined as a pattern of repeated self-administration that can result in tolerance, withdrawal, or compulsive drug-taking behavior, and has as a basis an anhedonia, the inability to gain pleasure from normally pleasurable experiences. Tolerance is evident as either a need for increased amount of substance to produce a desired effect, or the diminished effect of the same dose of substance over time. All substances of abuse produce tolerance, but the actual degree of tolerance varies across classes. Withdrawal involves maladaptive physiological changes that occur with declining drug concentrations. These changes tend to be unpleasant and produce cognitive and behavioral consequences that lead the individual to seek to maintain a constant dosing regimen. This can lead to compulsive drug-taking behavior that can include the individual taking large amounts of drug over a long period of time, spending significant amounts of time seeking a supply of substance, a reduction in time spent in social, occupational, or recreational activities, and an inability to stop or decrease drug use despite frequent attempts. This leads a situation of hedonic dysregulation with associated hypofrontality, a decrease in prefrontal cortex function, and cell loss and remodeling.

Statistics compiled by the National Institute on Drug Abuse (NIDA) indicate that the prevalence of substance abuse and the cost of this disorder are considerable. In 1994, an estimated 9.4% of the US population was involved in substance abuse. Since most of the drugs of abuse are illegal, prevalence estimates often come from either treatment program data or an assessment of the incarcerated population. In 2003, 1.7 million people were admitted to publicly funded treatment programs. A survey of 14 major metropolitan areas between 2000 and 2002 found that 27-49% of male arrestees tested positive for cocaine. Substance abuse is also surprisingly common in school-aged children, with 2004 estimates of 8.4% of 8th-graders reporting illicit drug use during the last 30 days, a number that rises to 23% in the 12th grade population. The cost to society is estimated to be in excess of $320 billion annually with significant amounts going directly to healthcare costs and law enforcement. Additionally, a large proportion of healthcare costs are due to medical complications associated with the substance abuse. For example, intravenous drug use is the major vector for transmission of human immunodeficiency virus (HIV), accounting for one-third of all acquired immune deficiency syndrome (AIDS) cases, and is reaching epidemic proportions.13

Current approved treatments for substance abuse are directed at decreasing craving and preventing relapse. These include methadone and buprenorphine treatment for heroin addiction, and naltrexone for the treatment of alcohol abuse. Currently no drug is approved for the treatment of cocaine addiction, although several, including disulfiram and modafinil, have shown promise in randomized control trials. Notably, none of these compounds was developed for their potential to treat substance abuse. This stems in part from the persistent and ill-informed prejudice that addicts use compounds like methadone as a surrogate 'crutch.' It is clearly evident from the current statistics that substance abuse represents a major unmet medical need and a significant opportunity for future drug development.

The prognosis for addicted individuals varies significantly depending on the class of abuse substance and the degree of available psychological and social support. For example, nicotine addicts have several over-the-counter options that have been proven effective and the recent approval of the neuronal nicotinic receptor agonists. The availability of treatment combined with strong social pressure to stop smoking leads to a relatively good prognosis. On the other hand, the prognosis for cocaine addicts is poor due to the fact that they are less likely to seek medical attention and have relatively few pharmacological treatments available.

Ongoing areas of research that may yield new treatments for substance abuse include novel DAT inhibitors with different pharmacokinetic and pharmacodynamic properties to cocaine, new classes of k-receptor opioid ligands and modulators of regulator of G protein signaling (RGS) protein function.

In addition to substance abuse there a number of addictions some of which are included in DSM-IV-TR under the classification of impulse control disorders which include kleptomania, pathological gambling, pyromania, and tricotillomania. Interestingly, recent reports have described an increase in compulsive gambling in Parkinson's disease patients receiving DA agonist treatment.

Addictions that may be added to these disorders include nymphomania, compulsive shopping, and overeating, all of which, in excess, lead to behaviors that are both illogical and harmful. Returning to the anhedonia context of addiction behaviors, the inability to gain pleasure from normally pleasurable experiences, it is debatable whether the milder forms of addiction are not in fact manifestations of depression. In this context, it is noteworthy that current medications for the treatment of obesity, the impulse dyscontrol related to food consumption, are antidepressants.

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