Andrea Aguglia, MD, PhD

SPECIAL REPORT: OCD AND RELATED DISORDERS

The key features of obsessive-compulsive-disorder (OCD) are obsessions and compulsions; in most cases of severe symptomatology, avoidance behaviors also are present. Anxiety is a secondary but very pervasive manifestation of OCD. The onset of OCD is typically in late childhood, early adolescence, or early adulthood. The pathophysiology of OCD is uncertain, largely because of the 

of manifestations and the high rates of comorbidity (anxiety, depressive or bipolar disorder). Furthermore, OCD symptoms can be quite difficult to recognize; intrusive thoughts and behaviors that are the primary features of the disease are internally driven. Not understanding what is happening, patients tend to be ashamed and suffer in silence, often resulting in a period of 8 to 10 years of untreated illness and long-term negative outcomes.

First-line treatment of OCD consists of cognitive behavioral therapy with exposure and prevention of response often in combination with selective serotonin reuptake inhibitors plus clomipramine. These treatment approaches usually guarantee symptom reduction and remission in at least 60% to 70% of cases. Quite often, they are used together 

 if symptoms are mild to moderate. International guidelines suggest the use of pharmacological treatment at maximum tolerated doses for at least 8 to 12 weeks, but clinicians should wait even longer to evaluate the potential improvement of symptoms.

For patients who do not achieve remission after a trial of adequate dosage and duration, a switch to another SSRI or clomipramine is recommended. If there is partial response, consider augmenting with a first-generation (eg, haloperidol) or second-generation antipsychotic (eg, risperidone, aripiprazole, olanzapine).

According to the National Comorbidity Survey Replication (NCS-R), 68% of patients in the US subjects with a psychiatric disorder have at least one co-occurring general medical condition (GMC). In addition, in those with primarily a GMC, 29% report to have a comorbid psychiatric disorder.

question has been widely examined in patients with schizophrenia or bipolar disorder as well as unipolar depression. Metabolic syndrome (primarily abdominal obesity, dyslipidemia, type II diabetes mellitus) and cardiovascular conditions (primarily hypertension) are the most common co-occurring medical condition, with cumulative incidences at age 47 of 56.2% versus 34.4% in the general population.

Medical comorbidities in OCD and other anxiety disorders have been insufficiently studied; researchers have only started to pay attention to this in the past few years.

 As in other psychiatric disorders, pharmacological treatment and unhealthy lifestyles play a leading role in causing these problems. OCD patients often conduct lonely lives, reduce their physical 

, and engage in drinking or smoking to control their symptoms.

Inherited factors such as hypothalamic pituitary adrenal (HPA) axis dysregulation have been considered for a long time as being responsible for altering metabolic profiles. Although a recent study ruled out shared genetic and environmental factors because family members of patients with OCD had the same metabolic and cardiovascular risk as the general population, patients with OCD have a 45% increased risk for any metabolic or cardiovascular complications.

Cardiovascular issues and antidepressants

 is higher in individuals suffering with depression. Some antidepressants, if given at full dose (eg, citalopram), can cause QT prolongation, resulting in an increased risk of arrhythmia. As demonstrated by a recent study, SSRIs would not be associated with an increased risk for arrhythmias, stroke, or transient ischemic attack in adults. Fluoxetine seems to reduce the hazard of a myocardial infraction.

Reduced physical activity and unhealthy food consumption determine obesity, which is one of the main risk factors for altered metabolic profiles in psychiatric patients. Apart from lifestyle causes, pharmacological treatments (ie, second-generation antipsychotics, antidepressants with high H

 affinity receptor, and mood stabilizers) are responsible for the weight gain that often reduce treatment adherence and determine relapses. Although they are commonly prescribed, only a few studies examined the relationship between antidepressants and weight change.

Tricyclics can determine weight gain through anticholinergic activity while SSRIs seem to lead to weight loss rather than weight gain, at least at the beginning of treatment. This effect could be due to the first improvement of depressive symptoms as well as the activation of the melanocortin system by an increase in serotonin levels. However, as treatment continues, 

 The reason is mostly unknown and not completely understood; it also could be produced by the physiological return to pre-illness weight, after a long period of appetite loss.

The most common metabolic risk factors are diabetes mellitus and insulin resistance. Chronic stress may result in decreased insulin sensitivity, even when there is no weight gain. It is unclear how it happens, most likely the association is multifactorial. A dysfunctional HPA axis may have a role on two levels:

1. At a behavioral level altered appetite, sleep disturbances and reduced activity may result in impaired glucose metabolism.

2. At a molecular level, neuroendocrine and inflammatory responses could develop diabetes mellitus.

Dyslipidemia is another important risk factor that contributes to mortality and morbidity in OCD patients. Relevant associations were discovered relating to the use of SSRIs and higher cholesterol level, increased triglyceride, and reduced high-density lipoprotein cholesterol (HDL-c). Second-generation antipsychotics also make a significant impact on eating behaviors and energy balance. Metabolism centers located in the central nervous system 

 balance the need for energy and the seeking of reward. At the peripheral level, all is ruled by connections between muscles, liver, pancreas, adipose tissue, and neuroendocrine organs. Neurotransmitter receptors, the main target of antipsychotic drugs, play a fundamental role in metabolism regulation. Bullet-receptor interaction can both protect and harm metabolism. Different second-generation antipsychotics can (at different levels) determine diabetes, obesity, and lipid profile alterations; pharmacodynamic profiles can only partially explain this difference.

Plot twist: are therapies the main problem?

A recent Swedish population-based study showed unexpected results: a higher dose of SSRIs and longer treatment duration were correlated with a lower risk of metabolic or cardiovascular problems. This evidence can be explained in many ways, including better disease control, appropriate pharmacological treatment, and unhealthy habits (smoking, unhealthy diet). Full doses of SSRIs could prevent secondary depression; comorbidity can be as high as 80%, but most prevalence rates are around 25% and 50%, considering OCD. Moreover, better symptom control could reduce anxiety, which plays a key role in causing metabolic and cardiovascular alterations.

Both depression and OCD have an impact on glycemic control, which is exacerbated with high anxiety with consequent hyperglycemia via activation of autonomic responses and triggering the HPA axis. Hyperglycemia can also lead to anxiety in different ways. By increasing cortisol secretion, altering heart rate, and modifying skin conductance levels it can lead to stress-like arousal patterns pervasive in psychiatric patients.

Patients affected by diabetes mellitus type II, if not well informed on their condition and not trained to deal with it, can develop secondary OCD. They may become obsessed by glycemic control, run unnecessarily frequent blood tests, and live with exaggerated concerns about the condition. Too many alterations of insulin doses can lead to even poorer glycemic control and higher manifestations of OC symptoms.

Physical well-being results in better quality of life and is associated with lower anxiety levels lowering the risk of a diabetes diagnosis. Mental well-being is linked to lower anxiety and depression, but not to metabolic disease duration or control. Planning psychological intervention for diabetes patients that are targeted on psychological health can result in better self-management and better health outcomes.

When comorbidity occurs, the impairment caused by the psychiatric disease reduces the ability to deal with the medical condition. Deficits in frontal-striatal function have been seen with OCD.

 The integrity of these structures and their connections play a key role in the affective, cognitive, and motor flexibility needed for actions that are goal-directed. Therefore, for OCD patients it could be much more difficult to focus on necessary behaviors to control the metabolic symptoms.

Patients with OCD as well as those affected by bipolar disorder and schizophrenia have an increased risk for comorbid medical illness. The presence of medical illness is probably multifactorial and can lead to a longer duration of untreated illness with a negative impact on the course of illness. Clinicians should keep in mind that the primary aim should always be to achieve symptom remission as the minimum effective dosage. Moreover, assessing the risk to benefit ratio in treatment planning will help in decision making for the best therapeutic strategies, resulting in reduced risk for relapse, better symptom control, and fewer adverse effects.

 is Researcher and Psychiatrist, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy

is Resident in Psychiatry, DINOGMI, Section of Psychiatry, University of Genoa, and IRCCS Ospedale Policlinico San Martino; 

 is Researcher and Psychiatrist DINOGMI, Section of Psychiatry, University of Genoa; IRCCS Ospedale Policlinico San Martino; and Mood Disorders Program, Tufts Medical Center, Boston, MA. 

 is Associate Professor, DINOGMI, Section of Psychiatry, University of Genoa, and IRCCS Ospedale Policlinico San Martino. 

 Professor, DINOGMI, Section of Psychiatry, University of Genoa, and IRCCS Ospedale Policlinico San Martino. The authors report no conflicts of interest concerning the subject matter of this article.

1. Hirschtritt ME, Bloch MH, Mathews CA. Obsessive-compulsive disorder: advances in diagnosis and treatment. 

2. Kessler RC, Berglund P, Chiu WT, et al. The US National Comorbidity Survey Replication (NCS-R): design and field procedures. 

3. Isomura K, Brander G, Chang Z, et al. Metabolic and cardiovascular complications in obsessive-compulsive disorder: a total population, sibling comparison study with long-term follow-up. 

4. Albert U, Aguglia A, Chiarle A, et al. Metabolic syndrome and obsessive-compulsive disorder: a naturalistic Italian study. 

5. Aguglia A, Signorelli MS, Albert U, et al. The impact of general medical conditions in obsessive-compulsive disorder. 

6. Coupland C, Hill T, Morriss R, et al. Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database. 

7. Olguner Eker O, Ozsoy S, Eker B, Dogan H. Metabolic effects of antidepressant treatment. 

8. Salvi V, Mencacci C, Barone-Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. 

9. Siafis S, Tzachanis D, Samara M, Papazisis G. Antipsychotic drugs: from receptor-binding profiles to metabolic side effects. 

10. Anderson RJ, Grigsby AB, Freedland KE, et al. Anxiety and poor glycemic control: a meta-analytic review of the literature. 

11. Martino G, Catalano A, Bellone F, et al. As time goes by: anxiety negatively affects the perceived quality of life in patients with type 2 diabetes of long duration. 

12. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. 

13. Vaghi MM, Vertes PE, Kitzbichler MG, et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive-compulsive disorder: evidence from resting-state functional connectivity. 

Articles

OCD symptoms can be quite difficult to recognize. Not understanding what is happening, patients tend to be ashamed and suffer in silence, often resulting in a period of 8 to 10 years of untreated illness and long-term negative outcomes.

Untangling the Web of Comorbid Obsessive-Compulsive Disorder and Medical Illness

BD-OCD comorbidity’s burden and clinical management is a critical issue in psychiatry.

The evidence so far on BD-OCD nosology, which is mainly based on the course of illness, supports the view that the majority of cases of comorbid BD-OCD are in fact BD cases. Obsessive-compulsive symptoms usually are secondary manifestations of depressive or manic mood episodes.

Mood stabilization should be the primary goal in treating patients with BD-OCD. Because of the risk of worsening BD via serotonin reuptake inhibitors-induced mania/hypomania, antidepressants should only be used in a minority of cases of refractory OCD.

In a classic 1970 publication, the famous epidemiologist Alvan R. Feinstein, MD, defined comorbidity in relation to a specific index condition as “any distinct additional entity that has existed or may occur during the clinical course of a patient who has the index disease under study.”

 In Feinstein’s formulation, the implication was that a completely different and independent disease occurred at the same time as another disease. These two diseases co-occurred, more often than not, randomly.

On the other hand, DSM explicitly offers overlapping clinical criteria for many diagnoses, especially mood and anxiety disorders, guaranteeing comorbidity in quite a different sense than in the medical meaning of the term as co-occurrence of independent diseases. Using the DSM definition, it is unclear whether concomitant diagnoses actually reflect the presence of distinct clinical entities or refer to multiple manifestations of a single clinical entity.

A good example of this problem is the comorbidity of bipolar disorder (BD) and OCD. More than half of patients with BD have an additional diagnosis, one of the most difficult to manage being OCD. More than 150 years ago, French psychiatrist BÃ©nÃ©dict-Augustin Morel first described patients with BD-OCD, which resulted in questions regarding nosology and the clinical meaning of this condition.

In a standard 1969 psychiatry textbook, Mayer-Gross and colleagues,

 who had a significant focus on course of illness, included patients with BD-OCD in the manic-depressive disorders.

In the hierarchical approach to diagnosis, which contradicts the DSM comorbidity approach, anxiety presentations like OCD should not be diagnosed as separate conditions when co-occurring with mood presentations such as BD. In other words, OCD should not be diagnosed unless BD is ruled out. If this non-DSM approach is correct, patients with OCD should be evaluated for family history for mood disorders, course of illness of mood symptoms in relation to OCD symptoms, and other evidence of bipolarity.

BD-OCD comorbidity has importance in nosology as well as therapeutic implications. The question of nosology is whether this common comorbidity represents two separate diseases that co-occur by chance, or a severe subtype of BD or OCD. The therapeutic question is whether and how to treat the comorbidity since the main treatment for OCD serotonin reuptake inhibitors (SRIs) can worsen BD.

Although recent studies have looked at the co-occurrence of anxiety and bipolar disorders, there is insufficient research and the relationship between BD and OCD remains unclear. Given the available scientific evidence, however, some observations can be made (

Apparent BD-OCD comorbidity is a common condition in psychiatry (

from a large cross-continental multiple OCD treatment center study (3711 patients with OCD), showed a lifetime prevalence of comorbidity with BD-I and BD-II of 4.5% and 23.7%, respectively.

In our meta-analysis, the pooled prevalence of OCD in BD was 17.0% (95% CI 12.7-22.4), which was comparable to the results reported by the pooled prevalence of BD in OCD (18.35%, 95% CI 13.2-24.8).

Although limited by retrospective study design, small sample size, different thresholds for BD diagnosis (ie, categorical versus dimensional approach) and a different accuracy in diagnosing OCD (ie, discrimination between true ego-dystonic obsessions and depressive ruminations), these results confirm the relevance of comorbid BD-OCD.

Most patients experience the onset of OCD before the onset of BD. Only in a 

, the onset of OCD is concomitant with the first mood episode, rather than preceding or following it.

As reported by recent studies, OC symptoms in 

 seem to increase the risk of a later BD diagnosis, this being suggestive of partially shared etiopathogenetic mechanisms between these severe psychiatric disorders.

 Moreover, results from our meta-analysis showed higher comorbidity rates in youths (24.2%, 95% CI 10.36-41.60, n = 345, z = -9.5) compared with adults (13.56%, 95% CI 10.4-16.25, n = 539).

 Considering course of illness as a key diagnostic validator, especially among patients with a primary diagnosis of BD, most comorbid OCD cases appeared to be related to mood episodes. Obsessive compulsive symptoms in comorbid patients appeared more often-and sometimes exclusively-during depressive episodes, and comorbid BD and OCD cycled together, with obsessive compulsive symptoms often remitting during manic/hypomanic episodes.

Taken together, the evidence so far on BD-OCD nosology, supports the view that most comorbid OCD appears to be related to mood episodes. Obsessive compulsive symptoms in childhood and adolescence may be expression of vulnerability to BD and an increased risk for BD. Obsessive compulsive symptoms would initially coexist with BD symptoms, even cycling together, and would gradually tend to decrease in the adulthood.

 assessed family history for OCD or BD in comorbid BD-OCD probands using clinical interviews and clinical records. The majority of these studies reported a higher prevalence of family history for mood disorders and lower prevalence for OCD in patients with BD-OCD.

 Moreover, a family history for mood disorders was reported to be more frequent in episodic OCD patients than in continuous/chronic OCD patients.

Investigators from the US analyzed the serotonin-transporter (5-HTT) binding potential using positron-emission tomography (PET) and [

C]DASB, a radioligand with high sensitivity and specificity for 5-HTT. They reported higher 5-HTT binding potential in the insula, the posterior cingular cortex, the subgenual anterior cingulate cortex, and the dorsal cingulate cortex in patients with OCD-BD.

From a neurobiological perspective, BD mostly 

hypoactivity in the orbitofrontal cortex (ie, decision making, impulse control) and in the dorsolateral prefrontal cortex (ie, planning, attentional set shifting) with grey matter volume reduction associated to manic episodes. OCD mainly presented hyperactivity of the orbitofrontal cortex with a deficit in emotional processing.

 The overlap of similar cortical-subcortical circuits may partially explain clinical features of comorbid BD-OCD during the course of illness.

If clinical observations are correct, then many patients who are said to have both BD and OCD in fact only have BD, with OCD symptoms being caused by or secondary to mood symptoms. Therefore, mood stabilization should be the primary goal in treating BD-OCD patients.

 The treatment implication would be that such patients would improve with mood stabilizers alone, for both mood and OCD symptoms.

Serotonin reuptake inhibitors would be unnecessary for OCD symptoms and, in fact, could undermine OCD treatment by worsening the underlying causal mood episodes. This worsening could occur in two ways: either by causing mania, which would trigger a mood cycle leading to later depression; or by causing a long-term worsening rapid-cycling course of illness, with more and more mood episodes, in turn producing more and more OCD symptoms. Adding SRIs may be needed only in a minority of patients who have BD with refractory OCD.

Besides mood stabilizers, neuroleptics may also be effective in both BD and OCD. Aripiprazole augmentation to lithium carbonate, even at low doses (10-15 mg/d), seemed to be the best option in comorbid patients with treatment-resistance.

 Reports of exacerbation of OC symptoms with neuroleptic agents tend to relate to schizophrenia, not BD.

Study findings suggest that most cases of DSM-based BD-OCD comorbidity are not in fact comorbidity as defined by Feinstein.

 Rather these are cases of BD, with OC symptoms as secondary manifestations of mood episodes. This observation does not deny the remaining patients who have two separate disorders, BD and OCD, that occur simultaneously.

 is Researcher and Psychiatrist, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy; and Mood Disorders Program, Tufts Medical Center, Boston, MA. 

is ChargÃ©e d'einsegment et de Recherche, Psychiatrist and Neurologist, Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Geneva, Switzerland; Department of Psychiatry, ASO Santi Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy

 is Researcher and Psychiatrist, DINOGMI, Section of Psychiatry, University of Genoa, and IRCCS Ospedale Policlinico San Martino; 

 is Conjoint Professor, School of Medicine, Western Sydney University, Blacktown Hospital, Sydney, NSW, Australia. 

 is Professor, DINOGMI, Section of Psychiatry, University of Genoa, and IRCCS Ospedale Policlinico San Martino. 

 is Professor, Mood Disorders Program and Department of Psychiatry, Tufts University Medical School, Boston, MA. 

 report no conflicts of interest concerning the subject matter of this article; 

 reports that he is employed by Novartis Institutes for Biomedical Research and holds equity in Novartis.

1. Maj M. Psychiatric comorbidity: an artefact of current diagnostic systems? 

 ed. London: Elsevier Health Sciences; 1969.

3. Brakoulias V, Starcevic V, Belloch A, et al. Comorbidity, age of onset and suicidality in obsessive-compulsive disorder (OCD): an international collaboration. 

4. Amerio A, Stubbs B, Odone A, et al. The prevalence and predictors of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review and meta-analysis. 

5. Tonna M, Amerio A, Odone A, et al. Comorbid bipolar disorder and obsessive-compulsive disorder: which came first? 

6. CederlÃ¶f M, Lichtenstein P, Larsson H, et al. Obsessive-compulsive disorder, psychosis, and bipolarity: a longitudinal cohort and multigenerational family study. 

7. Amerio A, Odone A, Liapis CC, et al. Diagnostic validity of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review. 

8. Amerio A, Tonna M, Odone A, et al. Heredity in comorbid bipolar disorder and obsessive-compulsive disorder patients. 

9. Joshi G, Mick E, Wozniak J, et al. Impact of obsessive-compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder. 

10. Ekman CJ, Lind J, RydÃ©n E, et al. Manic episodes are associated with grey matter volume reduction - a voxel-based morphometry brain analysis. 

11. Amerio A, Maina G, Ghaemi SN. Updates in treating comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review. 

12. Fonseka TM, Richter MA, MÃ¼ller DJ. Second generation antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature. 

This review highlights an important diagnostic and therapeutic task: the importance of differentiating true bipolar disorder/obsessive-compulsive disorder comorbidity from BD with secondary OCD.

Author | Andrea Aguglia, MD, PhD

Articles

Untangling the Web of Comorbid Obsessive-Compulsive Disorder and Medical Illness

Differentiating Comorbid Bipolar Disorder and OCD