The new england journal of medicine

Review Article

Allan H. Ropper, M.D., Editor Psychotic Disorders

Jeffrey A. Lieberman, M.D., and Michael B. First, M.D.​​

From the Department of , Co- he term “,” which is derived from the Greek word for lumbia University Vagelos College of abnormal condition of the mind, has been used in many different ways in Physicians and Surgeons, and the New York State Psychiatric Institute — both in clinical medicine. Before 1980, the term “psychotic” was applied generi- New York. Address reprint requests to T cally to persons whose mental functioning was sufficiently impaired to interfere Dr. Lieberman at the New York State Psy- with their capacity to meet the ordinary demands of life. Starting in 1980 with the chiatric Institute, Vagelos College of Physicians and Sur- publication of the third edition of the Diagnostic and Statistical Manual of Mental Dis- geons, 1051 Riverside Dr., New York, NY orders (DSM-III), the term indicated gross impairment in reality testing — that is, 10032, or at jeffrey­ .​ lieberman@­ nyspi​­ ​ disruption of the ability to distinguish between the internal experience of the .­columbia​.­edu. mind and the external reality of the environment. N Engl J Med 2018;379:270-80. To achieve greater diagnostic precision, DSM-IV, published in 1994, defined DOI: 10.1056/NEJMra1801490 Copyright © 2018 Massachusetts Medical Society. psychosis more specifically to apply to mental disorders characterized by symp- toms such as fixed false beliefs (, such as the belief that one is being poisoned by neighbors who are piping gas through the walls), , disorganized thoughts (illogical and incoherent speech, neologisms, and made-up words), clang associations (rhymed words), word salad (nonsensical sentences), echolalia (repetition of spoken words), and abnormal motor behavior (bizarre postures, , and waxy flexibility). The psychotic disorders in the current edition of the diagnostic manual, DSM-5, are defined by clinical syndromes rather than diseases and are distinguished from one another mainly by their duration (e.g., ≥6 months for symptoms of schizo- phrenia and <1 month for a brief psychotic disorder), by symptom profile (e.g., multiple types of psychotic symptoms in and only delusions in de- lusional disorder), by the relationship between psychotic symptoms and episodes of disturbed mood (i.e., whether the psychotic symptoms occur during, or extend beyond, a mood disturbance), and by cause (i.e., whether the psychotic symptoms are due to the use of such substances as phencyclidine [PCP] or to medical condi- tions that affect the brain, such as epilepsy, systemic erythematosus [SLE] and other autoimmune diseases, tumors, or ). In the current clinical nomenclature, “psychotic symptom” denotes a manifestation of cognitive or per- ceptual dysfunction, mainly delusions or hallucinations, whereas “psychotic disor- der” refers to a condition in which psychotic symptoms meet specific diagnostic criteria for a disease. Psychoses can be categorized into three broad groups: idiopathic psychoses, psychoses due to medical conditions (including neurodegenerative disorders), and toxic psychoses (due to substances of abuse, prescribed medications, or toxins) (Table 1). Conditions for which the cause or pathological features of psychosis are known and can be treated by directly targeting the causal agent or its pathological consequences are classified separately from the idiopathic conditions. These clas- sifications are arbitrary, reflecting the limitations of our knowledge about psy- chotic disorders, and are likely to change as scientific research reveals the patho- logical basis and causes of these disorders.

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Natural History of Psychosis ological characteristics have altered neurotrans- mission in the dopamine and glutamate pathways The age at which psychotic symptoms first ap- of the hippocampus, midbrain, corpus striatum, pear and their temporal evolution vary according and prefrontal cortex (Fig. 2), which leads to the to the underlying disorder. The most common emergence of psychotic symptoms. This patho- psychotic disorders, such as schizophrenia, bipo- physiological model of psychosis is based on lar disorder, and depression with psychotic symp- many studies that suggest that excess synaptic toms, begin in the late second or third decade of levels of dopamine and glutamate cause increased life, whereas delusional disorders more often postsynaptic stimulation, the downstream effects develop in middle age, and psychoses due to of which result in psychotic symptoms.7,8 The neurodegenerative diseases such as Alzheimer’s molecular bases of these disturbances include disease begin during senescence. Psychotic symp- deficiency of γ-aminobutyric acid (GABA) inhibi- toms caused by drug abuse or prescribed medi- tory interneurons and hypofunctioning N-methyl- cations and symptoms caused by medical disor- D-aspartate (NMDA) glutamate receptors ders such as SLE, seizures, or fevers can occur at (NMDARs), which alter the inhibitory–excitatory any age. Features that suggest a secondary psy- balance of neural systems mediated by gluta- chosis (i.e., toxic psychosis or psychosis due to mate and dopamine.9,10 A recent study suggests medical conditions) rather than an idiopathic that other molecular mechanisms that regulate type include a rapid decline in functional capac- glutamate synthesis or metabolism might also ity from premorbid levels; an abrupt onset of contribute to the dysregulation and increased symptoms without clear precipitants; a history synaptic level of glutamate.11 of headaches, seizures, or visual, olfactory, or Studies of several types of induced psychosis tactile hallucinations; and an absence of a fam- have been informative in understanding these ily history of psychotic disorders. neurotransmitter mechanisms. For example, Idiopathic psychotic disorders, especially natural and synthetic cannabinoid formulations schizophrenia and (the containing specific cannabis receptor–subtype latter characterized by symptoms of schizophre- agonists, particularly the cannabinoid-1 receptor nia and a such as depression or agonist, can induce psychosis or increase the ), usually evolve through premorbid, pro- risk of its occurrence. Cannabinoid receptors act dromal, syndromal, progressive, and chronic on molecular elements and guide the traffick- stages (Fig. 1).1 However, the course of illness is ing of dopamine and glutamate at neuronal unpredictable, and the frequency, number, and synapses.12,13 Other so-called designer drugs, types of psychotic symptoms vary according to such as “bath salts,” a synthetic cathinone that the specific psychotic disorder and can differ potently releases dopamine and serotonin, in- from one patient to another with the same dis- duce fulminant psychotic symptoms in a similar order (Table 1). fashion. Persons with psychotic disorders are at risk A specific type of psychosis is caused by for complications and derivative effects of psy- stimulation of the main serotonin receptor sub- chosis, particularly suicide attempts (lifetime prev- type, 5-hydroxytryptamine subtype 2A (5-HT2A). alence, 34.5%),2 (lifetime preva- Psychedelic drugs, such as lysergic acid diethyl- lence, 74%),3 homelessness (annual prevalence, amide (LSD), mescaline, and psilocybin, have 5%),4 victimization by others (prevalence over a mental effects that mimic psychotic symptoms 3-year period, 38%),5 and committing acts of vio- primarily through what has been termed “biased” lence (increase in the odds of violence, as com- stimulation of 5-HT2A receptors, meaning that pared with the general population, 49 to 68%).6 these drugs selectively activate noncanonical in- tracellular signaling pathways.14 Although this observation implicates serotonin and 5-HT Causes and Pathophysiological 2A Features receptors in the pathophysiology of psychotic disorders, psychedelic drugs induce mental ab- Neurotransmitters in Psychosis errations that are qualitatively different from As a consequence of their pathology, many dis- idiopathic psychotic disorders and from those orders that have different causes and pathophysi- caused by psychostimulants such as ampheta­

n engl j med 379;3 nejm.org July 19, 2018 271 The New England Journal of Medicine Downloaded from nejm.org at TUFTS UNIVERSITY on July 18, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Violence Complications ­ suicide, agitation, ­ victimization, ­ violence ­ suicide, agitation, violence ­ suicide, agitation, violence ­ suicide, agitation, violence ­ suicide, agitation, violence ­ suicide, agitation, violence ­ suicide, agitation, violence Substance abuse, Substance abuse, Substance abuse, Substance abuse, Substance Substance abuse, Substance Substance abuse, Substance abuse, Substance APDs Treatment APDs, CBT APDs, sants, mood sta ­ mood sants, psycho ­ bilizers, social therapies psychosocial ers, therapies ECT, sants, ­ psychosocial ­ therapies therapies therapies APDs, antidepres - APDs, stabiliz - mood APDs, antidepres - APDs, CBT APDs, APDs, psychosocial APDs, APDs, psychosocial APDs, Dopamine Pathophysiology developmental fac - developmental dopamine, tors, ­ glutamate glutamate mine, developmental fac - developmental dopamine, tors, ­ glutamate glutamate mine, developmental fac - developmental dopamine, tors, ­ glutamate developmental fac - developmental dopamine, tors, ­ glutamate ­ dopamine, ­ glutamate Genetic factors, neuro - factors, Genetic dopa - factors, Genetic Genetic factors, neuro - factors, Genetic dopa - factors, Genetic Genetic factors, neuro - factors, Genetic Genetic factors, neuro - factors, Genetic factors, Hormonal Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Basis for Diagnosis 0.12 0.18 0.32 0.33 0.07 0.05 0.07‡ Lifetime 0.30–0.87 Prevalence (%) (delusions and hal - and (delusions and lucinations) symptoms mood concur - occurring indepen - or rently dently manic during ­ episodes depres - during only episodes sive from apart paired delusions of impact symptoms with pro - with symptoms residu - and dromal symptoms, al-phase duration, ≥6-mo func ­ in ­ decline tioning† within 6 wk after wk 6 within ­ delivery lasting 1–6 mo 1–6 lasting mo <1 lasting Distinguishing Features Psychotic symptoms Psychotic symptoms Psychotic symptoms Psychotic im - not Functioning Active-phase psychotic Active-phase Psychotic symptoms Psychotic Psychotic symptoms Psychotic symptoms Psychotic Delusions (mostly auditory), (mostly think - disorganized or disorganized ing, psychomo - abnormal behavior tor (mostly auditory), (mostly think - disorganized or disorganized ing, psychomo - abnormal behavior tor tions, disorganized tions, thinking, disorga - abnormal or nized behav - psychomotor ior disorganized tions, thinking, disorga - abnormal or nized behav - psychomotor ior Psychotic Symptoms Delusions, hallucinationsDelusions, hallucinations Delusions, hallucinations Delusions, Delusions, hallucinationsDelusions, Delusions, hallucinations Delusions, Delusions, hallucina - Delusions, hallucina - Delusions,

with psychotic with features ­ disorder with disorder psychotic ­ features psychoses ­ psychosis disorder ­ disorder Clinical and Pathophysiological Features and Treatment of Disorders in Which Psychotic Symptoms Occur.* Symptoms Psychotic Which in Disorders of Treatment and Features Pathophysiological and Clinical 1. Table Psychotic Disorder Schizoaffective disorder Bipolar depressive Major disorder Delusional Idiopathic primary Idiopathic Schizophrenia Postpartum Schizophreniform psychotic Brief

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Treatment of medication of of underlying of ­ medical condition Drug elimination Drug elimination Toxin Discontinuation APDs, treatment APDs, Pathophysiology Dopamine, glutamate Dopamine, glutamine Dopamine, Dopamine, glutamine Dopamine,

Basis for Diagnosis for drugs for ciation with ciation medication a to cause known psychotic ­ symptoms tion with a med - a with tion condition ical to cause known psychosis Toxicologic assays Toxicologic Toxicologic assay Toxicologic Temporal asso ­ Temporal Temporal associa - Temporal 0.42 Lifetime Prevalence (%)

temporally related temporally intoxi - substance to withdrawal or cation asso ­ temporally toxin with ciated ­ exposure as a medication a as effect side temporally related temporally con ­ medical to dition Distinguishing Features Psychotic symptoms Psychotic symptoms Psychotic Psychotic symptoms Psychotic Psychotic symptoms Psychotic Psychotic Symptoms Delusions, hallucinations Delusions, hallucinations Delusions, Delusions, hallucinations Delusions, Delusions, hallucinations Delusions,

by recreational by substances§ toxins¶ by ­ psychosis‖ to medical to ­ conditions metabolic, crine, con ­ other and ditions** APD denotes antipsychotic drug, CBT cognitive behavioral therapy, and ECT electroconvulsive therapy. Active-phase symptoms include delusions, hallucinations, disorganized speech, grossly or catatonic behavior, and n egative symptoms. A person must have at least two of these to be considered in the active phase schizophrenia. Residual-phase symptoms include negative and accentuat ed versions active-phase (e.g., odd beliefs and unusual perceptual experiences). The 0.07% represents the incidence of hospitalization for . Recreational substances include alcohol, cannabis and its derivatives, hallucinogens, phencyclidine related substances, inh alants, sedatives, hypnotic agents, anxiolytic and stimulants (including cocaine). Toxins include anticholinesterase, organophosphate insecticides, sarin and other nerve gases, carbon monoxide, dioxide, volatile substances such as fuel or paint. Iatrogenic psychosis is induced by anesthetics and analgesics, anticholinergic agents, anticonvulsants, antihistamines, antihyp ertensive cardiovascular medications, antimicrobial medications, antiparkinsonian chemotherapeutic agents (e.g., cyclosporine and procarbazine), glucocorticoids, gast rointestinal muscle relaxants, nonsteroi - dal antiinflammatory drugs, other over-the-counter medications (e.g., phenylephrine and pseudoephedrine), antidepressant medica tions, disulfiram. Neurologic conditions include neoplasms, cerebrovascular disease, Huntington’s , epilepsy, auditory- or visual-nerve impairment, deafness, migraine, and central nervous system (CNS) infections; endocrine conditions include thyroid, parathyroid, and adrenocortical abnormalities; m etabolic hypoxia, hypercarbia, ; and other conditions include fluid or electrolyte imbalances, hepatic renal diseases, autoimmune disorders with CNS involvement (e.g., systemic lupus erythe - matosus). Psychotic Disorder Toxic psychoses Toxic induced Psychosis induced Psychosis Iatrogenic Psychoses due Psychoses Neurologic, endo - Neurologic, * † ‡ § ¶ ‖ **

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that occur only in a small proportion of cases Stages of Illness (approximately 2.4%) but are highly penetrant.

Healthy Common Genetic Variants with Low Penetrance Premorbid Prodromal Syndromal Chronic or Residual Of the many genes that have been associated Early intervention with a risk of psychotic disorders, only a few are Worsening Prevention of progression Severity biologically plausible. Several associations have of Signs Deterioration been found between idiopathic psychosis and and Symptoms No or few Attenu- Psychotic Psychotic symptoms genes controlling synaptic neurotransmission, symptoms ated symptoms Negative symptoms particularly genes involving pathways mediated symp- Cognitive symptoms 17 toms Functional disability by dopamine and glutamate. These associations, which are consistent with current neurotransmit- Birth 10 20 30 40 50 ter theories of psychotic disorders, are reason- Puberty Years able but have not been proved to be valid. A pro- vocative recent finding is an association between Figure 1. Natural History of Schizophrenia and the Rationale for Preventing Chronic Disease. psychosis and genes involved in immunologic Shown are the stages of illness in schizophrenia, the prototypical idiopathic function, such as the major histocompatibility 18 psychotic disorder. Detection and treatment in the early stages of illness, complex (MHC) locus and complement. MHC ideally close to the onset of the first episode of psychosis, shorten the du- molecules in the central nervous system regulate ration of psychotic episodes, reduce recurrences, and limit the progressive the development of neuronal connections through decline in functioning (deterioration) that occurs in the syndromal stage microglia-guided pruning of presynaptic termi- and leads to the chronic effects of the disease. The syndromal stage begins with the first episode of psychosis and continues through the progressive nals, thus influencing the formation of neural 19,20 stage. circuits and the functions that they mediate.

Rare Genetic Variants with High Penetrance mine and NMDA antagonists, which stimulate The most common genetic abnormality associ- glutamate activity.7,8,15 ated with a psychotic disorder is the chromo- some 22q11.2 microdeletion. This causes the Genetic Factors in Psychosis 22q11.2 deletion syndrome (also known as the Epidemiologic studies strongly implicate heredity velocardiofacial syndrome or the DiGeorge syn- in the pathogenesis of the idiopathic psychotic drome), which occurs in approximately 1 in 4000 disorders. Schizophrenia and live births. This disease is associated with car- with psychotic symptoms are characterized by diac, facial, and limb abnormalities, and approxi- approximately 50% concordance of certain ge- mately 25% of affected patients have symptoms netic loci between identical twins, and among of schizophrenia or schizophrenia-like features the siblings and parents of persons with an idio- that are largely indistinguishable from idio- pathic psychotic disorder, rates of the same pathic schizophrenia.21 Other copy-number vari- disorder are 10 to 15 times as high as the rates ations have been described that vary with respect in the general population. Although the specific to population frequency and penetrance, as well genetic markers and modes of heritance of psy- as their association with psychotic disorders.22 chotic disorders have not been determined, two general hypotheses have been proposed: the Neurodevelopmental Factors in Psychosis common disease–common allele hypothesis Exposure to prenatal environmental insults (e.g., (genes with >10% population frequency) and the maternal infections, drug toxicity, and nutritional common disease–rare allele hypothesis.16 Ac- deficiencies), birth complications, postnatal trau- cording to the first hypothesis, prevalent genes ma, and other forms of deprivation at critical with low penetrance act additively and through stages of development is associated with a risk epistasis with other such genes to confer a risk of subsequent psychotic disorders. Although their of schizophrenia and psychotic mood disorders. effect sizes are small, these environmental fac- The second hypothesis implicates rare inherited tors are thought to interact with genetic factors or de novo mutations, or copy-number variants, and increase susceptibility to psychotic disorders,

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Pathophysiology of Psychosis

HIPPOCAMPUS STRIATUM

D2R Interneuron ↑Dopamine

Corpus MIDBRAIN striatum Prefrontal NMDAR cortex PREFRONTAL CORTEX Midbrain ↑Glutamate Amygdala Hippocampus CORPUS STRIATUM Pyramidal CA1 cell NUCLEUS ACCUMBENS MIDBRAIN GABA-R

↓GABA HIPPOCAMPUS VTA

Figure 2. Pathophysiological Model of Psychotic Disorders. A sagittal view of the brain through the midline depicts the hippocampus, midbrain, corpus striatum, and prefrontal cortex, all regions that are implicated in psychotic symptoms and disorders. The affected neurotransmitters include dopamine (blue arrows), glutamate (purple arrows), and γ-aminobutyric acid (GABA) (green arrows). Idiopathic psychoses (e.g., schizophrenia and mood disorders with psychotic symptoms) are believed to arise from overactivity of neurons that release glutamate onto cells located in and projecting from the CA1 region of the hippocampus. Deficits in hippocampal GABAergic interneurons and hypofunctioning N-methyl-D-aspartate gluta- mate receptors (NMDARs) (the red X denotes hypofunction) are the main molecules that are thought to be responsible for these distur- bances. Shown in the hippocampus is a glutamate-expressing pyramidal cell and a GABA interneuron. Despite the increase in synaptic glutamate, there is underactivation of the interneuron. Also shown is the interneuron axon forming a synapse with the apical dendrite of the pyramidal cell. Because of understimulation, the interneuron releases less GABA, which in turn disinhibits the pyramidal cell and causes it to release more glutamate from hippocampal projections to the midbrain (ventral tegmental area [VTA]) and the corpus stria- tum (nucleus accumbens). Hippocampal overactivity augments dopamine release in the striatum either directly (at the level of the nu- cleus accumbens) or by stimulation of midbrain dopamine neurons, which project to the nucleus accumbens and the prefrontal cortex. Dopamine neurons in the midbrain further promulgate the dysregulation of dopamine and glutamate through a projection back to the hippocampus. Psychotic symptoms can be induced in nonidiopathic disorders that affect these pathways at various locations. For exam- ple, in autoimmune or toxic psychoses (e.g., psychoses due to PCP), the exogenous drug or antibody acts as an NMDAR antagonist, thus mimicking a constitutionally hypofunctioning NMDAR. In Alzheimer’s disease, the cholinergic system is compromised and cholin- ergic inhibitory inputs to glutamateric cells in the hippocampus and dopaminergic cells in the midbrain are diminished. D2R denotes D2 receptor.

exert effects independently, or produce pheno- disorders, in which autoantibodies stimulate or copies of psychotic disorders. block neurotransmitter function in the brain, particularly the glutamate system. Interest in Autoimmune and Inflammatory Disorders this group of disorders is both clinical, since the with Psychoses antibodies can be assayed and certain clinical A special category of psychoses consists of those syndromes identified, and biologic, in that these that develop with autoimmune and inflammatory disorders may reveal mechanisms of psychosis.

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Systemic Autoimmune Disorders and Psychosis nevertheless expose biologic principles in the Psychotic symptoms occur in association with pathophysiology of psychosis. autoimmune diseases that have nervous system manifestations, especially SLE. Approximately Neuroimaging 30% of persons with SLE have antibodies di- Magnetic resonance imaging (MRI) and positron- rected against double-stranded DNA that cross- emission tomography (PET) have revealed vari- react with epitopes of the glutamate NR2 sub- ous abnormalities in patients with psychotic dis- unit, a component of NMDAR.23-25 Psychotic orders. For example, patients with schizophrenia, symptoms develop in some of these persons. schizoaffective disorder, or bipolar disorder with psychosis have focal volume reductions in the Paraneoplastic and Nonparaneoplastic Autoimmune temporal, frontal, and parietal lobes and reduced Syndromes with Psychosis cortical thickness in these and other brain re- Psychotic symptoms similar to those in schizo- gions.27 In patients with schizophrenia, PET stud- phrenia are a central feature of certain forms of ies show increased synaptic dopamine levels in immune encephalitis (i.e., encephalitis due to the ventral striatum and decreased levels in the antibodies directed against the glutamate NR1 frontal cortex,28 and magnetic resonance spec- subunit of NMDAR).26 These antibodies and a troscopy shows increased glutamate levels in the psychotic syndrome occur mainly with ovarian prefrontal and medial temporal regions.29,30 How- teratomas, which are known to express dermoid- ever, as with other putative biomarkers for psy- tissue epitopes that cross-react with neuronal chotic disorders, these imaging findings differ- markers. Normally, the brain is immunoprivi- entiate groups of affected patients from healthy leged, preventing antibody access to receptors persons but are not sufficiently sensitive or on neurons. However, NMDAR expression on specific for reliable diagnosis in individual pa- ectopic cells within dermoid tissue sensitizes the tients and are therefore not used clinically. adaptive immune system to produce antibodies to NMDAR that are able to cross the blood– Neurophysiological Tests brain barrier to produce symptoms. Other auto- EEG assessment may be performed when psy- antibodies (e.g., anti–metabotropic glutamate chotic symptoms first appear in patients for receptor 5 antibody) have putatively caused psy- whom there are reasons to suspect a seizure dis- chosis, but none are as well established as the order, a causative medical condition, neurodegen- NMDAR type. erative disease, or substance abuse. Specialized brain potentials that require computerized tech- Diagnosis niques to extract the signal from background EEG activity, such as potentials elicited by a Despite various etiologic and physiological hy- variety of sensory, motor, and cognitive events potheses, the diagnosis of psychotic disorders is (“event-related potentials”), have been found to clinical and therefore based predominantly on be abnormal in patients with psychotic disorders. the patient’s history, observed behavior, and sub- These tests show differences between groups of jective reports, as well as results of the mental unaffected and affected persons and offer in- status examination (Table 1). Diagnostic tests, sights into the abnormal physiology in these including neuroimaging and electroencephalo- disorders, but they are not sufficiently sensitive graphic (EEG), genotypic, toxicologic, and sero- or specific to use clinically. logic assessments, are usually performed only in selected patients presenting with a first episode Serologic Tests of psychosis or with psychotic symptoms associ- Although the risk of tertiary of the ated with preexisting neurodegenerative diseas- brain, traditionally called “general paresis of the es, other medical conditions, or substance abuse. insane,” is low in developed countries, serologic Although some of these diagnostic tests reveal screening for syphilis is nevertheless recom- differences between psychotic patients and those mended in the evaluation of a first episode of without mental disorders, none have been shown psychosis. In addition, immunologic conditions to be sufficiently sensitive or specific to reliably should be considered in cases of a sudden onset diagnose individual cases of psychosis. They of psychotic symptoms associated with or follow-

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them with high-frequency electrical pulses. At of these observations, a structured service model present, DBS is approved by the Food and Drug for first episodes of psychosis, Coordinated Spe- Administration for the treatment of Parkinson’s cialty Care, has been developed to improve the disease and refractory obsessive–compulsive dis- clinical benefits of treatment.1,40,41 This model order,38 and potential applications for the treat- of care includes pharmacotherapy, psychosocial ment of refractory depression and idiopathic therapies (including those for substance abuse), psychotic disorders are being examined. and public outreach to promote identification of and reduction in the duration of untreated psy- Psychosocial Approaches to Treatment chotic symptoms.42 Cognitive and behavioral rehabilitation has been Enthusiasm for early intervention in and pre- used in the treatment of idiopathic psychotic vention of idiopathic psychotic disorders has led disorders — in particular, schizophrenia.39 The investigators and the National Institute of Men- most widely studied of these techniques is social tal Health to determine how to extend this ap- skills training, in which patients are instructed, proach to patients in the prodromal stage of after stabilization of their acute psychotic symp- illness in order to prevent the onset of a more toms, about appropriate modes of behavior and disturbing psychotic disorder. Before this ap- communication with others and about practical proach can be applied, better diagnostic meth- life skills that may have been impaired by psy- ods must be developed, because the current cri- chotic disorders. Another psychosocial treatment teria for identifying persons with attenuated with strong empirical support is family psycho- psychotic symptoms who are believed to have a education, which enables family members to help high clinical risk of conversion to a syndromal support the patient’s recovery. form of psychosis have a false positive rate that Cognitive behavioral therapy (CBT), a treat- is higher than 50%. Consequently, a diagnostic ment originally developed for mood and anxiety test is needed that can identify psychotic episodes disorders, may also be useful for psychotic symp- that will progress to a syndromal psychosis, as toms. Specific CBT approaches used in treating well as episodes that are stable or transient and patients with schizophrenia include cognitive those that can be attenuated. Treatments so far restructuring (i.e., engaging patients to change have been shown to be effective for alleviation of beliefs about their hallucinations and delusions), symptoms but not for prevention of conversion behavioral exposure to stimuli that trigger psy- to syndromal psychosis.43 chotic symptoms to enhance reality testing, self- monitoring, and graded coping skills. CBT in Innovative Treatments for Idiopathic patients with schizophrenia can also help to re- Psychotic Disorders duce the distress caused by hallucinations or It has been hoped that precision medicine will delusional beliefs. provide new targets such as the products of newly identified genes associated with psychotic Future Directions disorders. In this context, a strategy that has been used entails exome sequencing of large Early Intervention and Prevention cohorts of patients in the hope of identifying Current pharmacologic treatments for psychotic rare mutations for which compounds acting on disorders, which act on D2 receptors to inhibit the gene pathway can be sought. dopamine neurotransmission, are considered to be symptom-suppressing rather than disease- Summary modifying. However, in patients with idiopathic psychotic disorders who are in the early stages Psychosis consists of a constellation of symp- of illness, treatment at the first episode of toms reflecting gross disturbances in cognitive schizophrenia or schizoaffective disorder short- and perceptual functions that are mediated, in ens the duration of psychotic episodes, reduces most cases, by the dysregulation of dopamine recurrences, and limits progressive decline in and glutamate neurotransmission. Dopamine D2 intellectual and functional capacity over the receptor antagonists are the mainstay of pharma- course of the patient’s life (Fig. 1). On the basis cologic treatment for idiopathic psychotic dis-

278 n engl j med 379;3 nejm.org July 19, 2018 The New England Journal of Medicine Downloaded from nejm.org at TUFTS UNIVERSITY on July 18, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Psychotic Disorders orders and for psychotic symptoms associated Dr. Lieberman reports receiving grant support from Deno- with neurodegenerative diseases but are not con- vo, Taisho, Pfizer, Sunovion, Genentech, Alkermes, Allergan, Boehringer Ingelheim, and Eli Lilly, serving on advisory sistently useful for psychotic symptoms caused boards for Intracellular Therapeutics, Pierre Fabre, Pear Ther- by other medical conditions or drug toxicity. De- apeutics, Psychogenics, and Clintara, and holding an issued spite extensive research, few mechanistic innova- patent (US20070154534A1) on secretin for refractory schizo- phrenia, licensed to Repligen; and Dr. First, receiving consult- tions in the pharmacologic treatment of psychotic ing fees from Lundbeck International Neuroscience Foundation. symptoms have been achieved. Neuromodulation No other potential conflict of interest relevant to this article was (through DBS, TMS, and tDCS) and early detec- reported. Disclosure forms provided by the authors are available with tion and intervention strategies using D2 recep- the full text of this article at NEJM.org. tor antagonists in the context of Coordinated We thank Daniel Javitt, M.D., Ph.D., for suggestions regard- Specialty Care for schizophrenia and schizo­ ing the neurobiology and treatment of psychosis, Iris V. Delgado, M.A., for assistance in preparing an earlier version of the manu- affective disorder may lead to symptom reduction script, and Larry Kegeles, M.D., and Guillermo Horga, M.D., and disease-modifying treatment. Ph.D., for assistance in conceptualizing the figures.

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