Schizophrenia is a heterogeneous and complex psychiatric disorder that affects cognitive, perceptual, and emotional functioning. The difficulty of diagnosing schizophrenia increases significantly when other comorbid conditions are present. The diagnostic and treatment issues regarding overlapping psychiatric symptoms and disorders in schizophrenia remain controversial. The current epidemiological, clinical, and neurobiological evidence indicate that comorbid psychiatric illnesses in patients with schizophrenia are varied and highly prevalent. The preliminary research findings suggest that comorbid illnesses either can be derived as a part of a schizophrenic illness or may be characterized as distinct separate entities. The shift toward specific symptom dimensional based Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),1 as well as the advances in neurobiological bases of psychiatric disorders and emphasis for the real-world based clinical research criterion has led to the US Food and Drug Administration statement, “the comorbidity is more the rule than the exception in schizophrenia.”2,3
However, the examination and emerging reports of obsessive-compulsive symptoms (OCS) in patients with schizophrenia may present as a difficult task for practicing clinicians, and the diagnosis of a comorbid obsessive-compulsive disorder (OCD) or OCS is often missed in this population. The current epidemiological evidence suggests a significantly greater prevalence rate of OCS in patients with schizophrenia, ranging from 10% to 50%, and OCD in the schizophrenia population, ranging from 7.8% to 26%.4 The treatment approach in schizophrenia with comorbid OCS varies based on the pathogeneses of OCS. Understanding the nature of multifaceted bio-psychosocial pathogeneses of the obsessive compulsive OCS symptoms and its interface with psychotic symptoms is essential in management and will facilitate optimal clinical outcomes.
Subtyping Strategy and Understanding the Spectrum
Initially examined as subgroups, the coexistence of OCD, OCS, and schizophrenia has transformed into a spectrum of disorders.5–8 The proposed spectrum includes typical OCD, OCD with poor insight, OCD with schizotypal personality disorder, schizophrenia with transient OCS, schizophrenia with OCD, and schizophrenia. This addition of schizo-obsessive disorder provides diagnostic options for patients with OCS/OCD who also meet criterion A for schizophrenia.9
Furthermore, the DSM-5 modification provides a symptom dimensional approach allowing for the exploration of a biopsychosocial basis of specific symptoms in schizophrenic illness and its clinical management.1 These include mood disorders such as manic-depressive, anxiety, panic attacks, and OCD, which have been clinically acknowledged as schizoaffective and schizo-obsessive disorders. The DSM-5 also includes dimensional assessments of eight domains of psychopathology in Section III (conditions listed in this section require further research before their consideration as formal disorders).1 These eight domains include the five diagnostic standards under criterion A of schizophrenia (delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms) as well as depression, mania, and impaired cognition, which are common comorbid conditions in schizophrenia.1 This dimensional diagnostic approach reflects the increasing recognition and importance of the clinical and biological heterogeneity of the illness, and the need for individualized symptom assessment in patients with psychotic disorders. Although OCS were not included in these research criteria, the occurrence of OCS in schizophrenia as well as in other psychotic disorders, including bipolar disorder, has been long recognized and extensively studied in recent years.10,11 Furthermore, the introduction of the National Institute of Mental Health initiative, Research Diagnostic Criteria (RDoC) initiative12 has promoted exploration of the biopsychosocial basis of the specific psychopathology, which fosters examination of specific psychiatric conditions.
Current evidence suggests4–6 multiple causal factors and pathogeneses of comorbid symptoms in schizophrenia. The onset, clinical course, treatment response, and prognosis of comorbid conditions in patients with schizophrenia can vary. For example, obsessive compulsive (OC) phenomena may manifest during the premorbid phase as well as during the late phase of schizophrenic illness.
This may be due to premorbid OCD prior to the diagnosis of schizophrenia or part of psychotic preoccupation.5,6 However, there is a high prevalence of patients with chronic schizophrenia who developed OCS with serotonergic-blocking agents such as clozapine.13 The course of illness and treatment response may also vary widely and may often be unpredictable. We have proposed subtyping strategies to better characterize its clinical, neuropsychological, and pharmacological profiles in OC schizophrenia.14
Comorbid OCD or OCS
OCS or OCD progress and persist independent of the psychotic illness of schizophrenia as an independent, distinct comorbid disorder. OCS may develop as a part of acute psychotic exacerbation of preoccupation, with or without ritualistic behaviors. The psychotic preoccupations or ruminations that emerge along with the acute phase of psychotic illness may resolve with overall improvement of psychosis.
OCS may develop or exacerbate after treatment with atypical antipsychotics (AAPs) that possess a potent antiserotonergic receptor profile. Recent reports found that such drugs may induce OC manifestations that may respond to the anti-OC pharmacological regimen.
OCS occurring during prodromal phase of psychotic illness leading to the development of schizo-obsessive disorder. OCS symptoms are present and meet Criterion A for OCD at some time point during the schizophrenic illness.
Antipsychotic Drug-Induced Obsessive Compulsive Phenomena
Emerging evidence has shown that AAPs can induce new or exacerbate preexisting OCS in schizophrenia. Available evidence show that the prevalence rate of treatment-induced OCS varies between antipsychotic medications. Clozapine-treated subjects (20.6%) experienced an increase of OCS more than subjects treated with other antipsychotic drugs (1.3%).15 The neurochemical etiology of these drug-induced symptoms appears to be multifactorial. The development of OCS in patients treated with neuroleptics is significantly less prevalent with the first-generation antidopaminergic medications in comparison to the predominantly anti-serotonergic AAPs.16 This emergence of OCS with AAP treatment is thought to be related to its inverse agonist effect on 5-HT2A receptors.17 These AAPs with serotonin/dopamine effects block the 5HT2A receptors in presynaptic dopamine neurons that disinhibit dopaminergic firing, thus increasing dopaminergic activity, particularly in the basal ganglia, leading to de novo or exacerbation of OCS in schizophrenia. This belief is supported by a pharmacological animal study in which quinpirole, a D2/D3 receptor agonist, triggered compulsive checking behavior in rats; in humans, dopamine agonists, such as levodopa are associated with the development of obsessive-compulsive spectrum disorders, such as compulsive shopping, compulsive drug use, and hoarding.18,19 Another theory concerns glutamate. Patients with OCD have increased levels of glutamate in their cerebral spinal fluid (CSF) compared to the general population.20 Examining AAPs closely, clozapine is known to increase concentrations of L-glutamate in the CSF and increase L-glutamate release in the prefrontal cortex leading to the hypothesis that glutamate modulation may lead to the development of OCS in patients with schizophrenia. Furthermore, the orbitofrontal cortex (OFC), known for its executive functioning such as mental flexibility, inhibition of action, and decision-making, appears to be modulated via strong antiserotonergic AAPs. functional magnetic resonance imaging data have noted an increase in BOLD (blood-oxygen-level dependent) activity in the OFC with patients who are taking AAP with strong antiserotonergic activity compared to patients taking primarily prominent dopaminergic blocking agents.21
Clinically, clozapine treatment has been associated with emergence of OCS or exacerbation of OCD (28% de novo vs 18% exacerbation)13 in patients with schizophrenia with similar findings noted with other subsequent AAPs, such as olanzapine and risperidone.22,23 These findings also appear to be related to the duration of treatment and dose rather than the chronicity of the illness.24
On the contrary, the efficacy of the dopamine-receptor blocking antipsychotic medications that lack antiserotenergic effects is thought to be related to their antiobsessional effect. Amisulpride, an AAP, is a selective potent dopamine-blocking agent that is associated with a low propensity to induce OCS and may relieve the AAP-induced OCS in schizophrenia.25 Neuroimaging studies have shown that the inhibition of the nigrostriatal dopamine system via 5HT2A receptor by serotonin reuptake inhibitors, which are widely used in the treatment of OCS, support the dopamine hypothesis of OCS in patients with schizophrenia.26
The treatment guideline for OC schizophrenia is based on its pathogenesis. Although the therapeutic efficacy of the adjunctive anti-OCD medication and atypical antipsychotics in schizophrenia with OCD have been extensively studied and current evidence suggests a positive therapeutic effect of adjunctive anti-OCD pharmacotherapy, further controlled systematic studies are needed. A recent meta-analysis of randomized trials in treatment-refractory OCD found adjunctive haloperidol and risperidone, but neither the olanzapine or quetiapine treatment improved OC symptoms in schizophrenia.27 The current evidence suggests that use of antipsychotics with a minimal 5HT2A receptor affinity and an antidopaminergic drug (D2/D3), such as haloperidol, offers a greater therapeutic option to minimized neuroleptic-induced OCS in schizophrenia. In addition, clinical reports suggest the AAPs that induced OCS may respond to adjunctive therapy with a selective serotonin reuptake inhibitor.28–30 Finally, individualized cognitive-behavioral psychotherapy should be considered in stabilized OC schizophrenia.31
Although the schizophrenic disorder was originally conceptualized as a distinct and unique category without concern for plausible psychiatric comorbidity, a high prevalence of coexisting psychiatric conditions in schizophrenia and emerging evidence of shared neurobiological basis in the behavioral phenotypes have promoted a conceptual shift from categorical diagnoses toward a symptom dimensional approach. Emerging research findings4,6 of OC schizophrenia suggest a distinct neurobiological subgroup with unique neuropsychological attributes and complex biopsychosocial pathogeneses. We have previously proposed that the OC schizophrenia may constitute three distinct subtypes including (1) a unique neurobiological subgroup, (2) a subtype of psychotic spectrum disorder, or (3) an ephemeral psychopathology. Systematic studies of schizophrenia with comorbid OCD suggest a distinct neurobiological subgroup with a unique neuropsychological attribute with complex biopsychosocial pathogeneses.
Comorbidity: Categories, Dimensions, or Both?
Clinicians will need to assess a patient's conditions through the lens of the DSM-5, while using the tools such as the RDoC to understand how patient's genomics, cognitive dimensions, physiological traits, and psychosocial factors may have led to the psycho-behavioral phenotype. For now, it is the best way of describing psychiatric disorders and, like the DSM-5, it allows for comorbid conditions.
Finally, the simultaneous introduction of the RDoC project need not be seen as an attack on the DSM-5, but rather as a call to find the meaningful dimensions that will advance understanding of biopsychosocial interface and their pathogenesis of the psychopathology as we move from the DSM-5 to “precision psychiatry.”28
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
- Laughren Thomas P. Comorbid mood disorders and medical illness: a Food and Drug Administration perspective. Biol Psychiatry. 2003;54(3):195–199. doi:10.1016/S0006-3223(03)00529-8 [CrossRef]
- Brostedt EM, Msghina M, Persson M, Wettermark B. Health care use, drug treatment and comorbidity in patients with schizophrenia or non-affective psychosis in Sweden: a cross-sectional study. BMC Psychiatry. 2017;17(1):416. doi:. doi:10.1186/s12888-017-1582-x [CrossRef]
- Bottas A, Cooke RG, Richter MA. Comorbidity and pathophysiology of obsessive-compulsive disorder in schizophrenia: is there evidence for a schizo-obsessive subtype of schizophrenia?J Psychiatry Neurosci. 2005;30:187–193.
- Hwang MY, Opler LA. Schizophrenia with obsessive-compulsive features: assessment and treatment. Psychiatr Ann. 1994;24(9):468–472. doi:. doi:10.3928/0048-5713-19940901-08 [CrossRef]
- , eds. Schizophrenia and Comorbid Conditions: Diagnosis and Treatment. Washington, DC: American Psychiatric Association; 2001
- Poyurovsky M, Koran LM. Obsessive-compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications. J Psychiatr Res. 2005;39(4):399–408. doi:. doi:10.1016/j.jpsychires.2004.09.004 [CrossRef]
- Scotti-Muzzi E, Saide OL. Schizo-obsessive spectrum disorders: an update. CNS Spectr. 2017;22(3):258–272. doi:. doi:10.1017/S1092852916000390 [CrossRef]
- Poyurovsky M, Zohar J, Glick I, et al. Obsessive-compulsive symptoms in schizophrenia: implications for future psychiatric classifications. Compr Psychiatry. 2012;53(5):480–483. doi:. doi:10.1016/j.comppsych.2011.08.009 [CrossRef]
- McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420–426. doi:. doi:10.1176/appi.ajp.158.3.420 [CrossRef]
- Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for BD (STEP-BD). Am J Psychiatry. 2004;161:2222–2229. doi:. doi:10.1176/appi.ajp.161.12.2222 [CrossRef]
- Insel T, Cuthbert B, Garvey M, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748–751. doi:. doi:10.1176/appi.ajp.2010.09091379 [CrossRef]
- Foneska TM, Richter MA, Müller DJ. Second generation antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature. Curr Psychiatry Rep. 2014;16(11):510. doi:. doi:10.1007/s11920-014-0510-8 [CrossRef]
- Hwang MY, Kim SW, Yum SY, Opler LA. Management of Schizophrenia with obsessive-compulsive features. Psychiatr Clin North Am. 2009;32(4):835–851. doi:. doi:10.1016/j.psc.2009.08.002 [CrossRef]
- de Haan L, Linszen DH, Gorsira R. Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J Clin Psychiatry.1999;60(6):364–365. doi:10.4088/JCP.v60n0603 [CrossRef]
- Kim JH, Ryu S, Nam HJ, et al. Symptom structure of antipsychotic-induced obsessive-compulsive symptoms in schizophrenia patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;39(1):75–79. doi:. doi:10.1016/j.pnpbp.2012.05.011 [CrossRef]
- Laroche DG, Gaillard A. Induced obsessive compulsive symptoms (OCS) in schizophrenia patients under atypical 2 antipsychotics (AAPs): review and hypotheses. Psychiatr Res. 2016;246:119–128. doi:. doi:10.1016/j.psychres.2016.09.031 [CrossRef]
- Voon V, Napier TC, Frank MJ, et al. Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update. Lancet Neurol. 2017;16(3):238–250. doi:. doi:10.1016/S1474-4422(17)30004-2 [CrossRef]
- Pittenger C. Glutamate modulators in the treatment of obsessive-compulsive disorder. Psychiatr Ann. 2015;45(6):308–315. doi:. doi:10.3928/00485713-20150602-06 [CrossRef]
- Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M. Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes. Br J Pharmacol. 2012;165:1543–1555. doi:. doi:10.1111/j.1476-5381.2011.01638.x [CrossRef]
- Schirmbeck F, Mier D, Esslinger C, et al. Increased orbitofrontal cortex activation associated with ‘pro-obsessive’ antipsychotic treatment in patients with schizophrenia. J Psychiatry Neurosci. 2015;40(2):89–99. doi:10.1503/jpn.140021 [CrossRef].
- Schirmbeck F, Esslinger C, Rausch F, Englisch S, Meyer-Lindenberg A, Zink M. Antiserotonergic antipsychotics are associated with obsessive-compulsive symptoms in schizophrenia. Psychol Med. 2011;41(11):2361–2373. doi:. doi:10.1017/S0033291711000419 [CrossRef]
- Chen CH, Chiu CC, Huang MC. Dose-related exacerbation of obsessive-compulsive symptoms with quetiapine treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:304–305. doi:. doi:10.1016/j.pnpbp.2007.07.024 [CrossRef]
- Ertugrul A, Yagcioglu AEA, Nurhayat E, Kazim M. Obsessive-compulsive symptoms in clozapine-treated schizophrenic patients. Psychiatry Clin Neurosci. 2005;59(2):219–222. doi:. doi:10.1111/j.1440-1819.2005.01362.x [CrossRef]
- Miodownik C, Bergman J, Lerner PP, Kreinin A, Lerner VM. Amisulpride as add-on treatment for resistant obsessive-compulsive disorder: retrospective case series. Clin Neuropharmacol. 2015;38(1):26–29. doi:. doi:10.1097/WNF.0000000000000065 [CrossRef]
- Vermeire S, Audenaert K, De Meester R, et al. Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatry Res. 2012;201:78–87. doi:. doi:10.1016/j.pscychresns.2011.06.006 [CrossRef]
- Sa AR, Hounie AG, Sampaio AS, Arrais J, Miguel EC, Elkis H. Obsessive-compulsive symptoms and disorder in patients with schizophrenia treated with clozapine or haloperidol. Compr Psychiatry. 2009;50(5):437–442. doi:. doi:10.1016/j.comppsych.2008.11.005 [CrossRef]
- Poyurovsky M, Hermesh H, Weizman A. Fluvoxamine treatment in clozapine-induced obsessive-compulsive symptoms in schizophrenic patients. Clin Neuropharmacol. 1996;19:305–313. doi:. doi:10.1097/00002826-199619040-00003 [CrossRef]
- Marsanić VB, Aukst-Margetić B, Grgić N, Kusmić E. Misdiagnosis and exacerbation of unusual obsessive-compulsive disorder presentation with risperidone and clozapine in an adolescent girl - a case report. Coll Antropol. 2011;35(suppl): S293–S296.
- Levy E, Margolese HC, Sultan S, Chouinard G. Obsessive-compulsive symptoms in schizophrenia induced by risperidone and responding to fluoxetine. Can J Psychiatr. 2003;48:709–710. doi:. doi:10.1177/070674370304801012 [CrossRef]
- Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HBAmerican Psychiatric Association. Practice guidelines for the treatment of patients with obsessive-compulsive disorder. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/ocd.pdf. Accessed November 9, 2018.