Obsessive Compulsive Disorder (OCD) – A Primer on Neurobiology, Diagnosis and Treatment

CLINICAL PRESENTATION AND DIAGNOSIS

Obsessions:

• Persistent, unwanted, repetitive, intrusive thoughts, images, and urges which are ego-dystonic and cause anxiety and distress

Compulsions:

• Repetitive behaviours or mental acts performed in response to an obsession to reduce the anxiety or distress to prevent a feared consequence.

Based on a factor analysis of symptoms, a five-factor model of symptom dimensions in OCD has been proposed. [Stein et al, 2019]

Screening

Recently validated screening tools include the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), which has good reliability and is widely used in clinical research.[Goodman et al. 1989], [Goodman et al. 1989]

However, utilising the Y-BOCS screening tool requires adequately trained medical staff to accurately assess the presence and severity of 64 unique obsessions and compulsions.

There are other screening tools that, although not as well validated, are still as reliable and sensitive. These include the obsessive-compulsive inventory short version (OCI-SV), which only takes 5 minutes to complete and has 18 items that are scored based on the degree of distress associated.

There is also, the Florida Obsessive-Compulsive Inventory, which has a 20-item checklist on a 5-choice scaling system.

Diagnosis

Read the diagnostic interviewing for OCD. 

An OCD diagnosis is based on clinical assessments of obsessive thoughts or compulsive behaviours that last more than one hour per day and are not the result of a medical condition or substance abuse. Patients also do not have to show both obsessive and compulsive traits to be diagnosed as suffering from OCD.

DSM-5 

The Diagnostic and Statistical Manual of Mental Disorders (5^th edition) specifies OCD symptoms as clinically separate from delusions or persistent negative thoughts that may be associated with other psychiatric disorders such as depression or generalised anxiety.

Three insight specifiers are included in the DSM-5:

• With good or fair insight
• With poor insight
• With absent insight or delusional beliefs

The DSM-5 includes a tic specifier which is relevant due to the close association between OCD and Tourette syndrome.

The DSM-5 created a separate section called OCD and related disorders due to phenotypic, genetic, neuroimaging and treatment response data suggesting OCD and related disorders are a distinct entity.

The related disorders included are:

• Body Dysmorphic Disorder
• Hoarding Disorder
• Trichotillomania
• Skin picking disorder
• Substance/medication-induced OCD
• OCD due to another medical condition

ICD-11 Obsessive Compulsive or related disorders (OCRD): 

• Obsessive-compulsive disorder
• Body dysmorphic disorder
• Hypochondriasis: persistent preoccupation with or fear about the possibility of having one or more serious, progressive or life-threatening diseases.
• Olfactory reference disorder: persistent preoccupation with the belief that one is emitting a perceived foul or offensive body odour or breath that is either unnoticeable or only slightly noticeable to others.
• Hoarding Disorder: not associated with intrusive unwanted thoughts but rather is characterised by a compulsive need to accumulate possessions and distress related to discarding them
• Body-focused repetitive behaviour disorders: characterised by recurrent and habitual actions directed at the integument (e.g., hair-pulling (Trichotillomania), skin-picking (excoriation disorder)) and lack a prominent cognitive aspect.
• Tourette’s disorder (multiply coded) is also coded under OCRD because it frequently co-occurs with OCD.

NEUROBIOLOGY OF OCD

Genetics: [Bralten et al, 2020]

• OCD is a polygenic disorder with many identified risk loci of small effect
• Obsessive-compulsive symptoms (OCS) are heritable, with their heritability ranging from 30 to 77%.
• Genetic factors contribute to specific OCS dimensions, including contamination/cleaning and checking/ordering.
• Additive genetic effects account for ~40% of the variance, and the non-shared environment accounts for ~51% of the variance. [Taylor, 2011]
• Early-onset OCD with tics may have a higher heritability
• Variants in glutamatergic, serotonergic and dopaminergic genes have been identified. [Stein et al, 2019] , [Taylor , 2011]
• Large deletions associated with other neurodevelopmental disorders have been found in patients with OCD
• 50% of these deletions were located in a single locus 16p13.11. [McGrath et al, 2014]

Specific genes associated with OCD:

• SERT (Serotonergic)
• COMT (Dopaminergic)
• SLC1A1and GRIN2B (Glutamatergic)
• GRID2 and DLGAP1 (Glutamatergic)
• Insulin signalling genes
• A significant association between autosomal OCD genes centred around CNS insulin-regulated synaptic function and ‘symmetry/counting/ordering’. Peripheral insulin signalling link between Type 2 diabetes (T2D) and aggressive taboo thoughts and T2D and contamination/cleaning. [Bralten et al, 2020]

BRAIN CIRCUITS INVOLVED IN OBSESSIVE-COMPULSIVE DISORDER (OCD)

The cortico-striatal-thalamic-cortical loop (CSTC) is considered the critical brain circuit involved in the phenomenology of OCD. The CSTC circuits modulate several specific functions outlined below. In addition, the frontoparietal and fronto limbic network also plays a role in the pathophysiology of OCD. [Stein et al, 2019], [Hirschtritt et al, 2017], [Karas et al, 2019]

1. Sensorimotor CSTC circuit

• Supplementary motor area to putamen to the thalamus
• Stimulus-response-based habitual behaviour (S-R)

2. Dorsal Cognitive CSTC circuit

• Dorsolateral Prefrontal Cortex (DLPFC) & Dorsomedial Prefrontal Cortex (DMPFC) to caudate (dorsal) to thalamus
• Involved in working memory, planning and emotional regulation

3. Frontoparietal network

• Frontal cortex to the thalamus and parietal cortex
• Coordination of cognitive control
• Part of the alerting network

4. Ventral cognitive CSTC circuit

• Inferior frontal gyrus (IFG) and Ventrolateral Prefrontal cortex (VLPFC) to ventral caudate to thalamus
• Involved in response inhibition

5. Ventral motivational CSTC circuit

• Orbitofrontal cortex (OFC) to Nucleus Accumbens (NAc) to the thalamus
• Involved in Stimulus outcome-based motivational behaviour i.e Stimulus-outcome (S-O)

6. Frontolimbic circuit

• VMPFC to amygdala to thalamus
• Role in fear extinction

7. Frontal CSTC and Cerebellar Circuit

Direct and Indirect CSTC Loop Imbalance:  

In the normally functioning cortico-striato-thalamo-cortical circuit, direct and indirect pathways lead to increased or decreased inhibition of the thalamus, respectively, in a balanced manner.

In OCD, overactivation of the direct pathway out of proportion to the indirect pathway leads to pathologic overactivity of cortical regions in an insidious excitatory loop.

The imbalance indicates that the ‘brake’ that would control repetition is faulty.

According to Saxena et al., who proposed the model [Saxena et al. 1998] :

OCD is mediated by an imbalance between the direct (excitatory, OFC-striatum-globus pallidus-thalamus-cortical) and indirect (inhibitory, DLPFC-striatum-globus pallidus-subthalamic nucleus-cortical) pathways within this circuit, which causes a brain lock in the caudate nucleus and a mutual hyperactivation between the OFC and thalamus.

Whereas the CTSC hypothesis provides a useful framework, it doesn’t comprehensively explain the pathophysiology of OCD.

Imbalance of Goal-directed vs Habit areas: 

Studies are increasingly focusing on the role of the goal-directed and habit areas of the brain in OCD. [Lipton et al, 2019]

Proposed two-stage pathophysiology of OCD 

1. Early Phase of OCD: 

• Alterations within the dorsal cognitive, ventral cognitive, ventral reward CSTC circuits and the frontolimbic circuit are linked to symptoms involving anxiety, uncertainty, and goal-directed behaviours.

2. Late phase of OCD: 

• Alterations within the sensorimotor, dorsal cognitive and ventral cognitive CSTC circuits are linked to symptoms involving habitual behaviours.
• Patients with OCD show hyperactivation of the caudate nucleus which is associated with increased habit formation and this hyperactivity is remediated when treatments are successful [Gillan et al, 2016]

Brain activity in OCD during emotional processing vs cognitive processing

Functional neuroimaging studies have shown increased activation in the areas of basal ganglia (predominantly head of caudate), anterior cingulate, and orbitofrontal cortex (areas involved in emotional and cognitive processing) in OCD patients as compared to healthy controls. [Parmar & Sarkar, 2016], [Nakao et al, 2014]

OCD is characterised by dysfunctions in affective and cognitive processing. This cognitive affective dysfunction is a feature of many psychiatric disorders and may lack specificity. [Stein et al, 2019]

Emotional processing (Affective paradigm):

• Overactivation of brain networks involved in salience, arousal and habitual responding such as the anterior cingulate cortex, insula, head of the caudate nucleus and putamen.
• Underactivation of regions that have been implicated in cognitive control, such as the medial prefrontal cortex and posterior caudate, compared with healthy controls.

Cognitive processing: (Cognitive Paradigm)

• Increased activation in regions involved in self-referential processing, such as the precuneus and the posterior cingulate cortex.
• Decreased activation in subcortical regions involved in goal-directed behaviour and motor control, such as the globus pallidus, ventral anterior thalamus and posterior part of the caudate nucleus.

The net effect of cognitive-affective dysfunction is increased habitual responding and affective processing with impaired cognitive control in patients with OCD.

Role of the Anterior Cingulate Cortex (ACC)- The Dorsal Anterior Cingulate Cortex (dACC) Aberrant Control Signal in OCD: 

• The ACC, nucleus accumbens and caudate nucleus form the frontostriatal circuit.
• The ACC is a part of an extended medial prefrontal network, with connections to the amygdala and PFC. It plays an important role in emotion appraisal and regulation, evaluation of the salience of emotional stimuli, and emotion-related learning. [McGovern & Sheth, 2017]

NEUROTRANSMITTER SYSTEMS IN OCD

The neurotransmitter model of OCD postulates dopaminergic and glutamatergic overactivity in frontostriatal pathways, along with diminished serotonergic and GABAergic neurotransmission in frontolimbic systems. These neurotransmitter imbalances may explain frontostriatal hyperactivity and impaired frontolimbic emotion regulation. [Pittenger et al, 2017]

1. Serotonin (5-HT)

• Changes in serotonin levels and serotonergic genes have been implicated, but the evidence is inconclusive.

The role of serotonin is implicated due to the finding that SSRIs are effective treatments for OCD.

Some potential therapeutic effects of serotonergic transmission in OCD are:

• Central serotonin depletion is known to increase habitual responding at the expense of goal-directed behaviour. Serotonergic medication remediates goal-directed deficits in OCD by increasing 5-HT activity in OFC, facilitating a shift from automatic habitual to goal-directed behaviours. This effect again may be mediated by 5-HT2C agonist activity. [Gillan et al, 2016], [Fineberg et al, 2018]
• Significant pre and post-treatment (SSRI or CBT) increase in whole-brain 5-HT synthesis capacity was associated with patients that responded.  Increases in global 5-HT synthesis capacity correlated with reductions in OCD symptom severity. [Lissemore et al, 2018]
• The serotonergic innervation to the amygdala (part of the frontolimbic network) is influenced by SSRIs and leads to positive shifts in the way the brain appraises emotionally-valenced information. 5-HT activates the 5-HT2A receptors on GABA neurons which in turn exert an inhibitory action on NA neurons (amygdala) through enhanced GABA release. [Blier & El Mansari, 2013]
• Alterations in the amygdala have been found in unmedicated OCD patients.

2. Glutamate (Glu)

• Glutamate is the primary driver of the direct excitatory CSTC circuit.
• Glutamatergic neurons originating in the PFC project to the striatum and thus receive significant excitatory output from the PFC. Glutamatergic signalling regulates neurotransmission between the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and striatal structures (caudate, putamen and others).
• Glutamatergic hyperactivity associated with over-activity of the direct pathway is postulated to be one of the mechanisms in the pathophysiology of OCD. [Karthik et al, 2020]

3. Dopamine (DA)

The direct and indirect pathway of the CSTC covered earlier consists of D1 and D2 receptors, respectively, the imbalance of which affects the brake that controls repetition. D1 receptor types (D1Rs) are excitatory and D2 receptor types (D2Rs) are inhibitory. [Costa et al, 2022]

Dopamine has a key role in stereotypic behaviour

• A decrease in striatal dopamine D2 receptors has been identified in patients with OCD.
• A hyperdopaminergic state is postulated to underpin OCD as evidenced by increased endogenous DA levels at baseline due to increased phasic firing at rest. (and Tourette Syndrome which is commonly comorbid with OCD). [Denys et al, 2013]
• Dopamine neurons are known to represent Reward Processing Error (RPE) signals that can facilitate learning of reward predictions by the basal ganglia (striatum). [Costa et al, 2022]
• The dopaminergic neurons encode differences between rewards and expectations in the goal-directed system and differences between the chosen and habitual actions in the habit system. [Bogacz, 2020]
• This RPE processing plays an important role in action planning and decision-making.

There are 3 systems involved in reward processing-based learning.

1. Valuation (Ventral striatum)– assigns a value to the expected reward.
2. Goal-directed (Dorsomedial striatum)– planning actions to obtain the reward (Stimulus-outcome learning)
3. Habit system (Dorsolateral striatum)– automatic behaviours that do not require planning or organisation (Stimulus-Response )

OCD can thus be conceptualised as a disorder with an imbalance between the goal-directed and habit systems. (See earlier – Early phase to Late phase transition)

The striatal neurons for valuation, goal-directed, and habit systems can be approximately mapped on the ventral, dorsomedial, and dorsolateral striatum. [Lipton et al, 2019]

• Patients with OCD show hyperactivity in the caudate, which has been linked to deficits in goal-directed behaviour in OCD. [Gillan et al, 2016].
• Patients with OCD show an increased RPE signal in the ACC as well as in putamen indicating a hyperresponsive learning and monitoring system which may explain the indecisiveness and intolerance of uncertainty. [Hauser et al, 2017]
• In OCD, a shift is proposed from goal-directed to more automatic habitual movements through a DMS-centric to DLS-centric shift. This can happen through DLS activation or through a reduced OFC-DMS activity which leads to the DLS pathway prevailing.
• OFC hypoactivity also leads to increased automatic habitual behaviour. Activating OFC projections can counteract this automaticity, rather than drive it. [Lipton et al, 2019]
• Habits are also known to form more rapidly during or after a state of stress, or in negative reinforcement conditions which is present in OCD. [Smith & Graybiel, 2022]

NEURAL CORRELATES OF SYMPTOMS AND OTHER BRAIN CHANGES IN OCD

Neural Correlates with symptoms:

OCD has both overlapping and distinct neural correlates across symptom dimensions. [van den Heuvel OA et al, 2008]

According to the OCD loop network:

Caudate and ACC are associated with checking rituals, and large cortical brain regions are related to washing rituals in OCD patients. [Nakao et al, 2014]

Some distinct correlates identified are as follows:[van den Heuvel OA et al, 2008], [Nakao et al, 2014]

Harm checking:

• Negative correlation with bilateral temporal lobes
• Hypoactivation in the left caudate and left ACC

Contamination/washing:

• Negative correlation with bilateral caudate and right parietal region
• Hyperactivation in several bilateral cortico-cerebellar regions (Washing rituals)
• Decreased right insula (Contamination)

Symmetry/ordering:

• Negatively correlated with regional GM volume in the right motor cortex, left insula and left parietal cortex
• Positively correlated with bilateral temporal GM and white matter (WM) volume

Aggression symptoms

• Symptoms were modulated by connectivity between the ventral striatum, amygdala, and ventromedial frontal cortex.
• Decreased right cerebellum activity.

Sexual/religious symptoms

• Ventral striatal-insular connectivity

Other general brain changes: [Stein et al, 2019]

• A decreased volume of the hippocampus and an increased volume of the bilateral putamen in adults with OCD are more pronounced in medicated patients.
• Reductions in hippocampus volume are more pronounced in those with comorbid depression.
• Increased volume of the pallidum was mainly present in the adults with OCD who had a child-onset disease.
• In children with OCD, a larger thalamus volume was found in unmedicated individuals.
• Medicated patients with OCD had thinner cortex in frontal, temporal, parietal, temporal and occipital regions (adult sample) and smaller surface areas in frontal regions (paediatric sample). In contrast, unmedicated patients with OCD did not differ from controls.
• Changes in brain white matter have also been reported in patients with OCD.

AUTOIMMUNE OCD

There is increasing evidence of the existence of a subset of OCD associated with infections and autoimmunity.

The following subsets have been described: [Endres et al, 2022]

• Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS): proposed to be caused by an infection with group A beta-hemolytic Streptococcus pyogenes.
• Pediatric acute neuropsychiatric syndrome (PANS): Other pathogens such as Mycoplasma pneumoniae, Borrelia burgdorferi, Borna disease virus, and Toxoplasmosis gondii as possible causes.
• Autoimmune encephalitis-related OCD
• Neuropsychiatric involvement in Systemic autoimmune diseases: e.g. Systemic lupus erythematosus, Dermatomyositis, and Sjögren’s syndrome

Diagnostic criteria for PANDAS:

PANDAS can be diagnosed with all of the following symptoms (1–5) present:

1. Presence of OCD or a tic disorder
2. Prepubertal symptom onset
3. Acute symptom onset and episodic (relapsing-remitting) course
4. Temporal association between Group A streptococcal infection and symptom onset/exacerbations
5. Association with neurological signs (motor hyperactivity or choreiform movements

Red flags for suspicion of Autoimmune OCD:

TREATMENT GUIDELINES

The following has been summarised from several recent papers. [Hirschtritt M et al, 2017], [Reddy et al, 2017], [Stein et al, 2019] , [Del Casale et al, 2019]. 

Treatment consists of psychological, pharmacological and neuromodulation techniques.

PSYCHOTHERAPY IN OCD

Although a systematic review and meta-analysis showed that cognitive behavioural therapy (CBT) has been shown to be more effective than selective serotonin reuptake inhibitors (SSRIs), in clinical practice both SSRIs and CBT are often used together. [Ost L et al, 2015

CBT comprises two components:

• Cognitive reappraisal
• Behavioural intervention: Exposure-Response Prevention (ERP) is the psychological treatment of choice for OCD.

Both individual and group CBT are as effective as each other.

Exposure-response prevention CBT (ERP-CBT): 

• The patient is exposed to situations that would provoke obsessions and associated anxiety and distress
• The patient is instructed to resist the associated compulsions or avoidance behaviours.
• Integration of ERP with cognitive components, e.g discussion of feared consequences and dysfunctional beliefs, can make ERP less aversive and enhance its effectiveness particularly for patients with poor insight and for those who are less tolerant to exposure.
• ERPs postulated mechanism of action is the systematic breaking down of S-R associative links through repeated response prevention exercises. Hyperactivity in the caudate, which has been linked to deficits in goal-directed behaviour in OCD  is remediated when patients respond to ERP. [Gillan et al, 2016]
• Recommended 13 to 20 weekly sessions or 3 weeks of daily sessions. If necessary, additional sessions can then be offered to the patient 3 to 6 months after the first session.
• Patient adherence to between-session homework, e.g doing ERP exercises in the home environment is the most robust predictor of good short and long-term response.

The psychological mechanisms underpinning this technique are habituation and extinction.

• Habituation is the decline in response after repeated exposure to a stimulus.
• Extinction refers to the cessation or reduction of behaviour when a reinforcer is taken away or ceases.

PHARMACOTHERAPY IN OCD

SSRIs are considered the first line in the treatment of OCD. Approximately 50 % of patients respond to first-line treatments.

Mechanism of SSRIs in OCD: [Fineberg et al, 2018]

• Reduction of rumination and/or anxiety symptoms, positive shift in the appraisal of emotions and improved fear extinction through action on the amygdala indirectly improving OCD symptoms and increasing the possibility of response to exposure treatment aimed at extinguishing maladaptive compulsive habits and irrational fears. This however only partially explains efficacy as benzodiazepines which also reduce anxiety do not show significant efficacy in OCD.
• Remediation of goal-directed deficits by acting on OFC- striatal pathways reducing hyperactivation and facilitating a shift from habitual to goal-directed behaviours.

High-dose SSRIs have been shown to be more effective than lower doses. SSRIs should be prescribed for at least 12 weeks to determine responsiveness.

A recent meta-analysis showed that a significant benefit from SSRI treatment compared to placebo occurred already after 2 weeks after the start of treatment suggesting that the greatest incremental treatment gains in OCD are seen early on in SSRI treatment. [Issari et al, 2016]

Medication and target doses are: [Pittenger & Bloch 2014], [Del Casale et al, 2019], [Xu et al, 2021]

• Fluoxetine: 20-80 mg/day (most optimum 40-60 mg/day)
• Fluvoxamine: 100-300 mg/day
• Sertraline: 50-200 mg/day
• Paroxetine: 20-60 mg/day
• Citalopram: 20-60 mg with best results at doses of 60 mg/day
• Escitalopram: 10-40 mg/day

Maximum doses: 

• Used in patients who are rapid metabolisers
• No or mild side effects
• Inadequate response after 8 weeks or more with usual maximum dose
• Fluoxetine: 120mg/day
• Fluvoxamine: 400 mg/day
• Sertraline: 400 mg/day
• Paroxetine: 100mg
• Citalopram: 120mg
• Escitalopram: 60mg/day

The effectiveness of SSRIs was optimal at the fluoxetine equivalent dose of about 40 mg, and the efficacy decreased as the dose increased higher than 40 mg. [Xu et al, 2021]

Equivalent doses of other SSRIs and clomipramine at Fluoxetine dose of 20 mg :

• Fluvoxamine: 100 mg
• Sertraline: 50 mg
• Paroxetine: 20 mg
• Citalopram: 20mg
• Escitalopram:10 mg
• Clomipramine: 100mg

Key points in treatment: 

Sertraline:

• A rapid sertraline titration of up to 200 mg/day correlated with fast response rates.
• Higher doses of 250mg -400 mg have shown efficacy in refractory OCD.

Escitalopram:

• The most 5-HT-selective among SSRIs with little or no affinity for other neurotransmitter transporters or receptors.
• 20 mg/day escitalopram has also been associated with better OCD symptom remission compared to 40 mg/day paroxetine or placebo at week 12
• Higher doses of > 20 mg may be associated with QTc prolongation.
• Weak or minimal interactions with the cytochrome P450 system

Citalopram: 

• Risk of QTc interval prolongation with doses above 40 mg /day

Fluvoxamine:

• CYP1A2 inhibitor which may interact with other medications.
• Long-term treatment (40 weeks with a dose of 100-300 mg/day) was associated with improvements in psychosocial skills and obsessive symptoms. [Del Casale et al, 2019]

Predictors of response to SSRIs: [Del Casale et al, 2019]

• OCD family history
• Aggressive, sexual, and religious obsessions
• Orbitofrontal cortex hypometabolism
• Right caudate nucleus hypermetabolism
• Early reduction (by 4 weeks) of OCD severity was the best predictor of treatment response at 12 weeks

Predictors of non-response to SSRIs: [Del Casale et al, 2019]

• Hoarding behaviour
• Poor insight
• Severe concomitant depressive episode
• Higher levels of disability

Long-term treatment (24-52 weeks) with an SSRI was associated with a significantly lower probability of relapse. [Del Casale et al, 2019]

SSRIs should be maintained at the maximum effective dose for at least 12 months. [Del Casale et al, 2019]

Clomipramine

• Clomipramine is used as a second or third-line agent in OCD treatment.
• Some evidence supports the add-on of clomipramine to an SSRI before trying an antipsychotic add-on treatment.
• Clomipramine is a tricyclic antidepressant, which acts as a serotonin and noradrenaline reuptake inhibitor with a stronger affinity for the serotonin transporter (SERT) than other TCAs and SSRIs.
• The resulting action increases serotonergic and noradrenergic transmission. Clomipramine has larger effect sizes for a response than SSRIs. [Del Casale et al, 2019]
• Clomipramine is metabolised to its active metabolite desmethylclomipramine by CYP450 1A2. Desmethylclomipramine has more noradrenergic activity than serotonergic.
• Treatment response is significantly correlated with higher plasma clomipramine and a trend toward lower desmethylclomipramine. [Del Casale et al, 2019]
• Clomipramine is started at 25 mg/day and increased to a target dose of 250 mg/day.
• Clomipramine tolerability is affected by its significant anticholinergic side effects (dry mouth, blurred vision, fatigue, tremor and hyperhidrosis).
• Amongst severe side effects, arrhythmogenic potential and risk of seizures increase at doses at or above the upper limit of the recommended dosing range (250 mg). ECG monitoring is recommended.
• Combined levels of clomipramine and desmethylclomipramine should be kept below 500 ng/ml to minimise the risk of seizures and arrhythmias. [Del Casale et al, 2019]
• Clomipramine (≤75 mg/day) addition to fluoxetine ( ≤40 mg/day) was a safe and effective treatment for fluoxetine nonresponders and for those who could not tolerate a high dose of fluoxetine. This combination was also superior to augmenting fluoxetine with quetiapine. [Diniz et al, 2011].
• Citalopram (maximum dose of 60 mg/day) augmentation of Clomipramine in treatment-refractory OCD (patients who had failed 2 SSRI treatments and were on clomipramine) showed that approximately 50% of the patients improved significantly after 1 month of this regimen and after 1 year of treatment. [Marazziti et al, 2008]

Other antidepressants:

Agomelatine:

• Agomelatine 5-HT2C antagonism mediates anxiolytic effects which indirectly improves OCD symptoms
• Melatonin (MT1 and MT2 receptors agonist activity) could contribute to circadian rhythm restoration in OCD patients.
• Read about a clinical case study of treating comorbid Depression and OCD with agomelatine. 
• A Focus on Agomelatine – Mechanism of Action and Efficacy

SNRIs: 

• Venlafaxine (225 to 350 mg/day) has shown similar efficacy to clomipramine in the short-term treatment of OCD with better tolerability. [Albert et al, 2002]
• Most studies have shown efficacy in both naïve and treatment-resistant OCD patients at dosages between 150 mg/day and 375 mg/day with 30-60%  response rates. [Del Casale et al, 2019]
• Venlafaxine 300 mg/day showed similar response rates to Paroxetine (60 mg/day) in non-refractory OCD although paroxetine may be more effective than venlafaxine in refractory patients. [Del Casale et al, 2019]
• Duloxetine and milnacipran have shown some evidence.

TREATMENT REFRACTORY OCD

Approximately 25% of all OCD patients will be classified as treatment-resistant: this is defined as failing two different SSRI courses.

Furthermore, 40-60% of all patients may be considered as responding positively to treatment but will have ongoing residual symptoms.

Factors associated with poor treatment response: [Stein et al, 2019]

Clinical characteristics

• Greater severity
• Sexual, religious and hoarding symptoms
• Poor insight
• Higher number of comorbidities
• Comorbid major depression, agoraphobia or social anxiety disorder
• Lower willingness to fully experience unpleasant thoughts
• Greater resistance to change
• Lower adherence to treatment

Sociodemographic characteristics

• Male sex
• Single relationship status
• Lower socioeconomic status
• Lower educational level

Other characteristics

• Family history of OCD
• Poor therapeutic alliance
• Absence of early response to selective serotonin reuptake inhibitor treatment

Strategies in Treatment Refractory OCD: 

• High-dose treatment with serotonergic drugs
• Greater improvement with higher vs lower doses of SSRI e.g  250 to 400 mg/day vs 200 mg/day of sertraline and with escitalopram after an increase of dose from 20 up to 50 mg/d. [Del Casale et al, 2019]
• Approximately 25% of patients with refractory OCD to SSRIs may benefit from up to 28 weeks treatment after initiation. [Del Casale et al, 2019]

Antipsychotics

• Augmentation with antipsychotics is effective in 30% of treatment-resistant patients.
• Haloperidol, risperidone and aripiprazole are effective augmentation agents to SSRIs / CBT in refractory OCD.
• Haloperidol is also an effective augmentation agent in OCD with comorbid tics.

The World Federation of Societies of Biological Psychiatry (WFSBP) recommended a co-administration of SSRI with haloperidol, quetiapine, olanzapine or risperidone for treatment-resistant OCD. [Bandelow et al, 2022]

• Aripiprazole 5-10 mg/day
• Risperidone 1-3 mg/day
• Haloperidol 2.5-10 mg/day
• Olanzapine 5-10 mg/day 

NOVEL AGENTS

Glutamatergic agents [Del Casale et al, 2019]

• Memantine 10-20 mg/day as add on. [Kishi et al, 2018]
• Lamotrigine 100 mg/day
• Topiramate 100-200 mg/day- Add-on topiramate at daily dose ranges up to 400 mg improved refractory OCD
• N-Acetylcysteine (2000-3000 mg/day) (mixed results) [Sarris et al, 2022]
• D-cycloserine
• Ketamine
• Riluzole
• Glycine
• D-cycloserine: Partial agonism at the site of glycine recognition of the NMDA receptor, which is linked in the amygdala to learning and memory, could be the basis of the mechanism of action of D-cycloserine.

5 HT-3 Antagonists:

5-HT3 blockade produces a weak inhibitory effect on dopaminergic neurotransmission

• Ondansetron (1-8 mg/day) is a potential augmenting agent in patients for whom SGAs are problematic
• Granisetron (1 mg BD) also shows some evidence.

Opioids: 

• Add-on buprenorphine (400-600 μg/day sublingual) to SSRIs; 200 mg/day fluvoxamine or 200 mg/day sertraline or 150 mg/day clomipramine resulted in a significant improvement in the proportion of refractory patients, particularly in people who partially responded to SSRIs. [Liddell et al, 2013]
• 200-400 μg/day sublingual add-on buprenorphine to SSRIs or clomipramine showed symptom reduction in as early as 3 weeks suggesting the addition of buprenorphine may accelerate treatment response. [Ahmadpanah et al, 2017]

Dopaminergic agonists: [Kellner, 2010]

• Acute significant antiobsessional effects for a single dose of dextroamphetamine were reported in patients with severe OCD.
• Augmentation of serotonergic antidepressants in refractory OCD showed improvement of OCD.

Nutraceuticals

• Myo-inositol
• 5-HT
• Milk thistle

NEUROMODULATION THERAPIES

Neurosurgery

Ablative neurosurgery involves producing lesions in specific regions of the CSTC circuit. Neurosurgery is indicated in only severe cases of OCD. Approximately 60 per cent of patients improve 6-24 months post-surgery. [Stein et al, 2019]

Key techniques for surgery are:

• anterior cingulotomy
• capsulotomy
• subcaudate tractotomy
• limbic leucotomy (combination of anterior cingulotomy & capsulotomy)

Deep Brain Stimulation (DBS): [Acevedo et al, 2021].

• DBS is a neurosurgical procedure in which electrodes are implanted into specific regions of the brain to provide targeted stimulation of neurons and their connections in order to alleviate the symptoms of the disorder being treated.
• DBS is reversible and can be adjusted postoperatively in the outpatient clinic.
• In DBS, once the electrodes have been implanted, they generate continuous electrical stimulation through a pulse generator
• The impulse generator is also referred to as a ‘brain pacemaker’ and has a battery life of up to 15 years for those with externally rechargeable batteries.
• Most studies of DBS in OCD target striatal areas, including the anterior limb of the internal capsule, the ventral capsule and ventral striatum, the nucleus accumbens or the ventral caudate nucleus, the subthalamic nucleus, and the inferior thalamic peduncle. Approximately 30–60% of patients with severe refractory OCD respond to these different treatments. [Alonso et al, 2015]
• Proposed mechanisms may include normalisation of excessive baseline frontostriatal activity and normalisation of low baseline NAc activity after DBS. [Karas et al, 2019]
• Modulation of the dorsolateral prefrontal cortex correlated with excellent clinical outcomes. [Karas et al, 2019]
• High activation in the lateral OFC was associated with non-clinical responders. [Karas et al, 2019]
• The optimal target for DBS in OCD is unclear.

Repetitive Transcranial Magnetic Stimulation (rTMS):

• The regions associated with OCD are not usually accessible by rTMS. However, there is some evidence of efficacy.
• rTMS targets include the supplementary motor cortex and the DLPFC.
• The quality of evidence is currently low [Liang et al, 2021]

Transcranial Direct Current Stimulation (tDCS): [Stein et al, 2019]

• Targets are the supplementary motor cortex and the dorsolateral prefrontal cortex.
• Some promises but no RCTs.

Treatment for PANDAS / PANS: [Endres et al, 2022]

• Psychotherapy and psychopharmacological treatments are first line
• For treatment-resistant patients anti-microbial agents (antibiotics, anti-virals and anti-parasitic agents)
• For moderate to severe symptoms: steroids or intravenous immunoglobulins (IVIGs).
• For severe or chronic presentations: prolonged steroid trials or repeated high-dose steroids may be indicated.
• For patients with extreme impairment: Therapeutic plasma exchange is the first-line therapy alone or in combination with IVIGs, high-dose intravenous steroids, and/or rituximab.
• Children with PANDAS who have a severe form and/or recurrent courses of streptococcus-associated exacerbations or an initial manifestation: Antibiotic prophylaxis.

COMORBIDITIES IN OCD

OCD is associated with significant comorbidity. [Stein et al, 2019]

The most common comorbidities are anxiety disorders, mood disorders, impulse-control disorders and substance use disorders.

Other disorders that co-occur are ADHD, Tourette’s, and tic disorders.

Depression [Nestadt et al., 2001]:

• Depression is the most common comorbidity in OCD. We covered a case report on OCD and depression and how augmentation strategies can treat both OCD and depression.
• Depressive cognitions are ruminative and have an ego-syntonic quality with thought content revolving around guilt, self-criticality, self-doubt, nihilism, worthlessness and hopelessness.
• Both anxious and depressive cognitions are related to OCD, but only depressive cognitions are related to depression. [Moore & Howell, 2017]
• Both disorders can coexist and treatment strategies overlap. However, it has been proposed that depression is part of OCD but that OCD is not necessarily implicated in depression and is, in fact, a separate disorder. [Moore & Howell, 2017]
• First-line treatments are as in OCD. Second-line treatments include augmentation with AP, using ADs from two different classes with exception of SSRI and clomipramine combination. Melancholic and Psychotic Depression – Review of Diagnosis and Management

Anxiety Disorders [Nestadt et al., 2001]:

• Comorbid anxiety is associated with a poorer treatment outcome.
• Anxious thoughts are related to real-life concerns and are not associated with compulsions.
• SSRIs are effective in the treatment of anxiety and OCD.

Bipolar Disorder (BD): [Kazhungil & Mohandas, 2016]

• Lifetime prevalence rates of 11- 21%
• In comorbid bipolar disorder, OCD can manifest with increases in severity in depressive episodes but improvement during manic/hypomanic episodes.
• Mood stabilisers or atypical antipsychotics are considered the first choice of treatment.
• If OCD persists despite treatment with a mood stabiliser/atypical antipsychotic, then SSRIs can be used as an augmentation strategy.
• Adjuvant topiramate or olanzapine-selective serotonin reuptake inhibitor/clomipramine combination along with mood stabiliser is found to be effective for treating OCD in BD.
• SSRIs on their own may be associated with a worsening of underlying bipolarity.

Schizophrenia/Psychosis: 

Individuals with schizophrenia have a significant incidence of OCD symptoms (25%). This association may be related to

• The prodromal phase of psychosis
• Neuroleptic-induced OC symptoms (atypical antipsychotic medications, e.g. clozapine, risperidone and olanzapine can increase OC symptoms
• OCD occurring concurrently in psychosis
• Schizo-obsessive presentation [Bottas et al., 2005]

Read more about the management of OC symptoms in schizophrenia.

Personality Disorder:

• Obsessive-compulsive personality disorder / Anankastic personality disorder is the most commonly associated personality disorder.
• Excessive preoccupation with perfectionism, orderliness, and rigid control. Stubbornness, scrupulosity and over-conscientiousness are key traits.

ADHD: 

• There is increasing recognition of common pathophysiological and symptom overlap between ADHD and OCD.
• Both conditions involve the frontostriatal circuits with hyperactivation shown in OCD and hypoactivity in ADHD. [Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) – A Primer
• Treatment of ADHD improves treatment response
• Stimulants can worsen OC symptoms in some cases.
• Tic disorders, ADHD and OCD can coexist due to all 3 disorders involving the frontostriatal circuits.
• Symptoms of ADHD and tics, including impulsivity, improve when stimulant and non-stimulant medications are used, including methylphenidate, guanfacine, clonidine, and a combination of methylphenidate and clonidine.
• Methylphenidate and clonidine combination may be superior to either treatment alone in ADHD in children with comorbid tic disorders. [Osland et al, 2018]
• High-dose dexamphetamine (22.5 mg – 30 mg/day) in children was found to worsen tics with lower doses of 15mg/day showing no worsening. [Osland et al, 2018]

Read more detail – ADHD and Comorbidities – Management Principles

Tic Disorders and Tourette Syndrome: 

• There is increasing evidence of overlapping neurobiological correlates (CSTC circuit abnormalities) in tic disorders and OCD leading to the existence of an intermediate phenotype, known as Tourettic OCD (TOCD), in which symptoms are influenced by features of both OCD and TS and differ from either disorder alone. [Katz et al, 2022]
• TOCD lies in the middle of a spectrum from Tourette syndrome – TS with mild OCD – TOCD – OCD with mild tics – OCD.
• The presence of comorbid tics may predict a poor response to SSRIs in OCD; hence clinicians should consider the condition as a case of comorbid OCD and tic disorder rather than a tic-related subtype of OCD. [Katz et al, 2022]
• Tic disorders show the best response to antipsychotics (haloperidol, pimozide, risperidone and aripiprazole).
• Adrenergic α₂ agonists (clonidine and guanfacine) are also evidence-based.
• Habit-reversal therapy (HRT) is a potential first-line treatment option instead of or in combination with pharmacotherapy.
• TOCD: First-line treatment can be  CBT or ERP or Comprehensive Behavioral Intervention for Tics (CBIT).
• If psychological treatment does not lead to a response, consider combination medication treatment (augmentation of SSRI with α2 agonists (clonidine, guanfacine)) plus behavioural treatment.
• Third line: If OCD is prominent – consider the OCD algorithm
• Third line: If Tics are prominent – SSRI plus AP combined treatment
• Pharmacologic treatment of comorbid ADHD with α2 agonists, atomoxetine or stimulants can help control the disinhibition and impulsivity that is common in TOCD patients.

SUMMARY ALGORITHM

SUMMARY

OCD is a highly disabling psychiatric condition characterised by obsessions and compulsions.

OCD is often missed in routine clinical practice or misdiagnosed and mistreated. [Stein et al, 2019]

The condition has a high degree of comorbidity with mood and anxiety disorders and other neurodevelopmental disorders.

The neurobiology of OCD is complex and focuses on the imbalance between the goal-directed and habit areas of the brain mediated by the CSTC circuit.

While the condition is treatable in many patients, approx 25% of patients are classified as treatment refractory.

Recent advances in the use of pharmacological agents targeting non-serotonergic pathways, neurostimulation and neurosurgery for severe cases show promise.

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