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10/18/2017 Clinical manifestations, differential diagnosis, and initial management of psychosis in adults - UpToDate

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Clinical manifestations, differential diagnosis, and initial management of psychosis in adults

Authors: Stephen Marder, MD, Michael Davis, MD, PhD


Section Editor: Murray B Stein, MD, MPH
Deputy Editor: Richard Hermann, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Aug 06, 2017.

INTRODUCTION — Psychosis is a condition of the mind broadly defined as a loss of contact with reality. It is estimated that 13 to 23 percent of people experience
psychotic symptoms at some point in their lifetime, and 1 to 4 percent will meet criteria for a psychotic disorder [1,2].

Psychotic symptoms can increase patients’ risk for harming themselves or others or being unable to meet their basic needs. Most clinicians will encounter patients
with psychosis and will thus benefit from knowing how to recognize psychotic symptoms and make appropriate initial evaluation and management decisions. Other
clinicians, particularly mental health specialists, will conduct a more thorough patient assessment, consider the patient’s differential diagnosis, and determine the
patient’s diagnosis to guide long-term treatment.

This topic will characterize different types of psychotic symptoms, provide guidance for formulating a differential diagnosis, and suggest initial evaluation and
management practices. Issues related to antipsychotic medications, the treatment of specific disorders, and psychosocial interventions are discussed separately.
(See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "First-generation antipsychotic medications: Pharmacology,
administration, and comparative side effects" and "Schizophrenia in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations,
course, assessment, and diagnosis" and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Pharmacotherapy for schizophrenia:
Acute and maintenance phase treatment" and "Psychosocial interventions for co-occurring schizophrenia and substance use disorder" and "Evaluation and
management of treatment-resistant schizophrenia" and "Anxiety in schizophrenia" and "Depression in schizophrenia" and "Pharmacotherapy for schizophrenia: Side
effect management" and "Brief psychotic disorder" and "Psychosocial interventions for schizophrenia".)

CLINICAL MANIFESTATIONS — Psychosis can present with a wide variety of signs and symptoms [3], which are described below.

Delusions — Delusions are defined as strongly held false beliefs that are not typical of the patient’s cultural or religious background. They can be categorized as
bizarre or non-bizarre based on their plausibility (eg, a belief that family members have been replaced by body-doubles is bizarre and a belief that a spouse is having
an affair is non-bizarre). Frequently encountered types of delusions include:

● Persecutory delusions (eg, believing one is being followed and harassed by gangs)
● Grandiose delusions (eg, believing one is a billionaire CEO who owns casinos around the world)
● Erotomanic delusions (eg, believing a famous movie star is in love with them)
● Somatic delusions (eg, believing one’s sinuses have been infested by worms)
● Delusions of reference (eg, believing dialogue on a television program is directed specifically towards the patient)
● Delusions of control (eg, believing one’s thoughts and movements are controlled by planetary overlords)

Hallucinations — Hallucinations can be defined as wakeful sensory experiences of content that is not actually present. They are differentiated from illusions, which
are distortions or misinterpretations of real sensory stimuli. While hallucinations can occur in any of the five sensory modalities, auditory hallucinations (eg, hearing
voices) are the most common, followed by visual, tactile, olfactory, and gustatory hallucinations. Auditory hallucinations can present as speech (including spoken
commands or a running commentary on the patient’s actions) or other sounds. Visual hallucinations can range from recognizable objects to more unformed lights or
shadows. Olfactory hallucinations are frequently of unpleasant odors.

Thought disorganization — Evidence for thought disorganization is derived from patients’ patterns of speech during the interview. While disorganized speech is a
frequently observed symptom in psychosis, it is nonspecific and can also be present in delirium or other neurological or cognitive disorders. Commonly observed
forms of thought disorganization include:

● Alogia/poverty of content – Very little information conveyed by speech


● Thought blocking – Suddenly losing train of thought, exhibited by abrupt interruption in speech
● Loosening of association – Speech content notable for ideas presented in sequence that are not closely related
● Tangentiality – Answers to interview questions diverging increasingly from topic being asked about (called circumstantiality if content eventually returns to original
topic)
● Clanging or clang association – Using words in a sentence that are linked by rhyming or phonetic similarity (eg, “I fell down the well sell bell.”)
● Word salad – Real words are linked together incoherently, yielding nonsensical content
● Perseveration – Repeating words or ideas persistently, often even after interview topic has changed

Agitation/aggression — Agitation is an acute state of anxiety, heightened emotional arousal, and increased motor activity. Although not specific to psychosis,
untreated psychosis is associated with an increased risk for agitation and aggressive behaviors. These can sometimes lead to intentional or unintentional bodily harm
to self or others. Clinicians should observe the patient’s behaviors, including body language and voice intonation, and use appropriate safety measures for the
evaluation. (See "Assessment and emergency management of the acutely agitated or violent adult".)

DIFFERENTIAL DIAGNOSIS — Psychotic symptoms can be associated with a wide variety of primary psychiatric and medical illnesses. Clinical features of the
psychosis are not pathognomonic for particular diagnoses, but can provide evidence suggestive of primary psychiatric versus medical etiologies.

● Associated with primary psychiatric (psychotic) disorders:

• Family history often present


• Insidious onset
• Onset in teens to mid-thirties
• Variable presentation
• Auditory hallucinations

● Associated with primary medical condition:

• Family history variably present


• Acute onset

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• Onset in forties or older
• Presents in general medical or intensive care settings
• Non-auditory hallucinations (eg, visual, tactile, olfactory)

Each case should be evaluated thoroughly; possible causes for psychosis should not be ruled out by these features alone. A thorough history, physical examination,
mental status examination, and additional tests as indicated can help narrow the differential, rule out psychoses with treatable underlying causes, and guide the
appropriate intervention or referral [4].

Primary psychiatric illnesses — Psychiatric illnesses are generally classified by diagnostic criteria established by the DSM-5 [5] or the International Classification of
Diseases (ICD, World Health Organization). These constructs and criteria are periodically revised based on research findings and expert consensus. An algorithm
describes the differential diagnosis of psychotic symptoms (algorithm 1).

● Schizophrenia – This disorder is defined by the presence of psychotic symptoms (eg, delusions, hallucinations, disorganized speech, grossly disorganized or
catatonic behavior, or diminished emotional expression or volition) for a “significant portion of time during a one-month period (or less if successfully treated).”
DSM-5 requires that the symptoms be associated with a decline in functioning or failure to achieve the expected level of functioning. Signs of the disturbance
must persist for at least six months. Schizoaffective disorder, mood disorders with psychotic features, and attribution to substance use or medical conditions must
be ruled out. Additional diagnostic requirements must be met if there is a history of another childhood-onset psychiatric disorder. (See "Schizophrenia in adults:
Clinical manifestations, course, assessment, and diagnosis".)

● Schizophreniform disorder – This disorder can be considered to have similar symptomatic presentation as schizophrenia, except with an episode lasting
greater than one month but less than six months. In addition, functional decline does not need to be present. Schizoaffective disorder, mood disorders with
psychotic features, and attribution to substance use or medical condition(s) must be ruled out.

● Schizoaffective disorder – This disorder is defined by the individual having “an uninterrupted period of illness during which there is a major mood episode”
concurrent with psychotic symptoms as well as “delusions or hallucinations for two or more weeks in the absence of a major mood episode” during the duration
of the illness. Individuals with this disorder must have symptoms that meet criteria for a major mood disorder “for the majority of the total duration of the active
and residual portions of the illness.” Disorder presentation cannot be attributable to substance use or another medical condition.

● Delusional disorder – This disorder is characterized by the “presence of one (or more) delusions with a duration of one month or longer”; the absence of
meeting criteria for schizophrenia; a lack of marked impairment in functioning or obvious bizarre behaviors; and a lack of attribution to manic or depressive
episodes, substances, other medical conditions, or better explanation by another mental disorder. The delusions are classified as erotomanic type, grandiose
type, jealous type, persecutory type, somatic type, mixed type, or unspecified type, and by whether they have bizarre content. (See "Delusional disorder" and
"Delusional parasitosis: Epidemiology, clinical presentation, assessment and diagnosis" and "Treatment of delusional parasitosis".)

● Brief psychotic disorder – This disorder is characterized by the presence of psychotic symptoms (eg, delusions, hallucinations, disorganized speech, or grossly
disorganized or catatonic behavior) with duration ≥one day and <one month, with eventual return to premorbid functioning. The episode cannot be a culturally
sanctioned response or better explained by another mental disorder, substance, or medical condition. These episodes are often associated with an intense
stressor or traumatic event. (See "Brief psychotic disorder".)

● Schizotypal (personality) disorder – This is considered a personality disorder in the DSM-5 and schizotypal disorder in the ICD-9 and ICD-10. It is defined in
the DSM-5 as “a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as
by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of context, as indicated by five (or
more) of the following: ideas of reference, odd beliefs or magical thinking; unusual perceptual experiences; odd thinking and speech; suspiciousness or paranoid
ideation; inappropriate or constricted affect; behavior or appearance that is odd; lack of close friends or confidants; excessive social anxiety.” The criteria specify
that the syndrome does not occur exclusively during the course of schizophrenia, a mood disorder with psychotic features, other psychotic disorders, or autism
spectrum disorder. (See "Schizotypal personality disorder: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".)

● Major depressive disorder with psychotic features – Major depressive disorder is characterized by the individual experiencing five or more depressive
symptoms (including depressed mood, diminished interest in pleasure, change in appetite, sleep disturbance, psychomotor agitation or retardation, loss of
energy, feelings of worthlessness or guilt, poor concentration, and recurrent thoughts of death) for a two-week period, along with significant distress or functional
impairment. The depressive episodes cannot be attributable to substance use, other medical conditions, or other psychiatric illnesses including schizoaffective
disorder or bipolar disorder. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)

● Bipolar disorder with psychotic features – Bipolar (I) disorder is characterized by periods of mania (“distinct periods of abnormally and persistently elevated,
expansive, or irritable mood” for “at least one week and present most of the day, nearly every day” in conjunction with symptoms and behaviors such as
decreased need for sleep, racing thoughts, and increased goal-directed activity). The manic episodes must be severe enough to cause “marked impairment in
social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.” The episodes also cannot be
attributable to substance use or other medical conditions. (See "Bipolar disorder in adults: Clinical features", section on 'Psychosis'.)

Substance-induced psychoses — Many prescription medications as well as illicit substances can induce transient psychotic symptoms [6]. The DSM-5 defines
“substance/medication-induced psychotic disorder” as having the presence of delusions and/or hallucinations during or soon after intoxication, withdrawal, or
exposure to a substance, with the disturbance not being better explained by another type of psychotic disorder. The disturbance cannot “occur exclusively during the
course of a delirium” and must cause significant distress or impairment in function. A table lists major substances, medications, and toxins that can cause transient
psychoses (table 1).

Psychoses associated with medical or neurological conditions — A large number of medical illnesses can be accompanied by psychotic symptoms. Presenting
and distinguishing characteristics of these diseases are described separately.

● Delirium – A delirium is an acute mental disturbance characterized by problems of attention, confusion, and disorientation. It often presents suddenly and
fluctuates in intensity. Delirium frequently is associated with psychotic symptoms [7] and can improve following antipsychotic treatment [8]. Frequent causes of
delirium include fluid or electrolyte abnormalities, hypoglycemia, hypoxia, hypercapnea, infections, or medications, substance intoxication or withdrawal are
described in a table (table 1). (See "Diagnosis of delirium and confusional states".)

● Endocrine disorders – Thyroid disease, parathyroid disease, adrenal disease. (See "Diagnosis of hyperthyroidism" and "Primary hyperparathyroidism: Clinical
manifestations" and "Diagnosis of adrenal insufficiency in adults".)

● Hepatic and renal disorders – Hepatic encephalopathy, uremic encephalopathy. (See "Hepatic encephalopathy in adults: Clinical manifestations and
diagnosis".)

● Infectious disease – HIV, syphilis, herpes simplex encephalitis, Lyme disease, prion disorders. (See "Acute and early HIV infection: Clinical manifestations and
diagnosis" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection" and "Diagnosis of Lyme disease" and "Diseases of
the central nervous system caused by prions" and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients", section on
'Clinical manifestations'.)

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● Inflammatory or demyelinating disorders – Anti-NMDA receptor encephalitis, systemic lupus erythematosus, multiple sclerosis, leukodystrophies. (See
"Paraneoplastic and autoimmune encephalitis" and "Diagnosis of multiple sclerosis in adults" and "Diagnosis and differential diagnosis of systemic lupus
erythematosus in adults" and "Differential diagnosis of acute central nervous system demyelination in children".)

● Metabolic disorders or acute processes – Wilson’s disease, acute intermittent porphyria. (See "Wilson disease: Clinical manifestations, diagnosis, and natural
history" and "Porphyrias: An overview".)

● Neurodegenerative disorders [9] – Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, Huntington’s disease. (See "Evaluation of cognitive
impairment and dementia".)

● Neurological – Head trauma/traumatic brain injury, space-occupying lesions (tumors, cysts), seizure disorders; stroke. (See "Overview of the clinical features
and diagnosis of brain tumors in adults".)

● Vitamin deficiency – Vitamin B12 deficiency. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

DIAGNOSTIC EVALUATION — Primary psychiatric illnesses are generally diagnoses of exclusion. It is important to conduct a thorough evaluation of psychotic
symptoms, particularly on initial presentation [10], in order to identify treatable underlying causes.

Interview — The interview should focus on establishing a timeline of symptoms, a psychiatric history including prior diagnoses and treatments, a substance use
history, a family history for psychiatric illness, and a complete medical history. Disorganized thinking may prevent the patient from giving a coherent history.
Additionally, patients may not spontaneously report psychotic symptoms; any patient in whom psychotic symptoms are suspected should be asked directly about
experiencing hallucinations, suspiciousness, thought reading, special messages from TV or radio, and special powers or abilities. The clinician should seek
corroborative sources of information, whenever possible, for evidence of delusional or referential thinking or other unusual behaviors.

Mental status examination — A complete mental status examination should be conducted, paying particular attention to the patient’s appearance (grooming,
hygiene) and general behaviors, mood and affect, thought processes, evidence for perceptual disturbances (responding to internal stimuli), unusual thought content,
attention, and memory function.

Common medical workup

● Chemistry panel to evaluate for disturbances in fluid or electrolytes


● Complete blood count to evaluate for infectious processes; blood culture if indicated
● Hepatic function panel to evaluate for liver abnormalities
● Thyroid-stimulating hormone level to rule out thyroid disease
● Serum treponemal test such as fluorescent treponemal antibody absorption (FTA-ABS) to screen for syphilis
● Urinalysis to evaluate for urinary tract infection or other abnormalities; urine culture if indicated
● Urine drug screen to evaluate for recent substance use
● Vitamin B12 levels to evaluate for deficiency
● HIV to evaluate for infection

Additional tests to consider based on other evidence

● Computed tomography (CT) brain or magnetic resonance imaging (MRI) to evaluate for space-occupying lesions, demyelinating disorders, or stroke
● Electroencephalogram (EEG)
● Lumbar puncture
● Heavy metal screen
● Rheumatologic workup (eg, antinuclear antibody, antiribosome antibody, anti-NMDA receptor antibody)
● Hormone levels

Differentiation between DSM-5 psychotic disorders ─ If substances, medications, or underlying medical conditions have been ruled out as causes for psychotic
symptoms, a primary psychiatric disorder should be considered. When determining the specific disorder, the associated symptoms and time course are the primary
differentiators [11].

If clinically significant mood symptoms are present (depressive or manic symptoms), then major depressive disorder with psychotic features, bipolar disorder with
psychotic features, or schizoaffective disorder should be considered as possibilities. If the individual has never had psychotic symptoms without mood symptoms, the
diagnosis will be major depressive disorder with psychotic features or bipolar disorder with psychotic features (depending on a history of manic symptoms). If the
individual has an overlap of mood symptoms with psychosis for the majority (but not all) of the psychotic illness, schizoaffective disorder will be the likely diagnosis.

If there is a more limited overlap of psychosis and mood symptoms (either no overlap or overlap only for a minority of the illness duration), then brief psychotic
disorder, schizophreniform disorder, schizophrenia, or delusional disorder would be possible diagnoses. The duration of the psychotic episode will differentiate
between brief psychotic disorder (<one month), schizophreniform disorder (one to six months), and schizophrenia (>six months).

Delusional disorder would be considered if the psychotic symptoms are limited to delusions, functioning is not markedly impaired, and other symptoms and behaviors
associated with schizophrenia are not present. Schizotypal personality disorder would be considered if there is no period of significant persistent psychotic symptoms
and if there is a “pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as by
cognitive or perceptual distortions and eccentricities of behavior” [11].

INITIAL MANAGEMENT — Patients with psychosis should be evaluated for agitation, risk of harm to themselves or others, and their ability to take care of
themselves. Patients at risk of harm to themselves or others may need to be hospitalized. Management of agitated patients with psychosis is described in detail
separately. A rapidly acting first-generation antipsychotic and/or a rapidly acting benzodiazepine are suggested to sedate severely agitated, potentially violent patients
with psychosis. (See "Assessment and emergency management of the acutely agitated or violent adult".)

Patients with psychosis and their families should be educated about their illnesses, risks associated with psychosis (eg, increased risk of harm to themselves or
others), and risks and side effects associated with antipsychotic medications. Families or caregivers should be advised to reduce environmental stimulation, not argue
with delusional ideas, and interact with psychotic patients in a calm and gentle manner.

We recommend symptomatic treatment of psychosis with an antipsychotic medication, even if the psychiatric disorder or medical condition underlying the psychosis
has not yet been established. While antipsychotics have been most extensively studied in the treatment of schizophrenia, the medications appear to be broadly
effective for psychotic symptoms. As examples, meta-analyses have found antipsychotics are effective in the treatment of psychotic mania in bipolar disorder [12],
major depressive disorder with psychotic features (when combined with an antidepressant) [13], delirium [14], psychosis in Parkinson’s disease (clozapine) [15], and
psychosis of Alzheimer’s disease [16]. There is less of an evidence base for their use for rarer general medical conditions. The use and effectiveness of antipsychotic
drugs for individual disorders and diseases are discussed separately. (See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and
"Evaluation and management of treatment-resistant schizophrenia" and "Brief psychotic disorder" and "Management of neuropsychiatric symptoms of dementia" and

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"Treatment of delusional parasitosis" and "Treatment of postpartum psychosis" and "Unipolar major depression with psychotic features: Acute treatment" and
"Guidelines for prescribing clozapine in schizophrenia" and "Delusional disorder".)

If the psychosis is associated with a mood disorder exacerbation, the underlying mood disorder should be treated as well. If the psychosis is associated with a
general medical condition, antipsychotic therapy should be added to the appropriate treatment for the underlying condition. (See "Unipolar major depression with
psychotic features: Acute treatment" and "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania".)

Antipsychotic drugs are most effective at improving positive psychotic symptoms (eg, hallucinations, delusions) while offering less benefit for negative symptoms (eg,
blunted affect, avolition) or cognitive deficits that are frequently associated with psychosis. Antipsychotics can reduce agitation [17] and may reduce suicide risk [18].
The benefits of antipsychotics should, however, be weighed against their risks and possible side effects (table 2). Appropriate steps should be taken to mitigate risk
(eg, performing baseline EKGs on older adult patients or those with cardiac history and considering possibility for antipsychotic-induced QTc prolongation). (See
"Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment", section on 'Drug efficacy'.)

With the exception of clozapine, which is used for treatment-resistant chronic psychosis, there is an absence of rigorous evidence that any one antipsychotic drug is
more effective than other antipsychotics. The choice among antipsychotics is usually made on the basis of side effect profile, cost, and formulations available (table
2).

The dose of most antipsychotic drugs should be titrated from an initial dose to the therapeutic range, as described in the tables, as quickly as tolerated (table 2 and
table 3). As an example, risperidone can be started at 1 to 2 mg/day and titrated to a therapeutic dose (typically 2 to 6 mg/day). If a satisfactory clinical response is
not seen within seven days, the dose can be increased in 0.5 to 1 mg/day increments to a maximum of 8 mg/day. If there is no improvement in psychotic symptoms
after two weeks of a therapeutic dose, a different antipsychotic should be considered. The recommended duration of antipsychotic therapy varies according to the
underlying etiology: in chronic schizophrenia, antipsychotics should be offered indefinitely to reduce relapse risk [19]; with time-limited psychoses (such as delirium),
antipsychotic therapy can be continued for two weeks after the resolution of symptoms and then tapered off gradually. The selection among antipsychotic drugs and
their dosing are described in detail separately. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and
"Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Pharmacotherapy for schizophrenia: Acute and maintenance
phase treatment", section on 'Acute phase symptoms'.)

Consultation or referral to a psychiatrist — Any patient with an initial onset of psychosis should be evaluated by a psychiatrist, whether in the form of an urgent
outpatient psychiatric consultation or in an emergency room or an inpatient consultation by a hospital psychiatrist. Presenting patients engaged in longitudinal
treatment for a psychotic disorder (or other disorder/illness with psychosis) should be evaluated if he or she is:

● Experiencing a marked increase in symptom severity


● Displaying agitated or aggressive behavior
● A possible danger to themselves or others
● Unable to provide for their basic needs

Voluntary versus involuntary treatment — Patients at risk of harm to themselves or others may need to be hospitalized to ensure safety. Evaluation and treatment
for psychosis should be voluntary whenever possible, but the nature of the illness may lead patients to fear or avoid treatment. In most states, dangerousness to self
or others, or the inability to provide for one's basic needs of food, clothing, and shelter, is sufficient cause for involuntary treatment. The legal mechanism for initiating
this differs significantly by legal jurisdiction. Clinicians, especially those in emergency settings, should become familiar with involuntary treatment procedures within
their legal jurisdictions. The local community mental health agency or the nearest psychiatric emergency service should be able to assist with information, legal forms,
and other aid in arranging involuntary care.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education
pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

● Basics topics (see "Schizophrenia in adults: Epidemiology and pathogenesis" and "Patient education: Tardive dyskinesia (The Basics)" and "Patient education:
Bipolar disorder (The Basics)")

● Beyond the Basics topics (see "Patient education: Bipolar disorder (manic depression) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Psychosis is a condition of the mind broadly defined as a loss of contact with reality, which often presents with delusions, hallucinations, thought disorganization,
or unusual behaviors. (See 'Clinical manifestations' above.)

● Patients with psychosis are at elevated risk for agitated and aggressive behaviors, and safety precautions should be employed. (See 'Agitation/aggression' above
and 'Mental status examination' above.)

● Psychotic symptoms can present in a variety of psychiatric and medical illnesses; clinical features are not pathognomonic for particular diagnoses. (See
'Psychoses associated with medical or neurological conditions' above.)

● It is important to perform a thorough history, physical examination, mental status examination, and workup in order to rule out treatable underlying causes of
psychosis and guide appropriate therapy (See 'Diagnostic evaluation' above.)

● Patients with psychosis should be evaluated for agitation, risk of harm to themselves or others, and their ability to take care of themselves. Patients at risk of
harm may need to be hospitalized. Severely agitated patients with psychosis may immediate sedation or other restraint. (See 'Initial management' above and
"Assessment and emergency management of the acutely agitated or violent adult".)

● We recommend symptomatic treatment of psychosis with an antipsychotic medication, even if the specific psychiatric disorder or medical condition underlying the
psychosis has not yet been established (Grade 1B). As antipsychotic drugs are largely similar in efficacy, selection among them is typically made on the basis of
patient presentation and the medication’s side effect profile, cost, and formulations available (table 2 and table 3). (See 'Initial management' above.)

As an example, risperidone can be started at 1 to 2 mg/day and titrated to a therapeutic dose (typically 2 to 6 mg/day). If a satisfactory clinical response is not
achieved after seven days, the dose can be increased in increments of 0.5 to 1 mg/day to a maximum of 8 mg/day. (See 'Initial management' above.)

● Antipsychotic treatment is typically administered in combination with treatment of the underlying condition. This applies to medical conditions causing psychosis
as well as a mood disorder exacerbation or substance use disorder. (See "Unipolar major depression with psychotic features: Acute treatment" and "Bipolar

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disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and
"Psychosocial interventions for co-occurring schizophrenia and substance use disorder" and "Psychosocial interventions for schizophrenia" and "Brief psychotic
disorder".)

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GRAPHICS

Differential diagnosis of delusions

Adapted from: American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th Ed: DSM-5. Washington, D.C.:
American Psychiatric Association, 2013.

Graphic 100456 Version 2.0

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Substances and medications with capacity to induce psychosis

Substance or medication Examples

Alcohol and sedatives/hypnotics Alcohol (intoxication or withdrawal), barbiturates and benzodiazepines (particularly withdrawal)

Anabolic steroids Testosterone, methyltestosterone

Analgesics Meperidine, pentazocine, indomethacin

Anticholinergics Atropine, scopolamine

Antidepressants Bupropion, others if triggering a manic switch

Antiepileptics Zonisamide, other anticonvulsants at high doses

Antimalarial Mefloquine, chloroquine

Anti-parkinsonian Levodopa, selegiline, amantadine, pramipexole, bromocriptine

Antivirals Abacavir, efavirenz, nevirapine, acyclovir

Cannabinoids Marijuana, synthetic cannabinoids (ie, "spice"), dronabinol

Cardiovascular Digoxin, disopyramide, propafenone, quinidine

Corticosteroids Prednisone, dexamethasone, etc

Hallucinogens LSD, PCP (phencyclidine), ketamine, psilocybin-containing mushrooms, mescaline, synthetic "designer drugs" (eg, 2-CB, "N-
Bomb" [25I-NBOMe]) , salvia divinorum

Inhalants Toluene, butane, gasoline

Interferons Interferon alfa-2a/2b

Over-the-counter (OTC) Dextromethorphan (DXM), diphenhydramine, some decongestants

Stimulants Cocaine, amphetamine/methamphetamine, methylphenidate, certain diet pills, "bath salts" (MDPV, mephedrone),
MDMA/ecstasy

Toxins Carbon monoxide, organophosphates, heavy metals (eg, arsenic, manganese, mercury, thallium)

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Selected adverse effects of antipsychotic medications for schizophrenia

Weight
Hyper- Prolactin Anticholinergic Orthostatic QTc
gain/diabetes EPS/TD Sedation
cholesterolemia elevation side effects hypotension prolongation
mellitus

First generation agents

Chlorpromazine +++ +++ + ++ +++ +++ +++ +

Fluphenazine + + +++ +++ + –/+ – ND

Haloperidol + + +++ +++ ++ –/+ – +

Loxapine ++ ND ++ ++ ++ + + +

Perphenazine ++ ND ++ ++ ++ + – ND

Pimozide + ND +++ ++ + + + ++

Thioridazine* ++ ND + +++ +++ ++++ ++++ +++

Thiothixene ++ ND +++ ++ + + + +

Trifluoperazine ++ ND +++ ++ + + + ND

Second generation agents

Aripiprazole + – + – + – – –/+

Asenapine ++ – ++ ++ ++ – + +

Brexpiprazole ¶ + + + –/+ + –/+ –/+ –/+

Cariprazine ¶ + –/+ ++ –/+ + –/+ –/+ –/+

Clozapine Δ ++++ ++++ –/+ –/+ +++ +++ +++ +

Iloperidone ++ ++ –/+ –/+ + + +++ ++

Lurasidone –/+ –/+ ++ –/+ ++ – + –/+

Olanzapine ++++ ++++ + + ++ ++ + +

Paliperidone +++ + +++ +++ + – ++ +

Pimavanserin + - -/+ - + + ++ +

Quetiapine +++ +++ –/+ –/+ ++ ++ ++ +

Risperidone +++ + +++ +++ + + + +

Ziprasidone –/+ –/+ + + + – + ++

Adverse effects may be dose dependent.

EPS: extrapyramidal symptoms; TD: tardive dyskinesia; ND: no data.


* Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to text.
¶ Based upon limited experience.
Δ Clozapine also causes granulocytopenia or agranulocytosis in approximately 1 percent of patients requiring regular blood cell count monitoring. Clozapine has been associated with
excess risk of myocarditis and venous thromboembolic events including fatal pulmonary embolism. These issues are addressed in the UpToDate topic review of guidelines for prescribing
clozapine section on adverse effects.

References:
1. Lexicomp Online. Copyright © 1978-2017 Lexicomp, Inc. All Rights Reserved.
2. The Medical Letter on Drugs and Therapeutics (April 2016); Some Relative Adverse Effects of Second-Generation Antipsychotics (table 3); Vol. 58 (1493):52.
www.medicalletter.org.
3. Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-
analysis. Schizophr Res 2010; 123:225.
4. Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 2013; 69:1485.

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Pharmacology of antipsychotics: Dosing (adult), formulations, kinetics and potential for drug interactions

Adjustment
Usual of oral dose Usual Half-life after
Initial Enzyme(s)
oral dose in older* or maximum oral Primary
Agent oral dose Formulations inhibited Notes
range medically oral dose administration metabolism ◊
(mg/day) (see note) §
(mg/day) compromised (mg/day) Δ (hours)
patients ¶

First-generation antipsychotics (FGAs)

Chlorpromazine 400 to 600 25 to 200 Use low initial 800 Tab, IM 30 CYP2D6, other CYP2D6 Oral absorptio
dose and increase CYPs and UGT- is variable and
more gradually glucuronidation to may require
active and dose
inactive adjustment
metabolites based on
patient
response.
Older adults
and medically
patients are
unlikely to
tolerate
cardiovascular
sedating, and
anticholinergic
side effects.

Fluphenazine 2 to 15 2 to 10 1 to 2.5 mg daily 12 Tab, IM, LAI, oral 33 CYP2D6 CYP2D6 Oral absorptio
initially, adjust solution is highly
dose gradually variable and
based on response dose must be
individualized
based on
patient
response.

Haloperidol 2 to 20 2 to 10 1 to 5 mg daily; 30 Tab, IM, LAI, oral 20 CYPs 2D6, 3A4 CYPs 2D6, 3A4 The US labeled
adjust dose solution and UGT- (moderate) maximum
gradually based glucuronidation; recommended
on response some metabolites dose of 100
potentially active mg/day (oral)
or toxic considerably
higher than
more recent
practice
supports.
Bioavailability
with oral dosin
is about 60%;
dose
adjustments
between oral
and parentera
administration
should be mad
accordingly.
Intravenous u
has not been
approved by t
US Food and
Drug
Administration
and is
associated wit
increased risk
of QT
prolongation;
refer to
accompanying
text.

Loxapine 20 to 80 20 Generally follows 100 Capsule; oral 6 to 8 (parent drug) CYPs 1A2, 2D6, None Onset of oral
standard adult inhalation for use 12 (active 3A4 and UGT- (swallowed
dosing, although a in healthcare metabolites) glucuronidation to capsule) and I
dose reduction settings as active and within 30
may be indicated alternative to IM inactive minutes.
in some cases injection. metabolites
Oral solution and
IM injection
available in
countries other
than United
States.

Perphenazine 12 to 24 8 to 16 Initiate dose at 8 24 (a higher Tab 9 to 12 (parent CYPs 2D6, 3A4 CYP2D6 Bioavailability
mg/day and daily dose may drug) and other CYPs to variable (60 to
titrate more be acceptable, 10 to 19 (active active and 80%).
gradually to the refer to notes) metabolite) inactive Higher daily
usual adult range metabolites doses, eg, up
32 mg per day
were shown to
be similar in
tolerability and
efficacy to som
SGAs [1] and in

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practice up to
64 mg per day
total may be
acceptable in
some
circumstances

Pimozide ¥ 8 to 10 1 to 2 1 mg/day initially 10 Tab 55 CYPs 1A2, 2D6, CYP2D6 Bioavailability


and titrate more 4 (CYP2D6 poor 150 (CYP2D6 poor 3A4 and others variable due to
gradually to the metabolizer) metabolizers) extensive
usual adult range hepatic first-
pass
metabolism.

Thiothixene ¥ 10 to 20 5 to 10 Use low initial 30 Capsule 34 CYP1A2 and other None Oral absorptio
(tiotixene) dose and titrate CYPs is variable and
more gradually to dose must be
the usual adult individualized
dose range based on
patient
response.

Thioridazine 200 to 600 150 Use low initial 600 Tab 4 to 10 (parent CYP2D6 and other CYP2D6
dose and titrate drug) CYPs to active
more gradually to 21 to 25 (active (mesoridazine)
the usual adult metabolites) and inactive
dose range metabolites

Trifluoperazine ¥ 15 to 20 4 to 10 Initiate dose at 4 40 Tab 3 to 12 (parent CYP1A2 and other None Bioavailability
mg/day and drug) CYPs to active variable.
titrate more 22 (active and inactive
gradually to the metabolites) metabolites
usual adult range

Second-generation antipsychotics (SGAs)

Aripiprazole 10 to 15 10 to 15 None 30 Tab, ODT, LAI, 75 to 94 CYPs 2D6 and None For
oral solution 3A4 to active and augmentation
Aripiprazole inactive of
lauroxil LAI metabolites antidepressant
a lower daily
dose of 2 to 5
mg is useful.

Asenapine ¥ 10 to 20 10 None. 20 Sublingual tab 24 CYP1A2 and UGT- None Patient should
Exception: Use glucuronidation not eat or drin
contraindicated in within 10
severe hepatic minutes of
impairment. sublingual (SL
administration
SL preparation
should not be
swallowed due
to poor
gastrointestina
absorption.

Brexpiprazole 2 to 4 0.5 to 1 Dose adjustments 4 Tab 91 CYP2D6 and 3A4 None


are needed in
renal or hepatic
impairment ‡

Cariprazine 1.5 to 6 1.5 Not recommended 6 Capsule 48 to 96 (parent CYP3A4 to active † None
in severe renal or drug) and inactive
hepatic 7 to 21 days metabolites
impairment (active
metabolites) †

Clozapine ¥ 150 to 600 25 to 50 Titrate gradually 900 Tab, ODT, oral 12 CYP1A2, other CYP2D6 Hypotension is
to reduced suspension CYPs, and UGT- (moderate) the most
maintenance glucuronidation frequent dose
range of 100 to limiting factor
150 mg/day; during titration
maximum 300 Other side
mg/day. effects requirin
Lower doses monitoring
advised in renal or include
hepatic agranulocytos
impairment; sedation, and
specific dose sialorrhea.
adjustment Once titrated t
recommendations 300 to 450 mg
are not available. daily, rate of
titration may b
increased to
100 mg once o
twice weekly.

Iloperidone 12 to 24 2 Not recommended 24 Tab 18 to 26 CYP2D6 and other CYP3A4 Orthostatic


in severe hepatic 12 (CYP2D6 CYPs to active (moderate) hypotension is
impairment poor and inactive usually the do
metabolizer or metabolites limiting factor
receiving 2D6 titration.
inhibitor
cotreatment)

Lurasidone 40 to 80 40 Dose adjustments 160 Tab 29 to 37 (at steady CYP3A4 to active None Needs to be
20 (renal or are needed in 80 (moderate state) and inactive taken with a
hepatic renal and hepatic or severe renal metabolites meal to be
insufficiency) impairment ‡ impairment, adequately
moderate absorbed.

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hepatic
impairment)
40 (severe
hepatic
insufficiency)

Olanzapine ¥ 10 to 20 5 to 10 Initially 1.25 to 30 Tab, ODT, IM, LAI 30 to 38 CYP1A2 and UGT- None
2.5 mg/day; glucuronidation
typical
maintenance 5
mg/day;
maximum 10
mg/day

Paliperidone 6 to 12 6 Older adults or 12 ER tab, LAI 23 Paliperidone is None Tablets need t


renal impairment: excreted mainly be swallowed
3 mg/day ‡ unchanged in whole.
urine
necessitating
dose reduction in
renal
insufficiency ‡

Pimavanserin 34 34 Not recommended 34 Tab 57 parent drug CYP3A4 and 3A5 None Approved for
in hepatic (200 for active to active reducing
impairment or metabolite) metabolite Parkinson
severe renal disease related
impairment (not psychosis.
studied) Dose
adjustment
needed if used
with strong
inhibitors of
CYP3A. Efficac
may be reduce
if used with
strong inducer
of CYP3A. Refe
to separate
table of CYP3A
inhibitors and
inducers
available in
UpToDate.

Quetiapine 150 to 750 50 Initially 25 to 50 750 (immediate Tab, ER tab 6 to 12 CYP3A4 None Titration most
(immediate mg/day; use release) often limited b
release) substantially lower 800 (extended excessive
400 to 800 maintenance release) sedation or
(extended dose. orthostatic
release) Dose adjustment hypotension
needed in hepatic which should b
impairment ‡. monitored.

Risperidone 2 to 6 1 to 2 Initially 0.25 to 8 Tab, ODT, LAI, 20 CYP2D6 to active CYP2D6


0.5 mg/day; oral solution (paliperidone) and (moderate)
typical inactive
maintenance 1 metabolites; P-gp
mg/day; substrate
maximum 2
mg/day.
Dose adjustments
are needed in
renal and hepatic
impairment ‡.

Ziprasidone 40 to 160 40 to 80 Lower doses 200 Capsule, IM 7 oral CYP3A4 None Oral preparatio
advised in hepatic 2 to 5 IM is not
impairment; dependent on
specific renal function
adjustment for clearance
recommendations but a
are not available component of
the IM injectio
is cleared by
the kidney.

Important note: Doses shown are total daily dose, oral administration, for maintenance treatment of schizophrenia in otherwise healthy adults. The dosing and other
information provided in this table differs from dosing used in management of behavioral symptoms of dementia in older adults; in general these medications are not
recommended for that use. For additional information, refer to the relevant UpToDate clinical topics and the Lexicomp drug monographs included within UpToDate.

ODT: orally dissolving tablet; Tab: tablet; ER tab: extended-release tablet; IM: short-acting intramuscular injection; LAI: long-acting injectable (eg, depot); CYP: cytochrome P-450; P-gp:
membrane P-glycoprotein transporters; UGT-glucuronidation: uridine 5'diphosphate-glucuronyltransferases.
* First- and second-generation antipsychotics are included on the Beers list of medications to be used with caution in older adults and should in general be avoided except for schizophrenia
and bipolar disorder. [2]
¶ First-generation antipsychotics (FGAs) undergo extensive hepatic metabolism; levels may be elevated in hepatic impairment necessitating dose reduction and more gradual dose titration
to avoid toxicity. FGAs should be used with caution at significantly reduced doses or avoided in severe hepatic impairment.
Δ Usual maximum total oral daily dose for maintenance treatment of schizophrenia in adult patients without significant comorbidity. Doses shown may not be the maximum dose used in
some clinical trials or in exceptional patients.
◊ Dose adjustments of several antipsychotic medications listed in this table are recommended in presence of strong or moderate inhibitors or inducers of CYP drug metabolism; for specific
recommendations refer to the individual Lexicomp drug monographs.
§ Only potent to moderate inhibitor effects are listed in this table. For additional information including moderate to weak inhibitor or inducer effects, and to determine specific drug
interactions, refer to individual drug monographs section on drug interactions and the Lexi-Interact program included with UpToDate.
¥ Smoking may decrease blood concentrations of antipsychotics primarily metabolized by CYP1A2.
‡ For specific dose adjustments in setting of renal or hepatic impairment, refer to Lexicomp drug monograph.
† Active metabolites of cariprazine are equipotent to cariprazine. Due to the long half-life of cariprazine and active metabolites, changes in dose will not reach plasma steady-state for
several weeks or months.

References:
1. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209.

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10/18/2017 Clinical manifestations, differential diagnosis, and initial management of psychosis in adults - UpToDate
2. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older
Adults. J Am Geriatr Soc 2015; 63:2227.
Prepared with data from:
1. US product information (available online at http://dailymed.nlm.nih.gov/dailymed/about.cfm) and Health Canada product monograph (available online at http://webprod5.hc-
sc.gc.ca/dpd-bdpp/index-eng.jsp).
2. Lexicomp Online. Copyright © 1978-2017 Lexicomp, Inc. All Rights Reserved.
3. Wynn GH, et al (eds) Clinical Manual of Drug Interaction Principles for Medical Practice APA publishing, Washington DC. Copyright © 2009.

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