Obsessive Compulsive and Related Disorders: From the Biological Basis to a Rational Pharmacological Treatment

Obsessive Compulsive and Related Disorders: From the Biological Basis to a Rational... International Journal of Neuropsychopharmacology (2018) 21(1): 59–62 doi:10.1093/ijnp/pyx101 Advance Access Publication: October 26, 2017 Commentary Commentary Obsessive Compulsive and Related Disorders: From the Biological Basis to a Rational Pharmacological Treatment Gabriele Sachs, Andreas Erfurth Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Dr Sachs); 6th Psychiatric Department, Otto-Wagner-Spital, Vienna, Austria (Dr Erfurth) Correspondence: Gabriele Sachs, MD, PhD, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria (gabriele.sachs@meduniwien.ac.at). Keywords: obsessive compulsive and related disorders, comorbidity, serotonin, neurocognition, personalized treatment For the clinician, obsessive compulsive and related disor- Fineberg and colleagues (2017) have chosen an innovative and ders (OCRDs) as defined by the DSM-5 (American Psychiatric highly promising approach: focusing on compulsive activity in Association, 2013) are highly challenging. Treatment response, a broad range of disorders, a comprehensive review of cognitive both to medication and/or psychotherapy, can be slow and domains, neural circuitry, and treatment of OCRDs is provided. incomplete (Perugi et  al., 1997; Pallanti and Quercioli, 2006; This mapping should be understood as stimulus and starting Phillips and Hollander, 2008; Saxena, 2011; Van Ameringen et al., point for further neurobiological and clinical research on OCRDs: 2014; Skapinakis et al., 2016). The reasons for this are manifold a. Regulation of presynaptic and postsynaptic serotonin and include the following: (Gardier et  al., 1992, 2013; Erfurth et  al., 1994; Spies et  al., a. As w e know from the pre-pharmacological era of psychiatry 2015; James et al., 2017; Kraus et al., 2017) is a central strat- (Westphal, 1877; Thomsen, 1895; Janet, 1903), OCRDs includ- egy in psychopharmacology. Selective serotonin reuptake ing obsessive-compulsive disorder (OCD) are often lifespan inhibitors (SSRIs) are a leading option in the treatment of disorders. This means that achieving full recovery through major depression (Schatzberg, 1996; Dold et al., 2016; Novak treatment is difficult to start with. and Erfurth, 2017), anxiety disorders (Kasper, 2006), and b. Symptoms, including core symptoms of OCRDs, are multiple OCRDs including OCD (Soomro et  al., 2008). While major and to some extent unspecific. Already Janet pointed out depression can respond also to a variety of other interven- that “forced agitations” are central characteristics of OCD: tions (e.g., noradrenaline reuptake inhibition, serotonin “symptoms that are closely related to, but yet cannot prop- receptor antagonism), OCD so far has shown reliable clin- erly be called, obsessions and compulsions” (Pitman, 1987). ical response only to pharmacological interventions that c. OCRDs including OCD often are comorbid with other psychi- strongly increase serotonin within the synaptic cleft. Under atric disorders (Hasler et al., 2005), or expressed in other words: these circumstances, it is interesting that the finding of psychopathologic features that make individual patients meet impaired motor inhibition as a key neuroendophenotype in the criteria for OCRDs frequently are part of a broad cluster of OCD suggests a role for the neuromodulatory influence of clinical characteristics that let the same patient also meet the the noradrenergic, but not serotoninergic system. Would the criteria for, for example, bipolar disorder (Angst et  al., 2004, presence of impaired motor inhibition in an individual OCRD 2005; Fineberg et al., 2013), major depression (Degonda et al., patient be a risk factor for SSRI nonresponse? Would a clin- 1993), cyclothymia (Hantouche et al., 2003; Perugi et al., 2017), ical screening for impaired motor inhibition be able to iden- schizophrenia (Poyurovsky et  al., 2003; de Haan et  al., 2013), tify possible nonresponders to selective serotonin reuptake impulse control disorder (Issler et al., 2010), anxiety disorder, inhibition? Would these patients profit from a dual reuptake particularly social phobia (Perugi et al., 1999), or autism spec- inhibition strategy, for example, from selective serotonin trum disorder (Vannucchi et  al., 2014; Tsuchiyagaito et  al., and noradrenaline reuptake inhibitors (Denys et  al., 2007; 2017; Wikramanayake et al., 2017). Dougherty et  al., 2015) or from treatment with the strong, © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 59 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/59/4565843 by Ed 'DeepDyve' Gillespie user on 16 March 2018 60 | International Journal of Neuropsychopharmacology, 2018 but not selective, serotonin reuptake inhibitor clomipramine Aigner M, Sachs G, Bruckmüller E, Winklbaur B, Zitterl W, (Greist et al., 1990), with its mainly noradrenergic metabolite, Kryspin-Exner I, Gur R, Katschnig H (2007) Cognitive and desmethylclomipramine, or even monoamine oxidase inhib- emotion recognition deficits in obsessive-compulsive dis- itors (Carrasco et al., 1992; Erfurth and Schmauss, 1993)? order. Psychiatry Res 149:121–128. b. OCRD patients often show cognitive dysfunction (Aigner Alonso P, Cuadras D, Gabriëls L, Denys D, Goodman W, Greenberg et al., 2007; Abramovitch et al., 2013; Brennan and Flessner, BD, Jimenez-Ponce F, Kuhn J, Lenartz D, Mallet L, Nuttin B, 2015; Fineberg et  al., 2015; Liu et  al., 2017), a psychopatho- Real E, Segalas C, Schuurman R, du Montcel ST, Menchon JM logical feature, which in general is clearly linked to reduc- (2015) Deep brain stimulation for obsessive-compulsive dis- tions in functional outcome and quality of life (Sachs et al., order: a meta-analysis of treatment outcome and predictors 2012; Perna et  al., 2016). In particular, executive function of response. PLoS One 10:e0133591. has been shown to predict cognitive-behavioral therapy re- American Psychiatric Association (2013) Diagnostic and statis- sponse in childhood obsessive-compulsive disorder (Hybel tical manual of mental disorders. 5th ed. Washington, DC: et al., 2017). Would a thorough examination (“mapping”) of American Psychiatric Association. cognitive domains in OCRDs be able to contribute to a strati- Amodeo G, Fagiolini A, Sachs G, Erfurth A (2017) Older and newer fied therapeutic approach? Which role should cognitive re- strategies for the pharmacological treatment of agitation in mediation, cognitive training, or cognitive enhancement schizophrenia and bipolar disorder. CNS Neurol Disord Drug through psychopharmacology have in this context? Targets 16 doi: 10.2174/1871527316666170919115507. c. Some individuals diagnosed with OCRDs might profit from Angst J, Gamma A, Endrass J, Goodwin R, Ajdacic V, Eich D, a combination therapy of serotonin reuptake inhibitors Rössler W (2004) Obsessive-compulsive severity spectrum with other pharmacological agents (Hirschtritt et  al., 2017) in the community: prevalence, comorbidity, and course. Eur including antipsychotics (Dold et al. 2013). So far, such add- Arch Psychiatry Clin Neurosci 254:156–164. on-strategies have often been used in patients with par- Angst J, Gamma A, Endrass J, Hantouche E, Goodwin R, Ajdacic tial response or with psychiatric comorbidity. To give an V, Eich D, Rössler W (2005) Obsessive-compulsive syndromes example: agitation is a central challenge in clinical psych- and disorders: significance of comorbidity with bipolar iatry (Garriga et al., 2016; Erfurth, 2017; Amodeo et al., 2017); and anxiety syndromes. Eur Arch Psychiatry Clin Neurosci while serotoninergic neurotransmission is clearly linked to 255:65–71. agitation and aggression (Kavoussi et  al., 1997; Erfurth and Brennan E, Flessner C (2015) An interrogation of cognitive find- Sachs, 2017), SSRIs might not suffice to treat Janet’s “forced ings in pediatric obsessive-compulsive and related disorders. agitations” in OCRD. In clinical practice, the adjunctive use of Psychiatry Res 227:135–143. anticonvulsants such as valproate, gabapentin, or pregabalin Carrasco JL, Hollander E, Schneier FR, Liebowitz MR (1992) might be helpful (Perugi et al., 2002; Raja and Azzoni, 2004; Treatment outcome of obsessive compulsive disorder with Onder et  al., 2008; Oulis et  al., 2011) in treating individual comorbid social phobia. J Clin Psychiatry 53:387–391. OCRD patients with and without bipolar comorbidity. Could Degonda M, Wyss M, Angst J (1993) The Zurich Study. XVIII. examination of neural circuitry and cognitive domains iden- Obsessive-compulsive disorders and syndromes in the gen- tify patients early on that would profit from such add-on eral population. Eur Arch Psychiatry Clin Neurosci 243:16–22. approaches? De Haan L, Sterk B, Wouters L, Linszen DH (2013) The 5-year d. Reliable knowledge of the neuroanatomical basis of OCRD course of obsessive-compulsive symptoms and obsessive- symptoms and of neuropsychological endophenotypes compulsive disorder in first-episode schizophrenia and could lead to further develop and/or refine nonpharmaco- related disorders. Schizophr Bull. 39:151–160. logical treatment strategies, in particular rapid transcranial Dell’Osso B, Cremaschi L, Oldani L, Altamura AC (2017) New magnetic stimulation (Giupponi et al., 2009; Lee et al., 2017), directions in the use of brain stimulation interventions transcranial direct current stimulation (Dell’Osso et al., 2017; in patients with obsessive-compulsive disorder. Curr Med Fettes et al., 2017), and deep brain stimulation (Höflich et al., Chem. doi: 10.2174/0929867324666170505113631. 2013; Alonso et al., 2015; Naesström et al., 2016). Denys D, Van Nieuwerburgh F, Deforce D, Westenberg HG (2007) Prediction of response to paroxetine and venlafaxine by ser- In conclusion, understanding neurocognitive domains and otonin-related genes in obsessive-compulsive disorder in a neural circuitry of OCRD symptoms as reviewed by Fineberg randomized, double-blind trial. J Clin Psychiatry 68:747–753. et  al. (2017) might help to develop better and more personal- Dold M, Aigner M, Lanzenberger R, Kasper S (2013) Antipsychotic ized treatment recommendations. This understanding might augmentation of serotonin reuptake inhibitors in treatment- also contribute to validate the diagnostic categories proposed by resistant obsessive-compulsive disorder: a meta-analysis DSM-5 and to better comprehend the obvious clinical overlap of of double-blind, randomized, placebo-controlled trials. Int J OCRDs with affective disorders. Neuropsychopharmacol. 16:557–574. Dold M, Kautzky A, Bartova L, Rabl U, Souery D, Mendlewicz J, Porcelli S, Serretti A, Zohar J, Montgomery S, Kasper S (2016) Statement of Interest Pharmacological treatment strategies in unipolar depression None. in European tertiary psychiatric treatment centers: a phar- macoepidemiological cross-sectional multicenter study. Eur Neuropsychopharmacol 26:1960–1971. References Dougherty DD, Corse AK, Chou T, Duffy A, Arulpragasam AR, Abramovitch A, Abramowitz JS, Mittelman A (2013) The neuro- Deckersbach T, Jenike MA, Keuthen NJ (2015) Open-label psychology of adult obsessive-compulsive disorder: a meta- study of duloxetine for the treatment of obsessive-compul- analysis. Clin Psychol Rev 33:1163–11671. sive disorder. Int J Neuropsychopharmacol 18:pyu062. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/59/4565843 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Sachs et al. | 61 Erfurth A (2017) Agitation: a central challenge in psychiatry. 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Obsessive Compulsive and Related Disorders: From the Biological Basis to a Rational Pharmacological Treatment

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International Journal of Neuropsychopharmacology (2018) 21(1): 59–62 doi:10.1093/ijnp/pyx101 Advance Access Publication: October 26, 2017 Commentary Commentary Obsessive Compulsive and Related Disorders: From the Biological Basis to a Rational Pharmacological Treatment Gabriele Sachs, Andreas Erfurth Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Dr Sachs); 6th Psychiatric Department, Otto-Wagner-Spital, Vienna, Austria (Dr Erfurth) Correspondence: Gabriele Sachs, MD, PhD, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria (gabriele.sachs@meduniwien.ac.at). Keywords: obsessive compulsive and related disorders, comorbidity, serotonin, neurocognition, personalized treatment For the clinician, obsessive compulsive and related disor- Fineberg and colleagues (2017) have chosen an innovative and ders (OCRDs) as defined by the DSM-5 (American Psychiatric highly promising approach: focusing on compulsive activity in Association, 2013) are highly challenging. Treatment response, a broad range of disorders, a comprehensive review of cognitive both to medication and/or psychotherapy, can be slow and domains, neural circuitry, and treatment of OCRDs is provided. incomplete (Perugi et  al., 1997; Pallanti and Quercioli, 2006; This mapping should be understood as stimulus and starting Phillips and Hollander, 2008; Saxena, 2011; Van Ameringen et al., point for further neurobiological and clinical research on OCRDs: 2014; Skapinakis et al., 2016). The reasons for this are manifold a. Regulation of presynaptic and postsynaptic serotonin and include the following: (Gardier et  al., 1992, 2013; Erfurth et  al., 1994; Spies et  al., a. As w e know from the pre-pharmacological era of psychiatry 2015; James et al., 2017; Kraus et al., 2017) is a central strat- (Westphal, 1877; Thomsen, 1895; Janet, 1903), OCRDs includ- egy in psychopharmacology. Selective serotonin reuptake ing obsessive-compulsive disorder (OCD) are often lifespan inhibitors (SSRIs) are a leading option in the treatment of disorders. This means that achieving full recovery through major depression (Schatzberg, 1996; Dold et al., 2016; Novak treatment is difficult to start with. and Erfurth, 2017), anxiety disorders (Kasper, 2006), and b. Symptoms, including core symptoms of OCRDs, are multiple OCRDs including OCD (Soomro et  al., 2008). While major and to some extent unspecific. Already Janet pointed out depression can respond also to a variety of other interven- that “forced agitations” are central characteristics of OCD: tions (e.g., noradrenaline reuptake inhibition, serotonin “symptoms that are closely related to, but yet cannot prop- receptor antagonism), OCD so far has shown reliable clin- erly be called, obsessions and compulsions” (Pitman, 1987). ical response only to pharmacological interventions that c. OCRDs including OCD often are comorbid with other psychi- strongly increase serotonin within the synaptic cleft. Under atric disorders (Hasler et al., 2005), or expressed in other words: these circumstances, it is interesting that the finding of psychopathologic features that make individual patients meet impaired motor inhibition as a key neuroendophenotype in the criteria for OCRDs frequently are part of a broad cluster of OCD suggests a role for the neuromodulatory influence of clinical characteristics that let the same patient also meet the the noradrenergic, but not serotoninergic system. Would the criteria for, for example, bipolar disorder (Angst et  al., 2004, presence of impaired motor inhibition in an individual OCRD 2005; Fineberg et al., 2013), major depression (Degonda et al., patient be a risk factor for SSRI nonresponse? Would a clin- 1993), cyclothymia (Hantouche et al., 2003; Perugi et al., 2017), ical screening for impaired motor inhibition be able to iden- schizophrenia (Poyurovsky et  al., 2003; de Haan et  al., 2013), tify possible nonresponders to selective serotonin reuptake impulse control disorder (Issler et al., 2010), anxiety disorder, inhibition? Would these patients profit from a dual reuptake particularly social phobia (Perugi et al., 1999), or autism spec- inhibition strategy, for example, from selective serotonin trum disorder (Vannucchi et  al., 2014; Tsuchiyagaito et  al., and noradrenaline reuptake inhibitors (Denys et  al., 2007; 2017; Wikramanayake et al., 2017). Dougherty et  al., 2015) or from treatment with the strong, © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 59 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/59/4565843 by Ed 'DeepDyve' Gillespie user on 16 March 2018 60 | International Journal of Neuropsychopharmacology, 2018 but not selective, serotonin reuptake inhibitor clomipramine Aigner M, Sachs G, Bruckmüller E, Winklbaur B, Zitterl W, (Greist et al., 1990), with its mainly noradrenergic metabolite, Kryspin-Exner I, Gur R, Katschnig H (2007) Cognitive and desmethylclomipramine, or even monoamine oxidase inhib- emotion recognition deficits in obsessive-compulsive dis- itors (Carrasco et al., 1992; Erfurth and Schmauss, 1993)? order. Psychiatry Res 149:121–128. b. OCRD patients often show cognitive dysfunction (Aigner Alonso P, Cuadras D, Gabriëls L, Denys D, Goodman W, Greenberg et al., 2007; Abramovitch et al., 2013; Brennan and Flessner, BD, Jimenez-Ponce F, Kuhn J, Lenartz D, Mallet L, Nuttin B, 2015; Fineberg et  al., 2015; Liu et  al., 2017), a psychopatho- Real E, Segalas C, Schuurman R, du Montcel ST, Menchon JM logical feature, which in general is clearly linked to reduc- (2015) Deep brain stimulation for obsessive-compulsive dis- tions in functional outcome and quality of life (Sachs et al., order: a meta-analysis of treatment outcome and predictors 2012; Perna et  al., 2016). In particular, executive function of response. PLoS One 10:e0133591. has been shown to predict cognitive-behavioral therapy re- American Psychiatric Association (2013) Diagnostic and statis- sponse in childhood obsessive-compulsive disorder (Hybel tical manual of mental disorders. 5th ed. Washington, DC: et al., 2017). Would a thorough examination (“mapping”) of American Psychiatric Association. cognitive domains in OCRDs be able to contribute to a strati- Amodeo G, Fagiolini A, Sachs G, Erfurth A (2017) Older and newer fied therapeutic approach? Which role should cognitive re- strategies for the pharmacological treatment of agitation in mediation, cognitive training, or cognitive enhancement schizophrenia and bipolar disorder. CNS Neurol Disord Drug through psychopharmacology have in this context? Targets 16 doi: 10.2174/1871527316666170919115507. c. Some individuals diagnosed with OCRDs might profit from Angst J, Gamma A, Endrass J, Goodwin R, Ajdacic V, Eich D, a combination therapy of serotonin reuptake inhibitors Rössler W (2004) Obsessive-compulsive severity spectrum with other pharmacological agents (Hirschtritt et  al., 2017) in the community: prevalence, comorbidity, and course. Eur including antipsychotics (Dold et al. 2013). So far, such add- Arch Psychiatry Clin Neurosci 254:156–164. on-strategies have often been used in patients with par- Angst J, Gamma A, Endrass J, Hantouche E, Goodwin R, Ajdacic tial response or with psychiatric comorbidity. To give an V, Eich D, Rössler W (2005) Obsessive-compulsive syndromes example: agitation is a central challenge in clinical psych- and disorders: significance of comorbidity with bipolar iatry (Garriga et al., 2016; Erfurth, 2017; Amodeo et al., 2017); and anxiety syndromes. Eur Arch Psychiatry Clin Neurosci while serotoninergic neurotransmission is clearly linked to 255:65–71. agitation and aggression (Kavoussi et  al., 1997; Erfurth and Brennan E, Flessner C (2015) An interrogation of cognitive find- Sachs, 2017), SSRIs might not suffice to treat Janet’s “forced ings in pediatric obsessive-compulsive and related disorders. agitations” in OCRD. In clinical practice, the adjunctive use of Psychiatry Res 227:135–143. anticonvulsants such as valproate, gabapentin, or pregabalin Carrasco JL, Hollander E, Schneier FR, Liebowitz MR (1992) might be helpful (Perugi et al., 2002; Raja and Azzoni, 2004; Treatment outcome of obsessive compulsive disorder with Onder et  al., 2008; Oulis et  al., 2011) in treating individual comorbid social phobia. J Clin Psychiatry 53:387–391. OCRD patients with and without bipolar comorbidity. Could Degonda M, Wyss M, Angst J (1993) The Zurich Study. XVIII. examination of neural circuitry and cognitive domains iden- Obsessive-compulsive disorders and syndromes in the gen- tify patients early on that would profit from such add-on eral population. Eur Arch Psychiatry Clin Neurosci 243:16–22. approaches? De Haan L, Sterk B, Wouters L, Linszen DH (2013) The 5-year d. Reliable knowledge of the neuroanatomical basis of OCRD course of obsessive-compulsive symptoms and obsessive- symptoms and of neuropsychological endophenotypes compulsive disorder in first-episode schizophrenia and could lead to further develop and/or refine nonpharmaco- related disorders. Schizophr Bull. 39:151–160. logical treatment strategies, in particular rapid transcranial Dell’Osso B, Cremaschi L, Oldani L, Altamura AC (2017) New magnetic stimulation (Giupponi et al., 2009; Lee et al., 2017), directions in the use of brain stimulation interventions transcranial direct current stimulation (Dell’Osso et al., 2017; in patients with obsessive-compulsive disorder. Curr Med Fettes et al., 2017), and deep brain stimulation (Höflich et al., Chem. doi: 10.2174/0929867324666170505113631. 2013; Alonso et al., 2015; Naesström et al., 2016). 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International Journal of NeuropsychopharmacologyOxford University Press

Published: Jan 1, 2018

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