Clozapine and Obsessive-Compulsive Symptoms Across Major Psycho=c Disorders - a Review of Three Cases. P.1.g.069 Salta M.1, Mendes S.1, Gamito A.1 1Setúbal Hospital Centre, Setúbal, Portugal Background Clozapine is the single most effecCve drug to treat refractory schizophrenia and other resistant psychiatric disorders presenCng with psychoCc symptoms. In schizophrenia it also demonstrates anC-suicidal effects. Its main acCons are strong serotoninergic antagonism on 5-HT2A, 5-HT1C and 5-HT2C receptors, and less powerful dopaminergic antagonism on D2 and D4 receptors. It also acts on adrenergic, muscarinic and histaminic receptors. These acCons account for its clinical indicaCons but also for its adverse effects. One of these is the emergence of de novo obsessive and compulsive symptoms (OCS), with a prevalence of 20-70% reported in the literature. These are related to the duraCon of treatment and dose prescribed. The cases are mainly reported in schizophrenic but also in schizoaffecCve and bipolar paCents. The mechanism for the OCS is not fully known, but neuroimaging and geneCc studies are being developed to unravel this. Methods and Results The following are the descripCons of the cases of three paCents, the first ones diagnosed with schizophrenia and the other diagnosed with schizoaffecCve disorder, with a long-term follow up in a private pracCce – 15 to 19 years, to whom clozapine was prescribed at a certain point during their treatment, and that developed de novo obsessive thoughts and compulsive behaviours..

SR, male, 38 years old, born in Mozambique, worked in PT, male, 36 years old, born in Lisbon, 8th grade ES, female, 40 years old, born in Lisbon, 9th grade trading, single, no offspring. Daily cannabis and sporadic complete, single, no offspring. No toxic habits or medical complete, in a relaConship, no offspring. Daily cannabis alcohol consumpCon. Asthma. No known mental illness condiCons. No known mental illness in the family. consumpCon. No medical condiCons. Sister diagnosed in the family. with bipolar disorder type IV. September 2001 June 1997 February 1997 First appointment at age 20. Three months earlier: anxiety, First appointment at age 18. Since age 15: school and social First appointment at age 26. Diagnosed with schizophrenia, takes adenCon and concentraCon deficits, anhedonia, thought funcConing deterioraCon. Two months before appointment: risperidone 6mg + lorazepam 3 mg. Has persecutory delusions broadcasCng with insight, feelings of self-reference iniCally with overvalued ideas of persecutory type, delusional ideas of self- and delusional percepCons. Akathisic. Starts clozapine =tra=on insight, then in a delusional form, 3rd person commenCng verbal reference, delusion of control and thought broadcasCng, un=l 300mg/day. Stops risperidone. Gets beder. CogniCve hallucinaCons, thought echo and insomnia. Was euthymic. R/ delusional mood. R/ risperidone 2mg + lorazepam 2,5mg. deficits. Wants to stop medicaCon because of hypersalivaCon. pimozide 2mg, lorazepam 2,5mg, cyamemazine 40-60mg and 2002-2003 biperiden retard 4 mg. PosiCve symptoms beder, then stable, negaCve symptoms Stable, beder self-care. No insight, stops medicaCon - > psychoCc slightly beder – tried to return to work. Akathisia and acute outbreak. Restarts clozapine with progressive stability. Compliant to treatment. Remission of psychoCc symptoms. Was dystonic reacCons with a small dose of risperidone. Starts 2004-2005 on haloperidol then risperidone prescribed by another doctor. thioridazine 25mg 3/day. Episode of acute oculomotor dystonia, Rumina=ons in the form of contamina=on fear: afraid of geSng Started studying at the University. Reports “feeling lazy”. Blunted managed with biperiden. AIDS s=nging herself with needles that can be everywhere like affect and apathy. 1998-1999 the street floor. Starts verifica=on and washing rituals. R/ 1998 Stable. AffecCvity slightly beder. Didn’t manage to get back to Sertraline 100mg – non-compliance. Later, depressive mood and Stopped going to University. Neglect of self-care. Oro-buco-facial previous work, starts playing in a music band. Switch to OCS. R/ lorazepam 2,5mg 2/day. dystonic movements. Poor thought content and abstracCon olanzapine -> negaCve symptom improvement. 2006 deficits. Loosening of associaCons. Was feeling bad on 2000 Agoraphobia with panic adacks, depressed. R/ paroxeCne 20mg, risperidone. Blood count ok. Starts clozapine =tra=on un=l Worsening of negaCve symptoms. Starts clozapine, =trated un=l took only 10mg. Reports listening to an “inner voice” saying her 300mg/day. Then, voliCon slightly beder, more acCve and with 300mg. AvoliCon beder. to “kill your father”. ↑ Clozapine to 400mg, ↑paroxeCne to 2001 beder performance at everyday tasks. Taking Clozapine 300mg/ 20mg. Then slightly beder. Takes clozapine 400mg, and day. Stops pimozide. CogniCve training of everyday acCviCes. Feels beder, more lorazepam 2,5mg 2/day, only 10mg of paroxeCne. Later, reports 1999 acCve, plans of recording a CD. overvalued paranoid ideas. Stops paroxeCne. Later, is afraid of DayCme spleepiness, some anxiety, incipient negaCve symptoms. 2002 being poisoned with milk. 2007 Clozapine dose adjustments. Feelings of “having two persons inside”, thoughts about his 2000 mother and brothers’ death. ↑ Clozapine to 400mg/daily. Starts Doesn’t leave the house nor drinks milk or juices. R/ lamotrigine Kept complaints of dayCme sleepiness. Switch to olanzapine 10 to have obsessive rumina=ons and intrusive thoughts of sexual 100mg, non-compliance. Reduced clozapine to 300mg. mg then 20mg was tried – stopped clozapine for 2 months. contents. R/ fluvoxamine 100mg/daily. Then obsessive thoughts Overvalued ideas of poisoning, phobic symptoms and cleaning Worsening of the clinical picture with posiCve symptoms slightly beder. Secondary effects: tremor, blurred vision, urinary rituals. Hypersomnia, hyperphagia. resurgence. Restarts clozapine Ctrated to 300mg. urgency -> dose adjustments. Later, new agudizaCon of obsessive 2008-2010 2001 thoughts. Fluvoxamine -> sertraline 100mg. ↓ clozapine to Persecutory delusions: wants to change the door lock of her PsychoCc symptoms stable. Had one panic adack and complains 300mg/day. By the end of the year has control over obsessive house, atypical depressive and phobic symptoms. Refuses to run of globus histericus. Starts lorazepam 2,5mg. thoughts, less intrusive ideas. Keeps clozapine 300mg + sertraline blood tests being afraid of having HIV. VerificaCon rituals. Only 2002 100mg. taking clozapine 300mg/day, always refused lamotrigine. By the 2003-2007 PsychoCc symptoms stable. Agoraphobia. Starts fluvoxamine end of 2010 has again anxiety and new panic adacks. R/ 100mg and cetazolam 30mg. Stops lorazepam. Reports Stable. Starts a computer course. citalopram 10mg + clonazepam 2mg. worsening of anxiety and mood lability. Fluvoxamine is stopped. 2008 2011 2003 Took by mistake 100mg of his mothers’ fluoxeCne at bed Cme -> No panic adacks. Non-compliance to citalopram. Taking clozapine SCll has anxiety symptoms of changing intensity. Benzodiazepine worsening of psychoCc symptoms, then was back to baseline. + clonazepam. Winter: again delusional convicCon that “they dose adjusted. Clozapine at 300mg. Stops sertraline, starts lamotrigine 100mg/day. ↓ clozapine to have her house-door keys”. Suicidal ideaCon but no intenCon. 2004 200mg. 2012-2013 2009 Develops obsessive symptoms: verifica=on rituals of the car and FluctuaCon of psychoCc symptoms. Takes lamotrigine 50mg/day. house doors -> symptoms didn’t interfere with funcConality, is Stable, more acCve, no obsessive symptoms. + clozapine 300mg + clonazepam 2mg. Then stops lamotrigine. working with his father at a store. 2010-2016 2014 2005- 2016 Except for some periods of self-reference ideas, kept clinically New depressive episode, now with hapCc hallucinaCons, and PsychoCc symptoms stable. SCll some obsessive symptoms with stable. again delusional percepCons. Worsening of the clinical picture modest impact on everyday life. Remission of anxiety symptoms. with citalopram. R/ amisulpride 200mg, with efficacy. Later again Stable with clozapine 300mg only. more depressed with worsening of persecutory ideas and obsessive rituals. Keeps taking amisulpride 200mg + clozapine 300mg. 2015-2016 Beder. Reduced clozapine to 200mg/day. Sazonality, with remission of depressive symptoms and less intensity of the obsessive symptoms in the Spring. No insight for persecutory ideas. Regular medicaCon: clozapine 200mg + amisulpride 200mg + clonazepam 2mg.

Conclusions It is worth noCcing that the paCents had no OCS at presentaCon nor in their premorbid history nor traits or full blown obsessive personality disorder. All developed OCS aWer the introducCon of clozapine to their treatment, seven and two years for the 2 paCents with schizophrenia, and three years for the paCent with schizoaffecCve disorder. The strategies used for each case are according to the ones used in several studies and case reports. Pharmacological therapeuCc opCons include clozapine dose reducCon and/or adding another drug to the treatment, namely, specific serotonin receptor antagonists like sertraline, fluvoxamine or fluoxeCne; a tricyclic anCdepressant like clomipramine; a dopamine and serotonin receptor parCal agonist like aripiprazole – proven to have anC-obsessive potency; a dopamine D2 and D3 receptor antagonist (like amisulpride) or a voltage-gated sodium channel blocker like lamotrigine. The fact that these drugs reduce secondary OCS support the theories about the mechanisms involved in their origin. Also suscepCbility genes have been implied, like the SLC1A1 encoding the neuronal glutamate transporter. Careful exploraCon of symptoms and close monitoring are criCcal in managing serious psychiatric illnesses requiring treatment with clozapine, and importance must be given to the appearance of adverse effects. PaCents with OCS have proven to have pronounced deficits regarding cogniCve flexibility, visuo-spacial percepCon and visual memory correlated with OCS severity. Also, comorbid OCS in schizophrenia are associated with pronounced posiCve and negaCve symptoms, lower levels of social funcConing, higher treatment costs and worse social and vocaConal rehabilitaCon. AggravaCon of the clinical picture can be also most certainly responsible for

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