Contents

Search

schizophrenia

Etiology: 1) specific etiology unknown 2) dopamine hypothesis a) hypoactive dorsolateral prefrontal cortex (DLPFC) b) hyperactive limbic system dopaminergic neurons c) adolescence triggers onset of symptoms secondary to the need to use DLPFC dopaminergic neurons as higher cognitive functions develop 3) pharmacologic precipitants: a) amphetamines b) bromides c) glucocorticoids d) levodopa e) lysergic acid f) monoamine oxidase (MAO) inhibitors g) tricyclic antidepressants h) NMDA receptor antagonists 4) risk factors - paternal age [17] - substance abuse - urban residence - trauma - social adversity - cognitive impairment - daytime napping [50] - pregnancy & developmental complications [43] - gestational diabetes - emergency C-section - abnormal fetal development & low birth weight - preeclampsia - maternal malnutrition & vitamin D deficiency 5) Toxoplasma gondii infection may be a contributing factor [39,42] Epidemiology: 1) 1% per lifetime, affects about 1 in 300 people worldwide [45] 2) men & women equally affected - late onset (age > 45) women > men [4] - severity may be less in women than men* - women > 45 years have the greatest risk of hospitalization for relapse [45,46] 3) average age of onset: - 15-30 years: late teens to early adulthood [43] 4) worldwide distribution with similar prevalence 5) higher social class at birth associated with increased risk [6] * estrogen with antidopaminergic effect [43] Pathology: 1) the hippocampus & its CA1 subdivision is the brain region affected first & foremost in schizophrenia [44] 2) loss-of-function mutations in subunits of AMPA receptors & NMDA receptors 3) hyperactive limbic system dopaminergic neurons a) compensatory response to hypoactive DLPFC dopaminergic neurons b) thought to account for active phase (positive symptoms) of schizophrenia 4) hypoactive dorsolateral prefrontal cortex (DLPFC) a) hypoactive dopaminergic neurons secondary to problems in migration of neural tissue during development b) thought to account for chronic phase (negative symptoms) of schizophrenia c) alterations of mGluR3 receptors in the DLPFC might have a role in the pathogenesis of schizophrenia; schizophrenia subjects had lower mGluR3 than controls & had higher levels of glutamate carboxypeptidase-2, an enzyme that metabolizes N-acetylaspartylglutamate, the only known specific endogenous agonist of mGluR3 [10] 5) adolescence triggers onset of symptoms secondary to the need to use DLPFC dopaminergic neurons as higher cognitive functions develop Genetics: 1) often family history 2) schizophrenia susceptibility - loci: chromosomes 13q32, 8p21, 22q11-13 - proteins/genes: PDLIM5, PRODH, DISC1, RGS4 3) chromosomal translocation t(9;14)(q34;q13) involving NPAS3 is found in a family with schizophrenia 4) chromosomal translocation t(1;11)(q42.1;q14.3) involving DISC1 segregates with schizophrenia & related psychiatric disorders in a large Scottish family 5) overexpression of RIC3 in brains from patients with bipolar disease or schizophrenia 6) human endogenous retrovirus HERV-W antigenemia more common in patients than controls [9] 7) associated with variations in CACNA1C & CACNB2 [18] 8) 108 linked genetic loci [22] 9) other implicated genes: - DAOA, MICB, C6orf217, MAP6, CPLX2 Clinical manifestations: 1) active phase, psychosis (positive symptoms) a) 1st psychotic episode usually occurs at age 14-30 years [43] b) psychotic episodes present for at least 1 month c) hallucinations: - usually auditory hallucinations - multimodal hallucinations common with late-onset schizophrenia d) delusions - often persecutory delusions, common with late-onset schizophrenia - often bizarre rather than plausible delusions e) disorganized speech f) disorganized or catatonic behavior 2) chronic phase (negative symptoms) - present for at least 6 months - cataplexy - flat affect - poverty of speech, alogia - lack of initiative, apathy, anhedonia - social isolation, social withdrawal - cognitive dysfunction (distinct from negative symptoms) [43] - poor job performance, avolition - poor hygiene - unusual perceptions 3) mood symptoms: - no mania, no depression vs unusual expression of depression [43] 4) functional impairment 5) suicidal attempts in 50%; 10% are successful 6) mental status a) usually alert & oriented without fluctuations in level of consciousness b) motor activity variable - agitation - psychomotor retardation c) memory often impaired (less so in late onset form) [4] Diagnostic criteria: - 2 of the following: [12] - delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, negative symptoms - at least 1 functional impairment: [12] - occupation, social interactions, self care - duration of >= 6 months with >= 1 month of active symptoms [12] - continuous signs of disturbance [43] - disorders in differential diagnosis ruled out Laboratory: 1) tests of exclusion a) complete blood count (CBC) b) serologic test for syphilis c) basic chemistry panel d) thyroid function tests 2) CBC/WBC count if clozapine is used to monitor for potential agranulocytosis 3) not routine - N-acetylaspartylglutamate in CSF ? 4) therapeutic drug monitoring of serum antipsychotic levels [29] - 1/3 of patients referred for treatment-resistant schizophrenia in the UK with low or no plasma antipsychotic 5) see ARUP consult [2] Special laboratory: - mental status exam - EEG: frequently left sided abnormalities (non-specific) Radiology: 1) CT of head: ventricular enlargement 10-50% (non-specific) 2) PET scan: decreased frontal lobe metabolism 3) MRI neuroimaging: - may show periventricular hyperintensities (late onset) [4] - functional imaging & MRI demonstrates a dysfunctional hippocampus characterized by abnormal increases in glutamate levels, hyperactivity, & atrophy [44] Differential diagnosis: 1) substance abuse 2) schizophreniform disorder (symptoms < 6 months) 3) psychosis (symptoms < 1 month, > 1 day) 4) schizoaffective disorder 5) mood disorder with psychotic symptoms - psychosis brief compared with mood symptoms - bipolar disorder with psychotic features [43] 6) delusional disorder: delusion without other symptoms of schizophrenia 7) personality disorder a) paranoid b) borderline c) schizoid d) schizotypal 8) Huntington's diesase 9) Wilson's disease 10) temporal lobe epilepsy 11) heavy metal poisoning 12) Werneke-Korsakoff syndrome 13) HIV 14) syphilis 15) herpes encephalitis [12] * 22% of patients initially diagnosed with schizophrenia have their diagnoses changed during subsequent hospitalizations [12] Complications: 1) increased risk of mortality a) largely due to 1] cardiovascular disease [12] 2] lung disease 3] behavioral disorders 4] substance abuse [12] b) possible a result of 1] lifestyle of the mentally ill 2] adverse effects of medications [13] c) accelerated aging suggested [14] d) metformin may be of benefit for weight reduction [20] 2) increased risk of diabetes mellitus, obesity 3) adverse outcomes at 30 days after surgery - poor communication skills may play role [19] 4) health care costs for patients with chronic diseases & schizophrenia are particularly high [31] 5) early onset dementia, 28% at age 66 years [38] 6) frequent comorbidity of depression* with high risk of suicide in elderly with schizophrenia [15,41] * elderly with chronic schizophrenia may grapple with Erikson's final stage of psychosocial development-integrity vs despair; they may find themselves in a state of despair; this is diagnosed as major depression with schizophrenia in later life [15] Management: 1) improving activities of daily living is central to any meaningful intervention in schizophrenia [30] 2) bundling medication with psychosocial therapy improves outcomes [24] 3) pharmacologic agents a) long-acting injectable antipsychotic agents may be superior to oral agents in reducing rehospitalization for older [33,40] & younger [47] patients without an increase in adverse events [45,47] b) atypical antipsychotic agents - combined dopamine & serotonin receptor blockade - fewer extrapyramidal symptoms than other antipsychotic agents - clozapine (Clozaril) reduces mortality [11] - most effective but requires routine CBC/WBC count for potential agranulocytosis [12] - most effective antipsychotic in preventing relapse & reducing risk for substance use disorder [51] - least likely to cause extrapyramidal symptoms [12] - risperidone (Risperdal) [5] - decrease risperidone for parkinsonism & tardive dyskinesia prior to switching to clozapine (GRS11) [15] - olanzapine: weight gain, substantial [48]; greatest among antipsychotics [49] - olanzapine > quetiapine > risperidone > aripiprazole [48] - in adolescents 8.5 kg after 11 weeks of therapy [48] - other atypical antipsychotics not as effective as olanzapine or risperidone for core symptoms [28] c) high potency antipsychotic agents - dopamine D2 receptor antagonist - pharmaceutical agents - haloperidol (Haldol) - fluphenazine (Prolixin) - trifluoperazine (Stelazine) - perphenazine (Trilafon) - thiothixene (Navane) c) dosage: 5-30 mg d) extrapyramidal side effects e) preferred agents during pregnancy d) low potency antipsychotic agents - dopamine D2 receptor antagonist - pharmaceutical agents - chlorpromazine (Thorazine) - thioridazine (Mellaril) - dosage: 300-1000 mg - anticholinergic side effects e) 2/3 of patients relapse within 6 months after discontinuation of antipsychotic - changing an effective & well-tolerated regimen is not recommended f) muscarinic receptor agonist xanomeline maybe of benefit [8] - tropsium/xanomeline may mitigate cholinergic adverse effects [8] - tropsium/xanomeline (Cobenfy) FDA-approved ro schizophrenia Sept 2024 g) novel trace amine-associated receptor 1 target may be of benefit [36] h) add-on treatment with pimavanserin (Nuplazid) may improve negative symptoms i) caution in treating hyperlipidemia - increased serum cholesterol & serum triglycerides are associated with better cognitive function in patients with schizophrenia [23] 4) non-pharmaceutical measures a) cognitive behavioral therapy useful for patients who refuse antipsychotics [21] b) group therapy c) greater greenspace exposure linked to fewer symptoms of anxiety, depression, & psychosis, & better sleep [35] d) screening elderly for depression with PHQ-9 [15] 5) prescribe 2nd generation antipsychotic & refer to psychiatry 6) menopausal hormone replacement therapy lowers risk of psychosis relapse in midlife women with schizophrenia or schizoaffective disorder 16% [52] 7) patient education - Alliance for the Mentally ill (800) 950-NAMI

Interactions

disease interactions

Specific

catatonic schizophrenia (includes periodic catatonia) disorganized (hebephrenic) schizophrenia late-onset schizophrenia paranoid schizophrenia residual schizophrenia schizoaffective disorder schizophreniform disorder undifferentiated schizophrenia

General

chronic mental disorder psychiatric disease; behavioral disorder

Database Correlations

OMIM correlations

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1145-1147
  3. Prescriber's Letter 7(11):65 2000
  4. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  5. Journal Watch 22(4):32, 2002 Csernansky JG et al A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 346:16, 2002 PMID: 11777998
  6. Journal Watch 22(4):32, 2002 Mulvany F et al Effect of social class at birth on risk and presentation of schizophrenia: case-control study. BMJ 323:1398, 2001 PMID: 11744563
  7. Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005 Sep 22; 353:1209-23. PMID: 16172203
  8. Shekhar A et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 2008 Aug; 165:1033. PMID: 18593778 - Brannan SK, Sawchak S, Miller AC et al Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N Engl J Med 2021; 384:717-726 Feb 25 PMID: 33626254 https://www.nejm.org/doi/full/10.1056/NEJMoa2017015B
  9. Perron H et al, Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients. Biol Psychiatry 2008, 64:1019 PMID: 18760403 - Torry EF and Yolen RH The past is the future. Biol Psychiatry 2008, 64:1017 PMID: 19038602
  10. Ghose S et al Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: A mechanism for antipsychotic drug action? Am J Psychiatry 2009 Jun 1; [e-pub ahead of print]. PMID: 19487395 http://dx.doi.org/10.1176/appi.ajp.2009.08091445
  11. Tiihonen J et al. 11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). Lancet 2009 Jul 11 PMID: 19595447 http://dx.doi.org/10.1016/S0140-6736(09)60742-X
  12. Medical Knowledge Self Assessment Program (MKSAP) 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 2006, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - Schultz SH, North SW, Shields CG Schizophrenia: a review. Am Fam Physician. 2007 Jun 15;75(12):1821-9. PMID: 17619525
  13. Hoang U et al. Mortality after hospital discharge for people with schizophrenia or bipolar disorder: Retrospective study of linked English hospital episode statistics, 1999-2006. BMJ 2011 Sep 13; 343:d5422 PMID: 21914766
  14. Fernandez-Egea E et al. Testosterone in newly diagnosed, antipsychotic-naive men with nonaffective psychosis: A test of the accelerated aging hypothesis. Psychosom Med 2011 Oct; 73:643. PMID: 21949421
  15. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  16. ARUP Consult: Schizophrenia deprecated reference
  17. Physician's First Watch, Aug 27 2012 Massachusetts Medical Society http://www.jwatch.org
  18. Cross-Disorder Group of the Psychiatric Genomics Consortium Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet, Early Online Publication, 28 February 2013 PMID: 23453885 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62129-1/abstract
  19. Liao C-C et al. Surgical adverse outcomes in patients with schizophrenia: A population-based study. Ann Surg 2013 Mar; 257:433 PMID: 23241870
  20. Jarskog LF et al. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry. July 12, 2013 http://ajp.psychiatryonline.org/article.aspx?articleID=1712524
  21. Morrison AP et al Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial. The Lancet, Early Online Publication, 6 February 2014 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962246-1/abstract
  22. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014 Jul 24; 511:421. PMID: 25056061 - Flint J and Munafo M. Genesis of a complex disease. Nature 2014 Jul 24; 511:412. PMID: 25056056
  23. Brooks M Hyperlipidemia: Bad for the Heart, Good for the Brain? Medscape News from the American Psychiatric Association (APA) 2015 Annual Meeting http://www.medscape.com/viewarticle/844814
  24. Kane JM, Robinson DG, Schooler NR et al Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program. Am J Psychiatry. Oct 2015 PMID: 26481174 http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.15050632 - Insel TR RAISE-ing Our Expectations for First-Episode Psychosis Am J Psychiatry. Oct 2015 PMID: 26481175 http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.15091204
  25. NEJM Knowledge+ Question of the Week. April 12, 2016 - Freedman R Schizophrenia. N Engl J Med 2003; 349:1738-1749. October 30, 2003 PMID: 14585943 http://www.nejm.org/doi/full/10.1056/NEJMra035458
  26. Leucht S, Cipriani A, Spineli L et ak Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013 Sep 14;382(9896):951-62. Review. PMID: 23810019
  27. Viron M, Baggett T, Hill M, Freudenreich O. Schizophrenia for primary care providers: how to contribute to the care of a vulnerable patient population. Am J Med. 2012 Mar;125(3):223-30. Review. PMID: 22340915
  28. Agency for Healthcare Research and Quality (AHRQ) Treatment for Adults With Schizophrenia. Systematic Review. October 26, 2017 https://effectivehealthcare.ahrq.gov/topics/schizophrenia-adult/research-2017/
  29. McCutcheon R et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2017 Oct 26; PMID: 29072776 http://onlinelibrary.wiley.com/doi/10.1111/acps.12825/abstract
  30. Galderisi S, Rucci P, Kirkpatrick B et al Interplay Among Psychopathologic Variables, Personal Resources, Context-Related Factors, and Real-life Functioning in Individuals With Schizophrenia. A Network Analysis. JAMA Psychiatry. Published online Feb 14, 2018 PMID: 29450447 https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2671414
  31. Sporinova B, Manns B, Tonelli M et al. Association of mental health disorders with health care utilization and costs among adults with chronic disease. JAMA Netw Open 2019 Aug 2; 2:e199910. PMID: 31441939 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2748662
  32. McCutcheon RA, Marques TR, Howes OD. Schizophrenia - An Overview. JAMA Psychiatry. Published online October 30, 2019. PMID: 31664453 https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2753514
  33. Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  34. Rothaus C Schizophrenia. NEJM Resident 360. Oct 30, 2019 https://resident360.nejm.org/clinical-pearls/schizophrenia-2
  35. Henson P, Pearson JF, Keshavan M, Torous J. Impact of dynamic greenspace exposure on symptomatology in individuals with schizophrenia. PLoS One 2020 Sep 3; 15:e0238498. PMID: 32881899 PMCID: PMC7470425 Free PMC article https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238498
  36. Goff DC The Pharmacologic Treatment of Schizophrenia - 2021. JAMA. Published online December 28, 2020. PMID: 33369626 https://jamanetwork.com/journals/jama/fullarticle/2774656
  37. Brannan SK, Sawchak S, Miller AC et al Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N Engl J Med 2021; 384:717-726 Feb 25 PMID: 33626254 https://www.nejm.org/doi/full/10.1056/NEJMoa2017015B
  38. Grant K High Prevalence of Early-Onset Dementia in Schizophrenia Patients. More than a quarter had a dementia diagnosis by age 66. MedPage Today March 10, 2021. https://www.medpagetoday.com/psychiatry/generalpsychiatry/91574 - Stroup TS et al Age-specific prevalence and incidence of dementia diagnoses among older US adults with schizophrenia, JAMA Psychiatry 2021. March 10 PMID: 33688938
  39. Burgdorf KS, Trabjerg BB, Pedersen MG et al Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders. Brain, Behavior, & Immunity 2019 79:152-158 PMID: 30685531 https://www.sciencedirect.com/science/article/pii/S0889159118306998
  40. Lin CH, Chen FC, Chan HY et al. A comparison of long-acting injectable antipsychotics with oral antipsychotics on time to rehospitalization within 1 year of discharge in elderly patients with schizophrenia. Am J Geriatr Psychiatry. 2020;28(1):23-30 https://www.ajgponline.org/article/S1064-7481(19)30468-3/fulltext
  41. Hoertel N, Jaffre C, Pascal de Raykeer R et al Subsyndromal and syndromal depressive symptoms among older adults with schizophrenia spectrum disorder: prevalence and associated factors in a multicenter study. J Affect Disord. 2019;251:60-70 PMID: 30904777 https://www.sciencedirect.com/science/article/abs/pii/S0165032718318470
  42. Whitlock Burton K Cat Ownership in Childhood Linked to Psychosis Risk in Adulthood. Medscape. March 08, 2022 https://www.medscape.com/viewarticle/969852
  43. Soreff S Fast Five Quiz: Schizophrenia Practice Essentials. Medscape. November 22, 2022 https://reference.medscape.com/viewarticle/983935 - Ash ME, Pataki C Childhood-Onset Schizophrenia Medscape. Mqrch 25, 2019 https://emedicine.medscape.com/article/914840-overview
  44. Guo J, Rothman DL, Small SA Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia. JAMA Psychiatry. Published online January 25, 2023. PMID: 36696108 https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2800312
  45. Soreff S Medscape: Rapid Review Quiz: Schizophrenia. 2023, May 15 https://reference.medscape.com/viewarticle/991634
  46. Gonzalez-Rodriguez A, Monreal JA, Seeman MV The Effect of Menopause on Antipsychotic Response. Brain Sci. 2022 Oct 4;12(10):1342 PMID: 36291276 PMCID: PMC9599119 Free PMC article
  47. Wei Y, Yan VKC, Kang W et al Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia. JAMA Netw Open. 2022 Jul 1;5(7):e2224163. PMID: 35900760 PMCID: PMC9335136 Free PMC article.
  48. Correll CU et al Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents JAMA. 2009;302(16):1765-1773 PMID: 19861668 http://jama.ama-assn.org/cgi/content/short/302/16/1765 - Varley CK & McClellan J Implications of Marked Weight Gain Associated With Atypical Antipsychotic Medications in Children and Adolescents JAMA. 2009;302(16):1811-1812 PMID: 19861677 http://jama.ama-assn.org/cgi/content/short/302/16/1811
  49. Sabe M, Pallis K, Solmi M et al Comparative Effects of 11 Antipsychotics on Weight Gain and Metabolic Function in Patients With Acute Schizophrenia: A Dose-Response Meta-Analysis. J Clin Psychiatry. 2023 Feb 8;84(2):22r14490. PMID: 36752753
  50. Wang Z, Chen M, Wei YZ et al The causal relationship between sleep traits and the risk of schizophrenia: a two-sample bidirectional Mendelian randomization study. BMC Psychiatry. 2022 Jun 15;22(1):399. PMID: 35705942 PMCID: PMC9202113 Free PMC article.
  51. Lahteenvuo M, Luykx JJ, Taipale H et al Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts. Br J Psychiatry. 2022 Dec;221(6):758-765. PMID: 36004532
  52. Brand BA, Sommer IE, Gangadin SS Real-World Effectiveness of Menopausal Hormone Therapy in Preventing Relapse in Women With Schizophrenia or Schizoaffective Disorder. Am J Psychiatry. 2024 Oct 1;181(10):893-900. PMID: 39262210