01. Clozapine and OCD-Like Symptoms: What’s the Connection?

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Clozapine and Obsessive-Compulsive Disorder: A Puzzling Link

We’re going to look together at the link between obsessive-compulsive disorder, OCD, and clozapine.

I found an observational study by colleagues from Cambridge in the United Kingdom published in the British Journal of Psychiatry that shed some light on this link.

Clinical Dilemma: Clozapine-Induced OCD-Like Symptoms

Let me first give you some clinical context for this study and why I think it’s interesting.

If you use clozapine, you may be familiar with this clinical dilemma.

You start somebody on clozapine, and the psychosis gets better, but at some point, even many, many months later, the patient or a family member starts complaining about obsessive thinking and increased checking behaviors.

This has definitely happened to me in a significant minority of patients who I started on clozapine, and I always wondered if I caused this with my treatment and also what to do.

Confusing Literature on Clozapine and OCD Comorbidity

Unfortunately, the literature about this connection between clozapine and OCD, and we should really say OCD-like symptoms, is confusing and essentially based on case reports and cross-sectional symptom assessments.

Depending on the exact cohort, you will find high rates of comorbidity in the literature between schizophrenia and these OCD-like symptoms, with the highest rate of up to 50% reported in samples treated with clozapine.

This comorbidity is so common that people have suggested a subtype of schizophrenia called schizo-obsessive disorder.

The problem with interpreting this comorbidity and the clozapine connection is a bias called confounding by indication.

We know that the more severe the psychotic illness, the more you will find OCD-like symptoms, and it is exactly this group of patients that will then be treated with clozapine, creating this seeming link between clozapine and OCD-like symptoms.

On the other hand, it is not absurd to postulate that our medication could cause OCD given that we use pharmacological interventions to treat OCD, particularly as you know, SSRIs, which in a simplistic model increase serotonergic function.

Anti-serotonergic agents like clozapine that block 5HT1A receptors may then conceivably modulate brain circuits in such a way as to bring about obsessive-compulsive symptoms.

Longitudinal Study Sheds Light on Clozapine-OCD Link

Let’s look at the naturalistic observational study that adds to the literature using a longitudinal design and not just a one-time cross-sectional symptom assessment.

The authors had access to a clinical and research database of routinely collected clinical data from a clozapine clinic of 254 patients, including clozapine blood levels and rating scales for psychosis severity and OCD severity that were completed every two years or every year, respectively. Their final sample included 196 clozapine patients because not all patients had completed data for OCD and psychosis severity in particular, so about 200 people.

A decent sample size. Each participant was on average followed for almost three years. And for about half their sample, they also had genetic data that allowed them to look at genetic variants in the serotonergic pathway.

Four Key Findings from the Longitudinal Study

There were four main findings.

1. OCD-like symptoms, particularly checking, were common at the baseline assessment in 38% of patients, which is very consistent with the literature.
2. Psychosis severity correlated with OCD-like symptoms severity, which is also consistent with the literature.
3. The effect of psychosis on checking behaviors was indirect and mediated via obsessive thinking. That suggests that psychosis per se does not lead to compulsive checking. You do need these obsessions.
4. Looking at the role of clozapine, they found a correlation between clozapine dose and plasma levels and checking compulsions but not with obsessive thinking.

Unfortunately, the genetic analysis did not really go anywhere because of sample size issues, I think.

Limitations and Considerations of the Longitudinal Study

Initially, I was excited because I had assumed that this cohort study had data before and after clozapine initiation. That is actually not the case.

All patients were on clozapine at baseline if I interpreted the methodology correctly. So I think we’re still unsure if clozapine can induce OCD de novo and, if it does, how common it is.

Honestly, I also think the clinical evaluation and distinction between psychosis and obsessive thinking can be quite difficult and that is a factor when we study symptoms in a cohort of fairly ill psychiatric patients longitudinally. Let me suggest two considerations here.

• Phenomenologically obsessive thoughts and thought insertion are about intrusive thoughts from the patient’s perspective, experiences that are perceived as unwanted thoughts by the patient, only the interpretation of the origin and the cause will be different.
• In obsessions, the intrusive thoughts are experienced as dysphoric and being a product of their own mind. In psychosis, the intrusive thoughts are experienced as coming from the outside and may be even caused by an entity like the government.

This distinction, which is critical because you either end up with psychosis or with anxiety, obsessions, and OCD, may not always be clear-cut, and people with severe OCD and no insight, for example, can look rather psychotic. It is an important diagnostic consideration in fact.

To make it more complicated, I think some amount of checking is also very common in people with schizophrenia due to cognitive inflexibility which then gets called obsessive.

Sometimes, these personality traits are longstanding and not new at all but they are overshadowed by psychosis and then they get uncovered, if you will, as the patients get better and then people are able to pay attention to other things and not just the psychosis.

Two Phases of OCD-Like Symptoms in Psychosis

I still like the study as it suggests the following.

There are actually two phases for OCD-like symptoms in psychosis.

The first phase is an understandable goal-directed checking for safety that is part of the florid paranoia that you and I would do.

“Is the door locked given possible intruders?” is a sensible concern if you are paranoid. It’s not a habit. This first phase of paranoid concern and related checking is unrelated to clozapine.

As people become less psychotic, the psychosis-related safety behaviors disappear in many patients but not in all patients who continue to check in response to what now are more obsessions and compulsions since the paranoia is gone and the safety checks are no longer necessary.

You could say that the checking that was understandable and made sense during a time of florid psychosis can become habitual and is no longer sensible.

And it seems to be based on the study that in the second phase clozapine may contribute pharmacologically by facilitating the formation of this habit of compulsive checking.

Clinical Implications and Recommendations

This is my clinical bottom line.

If that two-phase model is correct, a clozapine dose reduction, if clinically feasible, may be helpful so that you interfere as little as possible with habit reversal training to undo this checking behavior that was initially triggered by paranoia.

The model would also suggest that just being off clozapine would not simply make the checking behavior go away, as it really represents a learned habit that has to be unlearned. You would still need to treat it separately with habit reversal training.

I usually clinically reduce the dose of clozapine to the extent possible and then treat it to make it maybe a little bit easier.

Abstract

The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study

Emilio Fernandez-Egea, M.D., Shanquan Chen, M.D., Estela Sangüesa, M.D., Patricia Gassó, M.D., Marjan Biria, M.D., James Plaistow, M.D., Isaac Jarratt-Barnham, M.D., Nuria Segarra, M.D., Sergi Mas, M.D., Maria-Pilar Ribate, M.D., Cristina B García, M.D., Naomi A Fineberg, M.D., Yulia Worbe, M.D., Rudolf N Cardinal, M.D., & Trevor W Robbins, M.D.

Background: A significant proportion of people with clozapine-treated schizophrenia develop ‘checking’ compulsions, a phenomenon yet to be understood.

Aims: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS).

Method: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.

Results: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction.

Conclusions: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians’ therapeutic decisions.

Keywords: Habit formation; clozapine; compulsion; serotonin; treatment-resistant schizophrenia.

Reference

Fernandez-Egea, E. M.D., Chen, S. M.D., Sangüesa, E. M.D., Gassó, P. M.D., Biria, M. M.D., Plaistow, J. M.D., Jarratt-Barnham, I. M.D., Segarra, N. M.D., Mas, S. M.D., Ribate, M. M.D., García, C. M.D., Fineberg, N. M.D., Worbe, Y. M.D., Cardinal, R. M.D., & Robbins, T. M.D. (2024). The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study. The British Journal of Psychiatry, 224(5):164-169. Epub 2024 Apr 23.