Margarita Abi Zeid Daou, MD • Jeffrey Stovall, MD
BASICS
Schizophrenia is a persistent and severe psychiatric condition characterized by neurocognitive decline and impairment in reality testing.
DESCRIPTION
• Major psychiatric disorder characterized by prodrome, active, and residual psychotic symptoms involving disturbances in appearance, speech, behavior, perception, and thought that last for at least 6 months.
• DSM-5 eliminated subcategories of schizophrenia (1).
• System(s) affected: central nervous system (CNS)
EPIDEMIOLOGY
Incidence
• 7.7 to 43/100,000
• Predominant sex: male-to-female ratio = 1.4:1.0
• Age of onset: typically <30 years, earlier in males (early to mid-20s) than females (late 20s), with a smaller peak that occurs in women >45 years
Prevalence
• Lifetime (1%): highest prevalence in lower socioeconomic classes and urban settings (2-fold higher risk)
• 1.1% of the population >18 years old; similar rates in all countries
ETIOLOGY AND PATHOPHYSIOLOGY
• Stems from a complex interaction between genetic and environmental factors; higher incidence if prenatal infection or hypoxia, winter births, first-generation immigrants, advanced paternal age, drug use, and genetic (velocardiofacial) syndromes
• Overstimulation of mesolimbic dopamine D2 receptors, deficient prefrontal dopamine, and aberrant prefrontal glutamate (NMDA) activity results in perceptual disturbances, disordered thought process, and cognitive impairments.
Genetics
If first-degree biologic relative has schizophrenia, risk is 8–10%; a 10-fold increase
GENERAL PREVENTION
• Currently, no known preventive measures decrease the incidence of schizophrenia.
• Interventions to improve long-term outcome and associated comorbid conditions are employed during management.
COMMONLY ASSOCIATED CONDITIONS
• Nicotine dependence (>50%) (1) and substance use disorders are common and lead to significant long-term medical and social complications (2).
• Metabolic syndrome, diabetes mellitus, obesity, and certain infectious diseases, including HIV, hepatitis B, and hepatitis C all occur in higher-than-expected rates in individuals with schizophrenia.
DIAGNOSIS
Focus on identifying an insidious social and functional decline per history with the onset of ≥2 of the following characteristic symptoms on mental status exam:
• Delusions (fixed, false beliefs)
• Hallucinations (auditory > visual disturbances)
• Disorganized thought (derailed or incoherent speech)
• Grossly disorganized/catatonic behavior (hyper- or hypoactive movements that are often repetitive)
• Negative symptoms (affective flattening, avolition, asociality, alogia, anhedonia) (1)
PHYSICAL EXAM
No physical findings characterize the illness; however, chronic treatment with neuroleptic agents may result in parkinsonism, tardive dyskinesia, and other extrapyramidal symptoms.
DIFFERENTIAL DIAGNOSIS
• Psychotic disorder due to another medical condition
– Disorientation, in particular, indicates delirium
– Possible medical illnesses include porphyria, TBI, infection, tumor, metabolic, endocrine, and intoxication, including withdrawal states and disorders that affect the CNS (i.e., epilepsy, Huntington disease, Wilson disease, lupus cerebritis, anti-NMDA limbic encephalitis, metachromatic leukodystrophy).
• Substance-induced psychosis: secondary to substance use/abuse, such as cocaine, hallucinogens (amphetamines, LSD, phencyclidine), cannabis (including synthetic), bath salts, alcohol, or prescribed medications including steroids, anticholinergics, and opiates
• Personality disorders (paranoid, schizotypal, schizoid, borderline personality disorder)
• Mood disorders: bipolar disorder, major depressive disorders with psychotic features or catatonia
• Other thought disorders: delusional disorder, schizoaffective disorder
• Posttraumatic stress disorder
• Cultural belief system
• Autism spectrum disorder or neurodevelopmental disorders
DIAGNOSTIC TESTS & INTERPRETATION
• No tests are available to indicate schizophrenia.
• Imaging (MRI), EEG, LP, and laboratory tests may be needed to rule out other causes and may be used as clinical presentation warrants.
Initial Tests (lab, imaging)
These are needed to rule out a medical etiology of psychotic symptoms and when starting antipsychotic medications; these may include the following:
• CBC, blood chemistries
• Thyroid-stimulating hormone (TSH)
• Blood glucose level, preferably fasting
• Hemoglobin A1C, fasting lipid panel
• Vitamin levels (thiamine, vitamin D, vitamin B12)
• Drug/alcohol screen of blood and urine
• Urinalysis, urine pregnancy test
• Rapid plasma reagin (RPR), HIV
• Heavy-metal exposure: lead, mercury
• Ceruloplasmin, urine porphobilinogen as indicated
• ECG, for baseline QTc
Follow-Up Tests & Special Considerations
Clinical and laboratory tests for routine monitoring, at least yearly, if using antipsychotic medications (3)[A]
• Blood pressure, weight, and waist circumference
• CBC, blood chemistries
• Fasting blood glucose level, hemoglobin A1C
• Lipid panel, TSH
• Pregnancy test and prolactin level, if indicated
• ECG, monitoring for QTc prolongation
Diagnostic Procedures/Other
Neuropsychologic testing: not a routine part of assessment but can help assess cognitive level to predict functioning and need for assistance
Test Interpretation
No diagnostic pathologic findings; however, ventriculomegaly is frequently seen on MRI with whole brain grey matter loss and white matter loss in medial temporal lobe structures preferentially (4)[A].
TREATMENT
MEDICATION
First Line
• Two classes of antipsychotic medications: typical and atypical. First-line treatment is with an atypical antipsychotic given lower potential for extrapyramidal side effects.
– Atypical (2nd generation)
Risperidone, olanzapine, ziprasidone, aripiprazole, quetiapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, brexpiprazole, cariprazine
– Typical (1st generation)
Haloperidol, chlorpromazine, fluphenazine, trifluoperazine, perphenazine, thioridazine, thiothixene, loxapine
• Medication choice is based on clinical and subjective response and side effect profile (3)[A].
• Sensitivity to extrapyramidal adverse effects: atypicals
• For least risk of tardive dyskinesia: quetiapine, clozapine
• For least risk of metabolic syndrome: aripiprazole, ziprasidone, lurasidone
• For poor compliance/high risk of relapse: injectable form of long-acting antipsychotic such as haloperidol, fluphenazine, risperidone, olanzapine, aripiprazole, or paliperidone
• Usual oral daily dose (initial dose may be lower)
– Chlorpromazine: 200 mg BID
– Aripiprazole: 10 to 30 mg/day
– Asenapine: 5 mg BID (sublingual)
– Fluphenazine: 5 mg BID
– Haloperidol: 5 mg BID
– Lurasidone: 40 to 80 mg/day (with meal)
– Olanzapine: 15 to 30 mg/day
– Paliperidone: 3 to 12 mg/day
– Perphenazine: 24 mg/day divided BID or TID
– Quetiapine: 200 to 300 mg BID
– Risperidone: 3 mg/day
– Ziprasidone: 60 to 80 mg BID (with meal)
– Cariprazine: 1.5 to 6 mg/day
– Brexpiprazole: 2 to 4 mg/day
– Clozapine: 200 mg BID
Start 12.5 mg/day and increase daily by 25 mg until dose of 300 mg/day split into BID dosing; do not exceed 900 mg/day.
Effective in treatment of refractory or suicidal patients (3)[A]
Serious risk of agranulocytosis mandates registration with National Clozapine Registry and monitoring regular periodic CBC with differential (weekly to once monthly).
Significant risk of seizure at higher doses
Side effects can include myocarditis, DVT, sialorrhea, tachycardia, and weight gain.
All antipsychotics are associated with weight gain and carry the risk of metabolic SE and tardive dyskinesia.
• Managing adverse effects of antipsychotics
– Dystonic reaction (especially of head and neck): Give diphenhydramine 25 to 50 mg IM or benztropine 1 to 2 mg IM.
– Akathisia (restlessness): propranolol 20 to 30 mg BID or lorazepam 0.5 to 1 mg BID
– Parkinsonism: trihexyphenidyl 2 mg BID (may be increased to 15 mg/day if needed) or benztropine 0.5 BID (1 to 4 mg/day); amantadine 100 mg daily (up to 300 mg daily)
– Neuroleptic malignant syndrome: hyperthermia, autonomic dysfunction, and extrapyramidal symptoms; requires hospitalization and supportive management (IVF and cessation of offending neuroleptic)
• Geriatric considerations: All antipsychotics carry a black box warning for increased mortality risk in elderly patients with dementia.
• Adjunctive treatments
– Benzodiazepines
May be effective adjuncts to antipsychotics during acute phase of illness
Useful for the treatment of catatonia
Withdrawal reactions with psychosis or seizures; risk for dependence and cognitive impairment
– Mood stabilizers (valproic acid, lithium, lamotrigine, carbamazepine): may be effective adjuncts for those with agitated/violent behavior (3,5)[A]
– Antidepressants: if prominent symptoms of depression are present
– Metformin: helps minimize risk of metabolic SE with use of AP (6)[A]
ISSUES FOR REFERRAL
• Consider in cases of suicidality, coexistence of an addiction, difficulty in engagement, or poor self-care.
• Patients with schizophrenia should receive multidisciplinary care from both a primary care physician and a psychiatrist.
• Family members often benefit from referral to family advocacy organizations such as NAMI (7)[A].
ADDITIONAL THERAPIES
• Family patient education and psychotherapy: These include specific treatments to reduce the impact of psychotic symptoms and to enhance social functioning. Cognitive-behavioral therapy has been shown to be effective for specific symptoms of schizophrenia (8)[C].
• Cognitive remediation is a new approach for cognitive retraining and psychosocial recovery.
• Vocational support programs have shown success in returning individuals to work.
COMPLEMENTARY & ALTERNATIVE MEDICINE
Omega-3 fatty acids may improve cognitive symptoms, but evidence remains inconclusive (9).
SURGERY/OTHER PROCEDURES
• Electroconvulsive therapy (ECT) should be considered early for patients presenting with catatonic features when response to benzodiazepines is insufficient (3)[B].
• Surgical interventions are not available.
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Initial stabilization focuses on maintaining a safe environment and reducing acute psychotic symptoms and agitation through the initiation of pharmacologic treatment.
• The decision to admit is usually based on the patient’s risk of self-harm or harm to others and the inability to care for self as governed by local legal statute.
• Monitor for safety concerns and establish a safe and supportive environment.
• Discharge criteria based on the patient’s ability to remain safe in the community. It reflects a combination of suicide risk, level of psychotic symptoms, support systems, and the availability of appropriate outpatient services.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Long-term symptom management and rehabilitation depend on engagement in ongoing pharmacologic and psychosocial treatment.
• Monitoring is based on evaluation of symptoms (including safety and psychotic symptoms), looking for the emergence of comorbidities, medication side effects, and prevention of complications.
DIET
• Newer atypical antipsychotics confer a higher risk of metabolic side effects such as diabetes, hypercholesterolemia, and weight gain.
• Although there are no specific dietary requirements, attention should be paid to the high risk of development of obesity and metabolic syndrome in individuals with schizophrenia.
PATIENT EDUCATION
• National Institute of Mental Health: Schizophrenia, at www.nimh.nih.gov/health/topics/schizophrenia/index.shtml
• Helping a Family Member with Schizophrenia: www.aafp.org/afp/20070615/1830ph.html
• National Alliance on Mental Illness (NAMI): www.NAMI.org
PROGNOSIS
• Typical course is one of remissions and exacerbations. Although uncommon, there are known cases of complete remission and of refractory illness.
• Negative symptoms are often most difficult to treat.
• About 20% attempt suicide. 5–6% die of suicide (1).
• Decreased life span related to comorbidities (coronary artery disease, pulmonary disease, or substance use disorders) and suboptimal care; guarded prognosis
COMPLICATIONS
• Side effects from antipsychotic medications including tardive dyskinesia, orthostatic hypotension, QTc prolongation, and metabolic syndrome
• Self-inflicted trauma and suicide
• Combative behavior toward others (only 5% of crimes are caused by mental illness including psychosis) (10)
• Comorbid addictions, including nicotine (11)[A]
REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.
2. Fagerström K, Aubin HJ. Management of smoking cessation in patients with psychiatric disorders. Curr Med Res Opin. 2009;25(2):511–518.
3. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318–378.
4. Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49(1–2):1–52.
5. Essali A, Al-Haj Haasan N, Li C, et al. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;(1):CD000059.
6. Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2014;40(6):1385–1403.
7. Mojtabai R, Nicholson RA, Carpenter BN. Role of psychosocial treatments in management of schizophrenia: a meta-analytic review of controlled outcome studies. Schizophr Bull. 1998;24(4):569–587.
8. Grant PM, Huh GA, Perivoliotis D, et al. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry. 2012;69(2):121–127.
9. Knöchel C, Voss M, Grüter F, et al. Omega 3 fatty acids: novel neurotherapeutic targets for cognitive dysfunction in mood disorders and schizophrenia? Curr Neuropsychopharmacol. 2015;13(5):663–680.
10. Fazel S, Grann M. The population impact of severe mental illness on violent crime. Am J Psychiatry. 2006;163(8):1397–1403.
11. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123–1131.
ADDITIONAL READING
Saks E. The Center Cannot Hold: My Journey Through Madness. New York, NY: Hyperion; 2007.
SEE ALSO
Algorithm: Delirium
CODES
ICD10
• F20.9 Schizophrenia, unspecified
• F20.0 Paranoid schizophrenia
• F20.1 Disorganized schizophrenia
CLINICAL PEARLS
• A debilitating chronic mental illness that affects all cultures
• Schizophrenia is characterized by positive symptoms, including hallucinations such as voices that converse with/about the patient, delusions that are often paranoid and negative symptoms, including flattened affect, loss of a sense of pleasure, loss of will/drive, and social withdrawal.
• Requires a multidisciplinary team approach to assist with coping and treatment and promote recovery