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

For the clinician, obsessive compulsive and related disorders (OCRDs) as defined by the DSM-5 (American Psychiatric Association, 2013) are highly challenging. Treatment response, both to medication and/or psychotherapy, can be slow and incomplete (Perugi et al., 1997; Pallanti and Quercioli, 2006; Phillips and Hollander, 2008; Saxena, 2011; Van Ameringen et al., 2014; Skapinakis et al., 2016). The reasons for this are manifold and include the following:

As we know from the pre-pharmacological era of psychiatry (Westphal, 1877; Thomsen, 1895; Janet, 1903), OCRDs including obsessive-compulsive disorder (OCD) are often lifespan disorders. This means that achieving full recovery through treatment is difficult to start with.

Symptoms, including core symptoms of OCRDs, are multiple and to some extent unspecific. Already Janet pointed out that “forced agitations” are central characteristics of OCD: “symptoms that are closely related to, but yet cannot properly be called, obsessions and compulsions” (Pitman, 1987).

OCRDs including OCD often are comorbid with other psychiatric disorders (Hasler et al., 2005), or expressed in other words: psychopathologic features that make individual patients meet the criteria for OCRDs frequently are part of a broad cluster of clinical characteristics that let the same patient also meet the criteria for, for example, bipolar disorder (Angst et al., 2004, 2005; Fineberg et al., 2013), major depression (Degonda et al., 1993), cyclothymia (Hantouche et al., 2003; Perugi et al., 2017), schizophrenia (Poyurovsky et al., 2003; de Haan et al., 2013), impulse control disorder (Issler et al., 2010), anxiety disorder, particularly social phobia (Perugi et al., 1999), or autism spectrum disorder (Vannucchi et al., 2014; Tsuchiyagaito et al., 2017; Wikramanayake et al., 2017).

Fineberg and colleagues (2017) have chosen an innovative and highly promising approach: focusing on compulsive activity in a broad range of disorders, a comprehensive review of cognitive domains, neural circuitry, and treatment of OCRDs is provided. This mapping should be understood as stimulus and starting point for further neurobiological and clinical research on OCRDs:

Regulation of presynaptic and postsynaptic serotonin (Gardier et al., 1992, 2013; Erfurth et al., 1994; Spies et al., 2015; James et al., 2017; Kraus et al., 2017) is a central strategy in psychopharmacology. Selective serotonin reuptake inhibitors (SSRIs) are a leading option in the treatment of major depression (Schatzberg, 1996; Dold et al., 2016; Novak and Erfurth, 2017), anxiety disorders (Kasper, 2006), and OCRDs including OCD (Soomro et al., 2008). While major depression can respond also to a variety of other interventions (e.g., noradrenaline reuptake inhibition, serotonin receptor antagonism), OCD so far has shown reliable clinical response only to pharmacological interventions that strongly increase serotonin within the synaptic cleft. Under these circumstances, it is interesting that the finding of impaired motor inhibition as a key neuroendophenotype in OCD suggests a role for the neuromodulatory influence of the noradrenergic, but not serotoninergic system. Would the presence of impaired motor inhibition in an individual OCRD patient be a risk factor for SSRI nonresponse? Would a clinical screening for impaired motor inhibition be able to identify possible nonresponders to selective serotonin reuptake inhibition? Would these patients profit from a dual reuptake inhibition strategy, for example, from selective serotonin and noradrenaline reuptake inhibitors (Denys et al., 2007; Dougherty et al., 2015) or from treatment with the strong, but not selective, serotonin reuptake inhibitor clomipramine (Greist et al., 1990), with its mainly noradrenergic metabolite, desmethylclomipramine, or even monoamine oxidase inhibitors (Carrasco et al., 1992; Erfurth and Schmauss, 1993)?

OCRD patients often show cognitive dysfunction (Aigner et al., 2007; Abramovitch et al., 2013; Brennan and Flessner, 2015; Fineberg et al., 2015; Liu et al., 2017), a psychopathological feature, which in general is clearly linked to reductions in functional outcome and quality of life (Sachs et al., 2012; Perna et al., 2016). In particular, executive function has been shown to predict cognitive-behavioral therapy response in childhood obsessive-compulsive disorder (Hybel et al., 2017). Would a thorough examination (“mapping”) of cognitive domains in OCRDs be able to contribute to a stratified therapeutic approach? Which role should cognitive remediation, cognitive training, or cognitive enhancement through psychopharmacology have in this context?

Some individuals diagnosed with OCRDs might profit from a combination therapy of serotonin reuptake inhibitors with other pharmacological agents (Hirschtritt et al., 2017) including antipsychotics (Dold et al. 2013). So far, such add-on-strategies have often been used in patients with partial response or with psychiatric comorbidity. To give an example: agitation is a central challenge in clinical psychiatry (Garriga et al., 2016; Erfurth, 2017; Amodeo et al., 2017); while serotoninergic neurotransmission is clearly linked to agitation and aggression (Kavoussi et al., 1997; Erfurth and Sachs, 2017), SSRIs might not suffice to treat Janet’s “forced agitations” in OCRD. In clinical practice, the adjunctive use of anticonvulsants such as valproate, gabapentin, or pregabalin might be helpful (Perugi et al., 2002; Raja and Azzoni, 2004; Onder et al., 2008; Oulis et al., 2011) in treating individual OCRD patients with and without bipolar comorbidity. Could examination of neural circuitry and cognitive domains identify patients early on that would profit from such add-on approaches?

Reliable knowledge of the neuroanatomical basis of OCRD symptoms and of neuropsychological endophenotypes could lead to further develop and/or refine nonpharmacological treatment strategies, in particular rapid transcranial magnetic stimulation (Giupponi et al., 2009; Lee et al., 2017), transcranial direct current stimulation (Dell’Osso et al., 2017; Fettes et al., 2017), and deep brain stimulation (Höflich et al., 2013; Alonso et al., 2015; Naesström et al., 2016).

In conclusion, understanding neurocognitive domains and neural circuitry of OCRD symptoms as reviewed by Fineberg et al. (2017) might help to develop better and more personalized treatment recommendations. This understanding might also contribute to validate the diagnostic categories proposed by DSM-5 and to better comprehend the obvious clinical overlap of OCRDs with affective disorders.

Statement of Interest

None.