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.

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