Clozapine discontinuation – some experiences and a new animal model of schizophrenia

It’s four days today since I stopped clozapine (50mg at night). Some rebound insomnia was expected but it’s proving to be more problematic than I’d hoped. That, coupled with the activating effects of aripiprazole (30mg) has left me quite sleep deprived but thankfully not psychotic. It’s a fine line though… one I don’t want to cross yet another time. I attempted to sleep on doxylamine (25mg) but even that was ineffective, giving me a fragmented drowsiness but no proper sleep.

A case of rebound insomnia (on ceasing 75mg) has been reported [1]:

“Rebound insomnia has been reported upon discontinuation of benzodiazepines. We describe the first case of a sleep polygraphically documented rebound insomnia with an unusual somatic fatigue syndrome after long-term use of clozapine in a 30-year-old schizophrenic male. The withdrawal symptoms occurred the first day after drug discontinuation and could be stopped by readministering clozapine. In our opinion, the sudden occurrence of the withdrawal symptoms cannot be explained by a dopaminergic hypersensitivity or a cholinergic rebound, but indicates an involvement of GABAergic and perhaps antiglutamatergic properties of clozapine.”

The whole aim was to avoid getting back on any sedating/weight gaining antipsychotics (which is the next step if I can’t sleep) so I’ll persist with doxylamine for a few nights and maybe see if melatonin can help ‘reset’ things.

Update: Doxylamine (50mg) on the fourth night was slightly more effective but I still only had a broken sleep. Doxylamine (50mg) and melatonin (10mg) on the fifth night resulted in a more solid sleep.

More severe withdrawal symptoms have also been reported  “withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms” [2] The authors in this article concluded: “The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity”.


Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients.

Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.

It’s interesting to see an animal model of schizophrenia using abrupt clozapine withdrawal, this one implicating changes in GABA release on discontinuation of clozapine [3 [full text]]:

“Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.”

Hopefully my experiences will be transient and resolve on their own but management of clozapine discontinuation is an area that needs careful consideration.  If anyone has any experiences with clozapine discontinuation and how they managed any rebound phenomena, please feel free to share.

2 thoughts on “Clozapine discontinuation – some experiences and a new animal model of schizophrenia

  1. Hi I came across your website when I Googled “Clozapine discontinuation”.
    I have experience of withdrawing from Clozapine. I was forced to take clozapine against my will even though I was not experiencing psychosis at the time.

    I had been on clozapine for a year and then decided to gradually withdraw from it as the side effects made me feel suicidal. I knew I had to reduce the dose very very slowly. Nurses said that if you come off clozapine you get more psychotic than what you were in the first place. (I was not psychotic when I was put on clozapine). I gradually reduced my clozapine dose over a period of a year until finally I stopped taking it altogether when I got down to 25mg clozapine (starting dose 200mg).

    I experienced a severe discontinuation syndrome which included mental and physical symptoms.
    I expereinced this severe withdrawal even though I reduced the dose extremely slowly over the period of a year.

    The worst withdrawal symptoms were development of psychotic symptoms NONE of which I had experienced before. I started hearing really loud voices in my head, I had never heard voices before. The voices meant I could barely think and my speech had become incoherent as a result of all the voices in my head.
    I was hospitalised as a direct result of coming off clozapine. I was prescribed olanzapine which only helped the psychotic symptoms a little bit, but at least it quietened a lot of the voices down. However I was still very troubled by the voices.

    In terms of physical withdrawal symptoms I experienced nausea and actual vomiting. I hardly ate anything for about a week as any food made me feel sick, I lost 14kg in weight in about 2 weeks!
    Another clozapine withdrawal symptom was insomnia and agitation. Fortunately the high dose of olanzapine I was given was quite sedating so that helped with the initial insomnia.

    I am still on olanzapine now. However I can say that it has taken several years to recover from the severe discontinuation syndrome I experienced from coming off clozapine. However despite still hearing voices I am suprisingly a lot happier to be on olanzapine and finally off the terrible clozapine which made me feel suicidal because of the side-effects.

    How long were you on clozapine for before you decided to come off? Also what was your clozapine maintenance dose?

    I am glad to read that you have not experienced any new psychotic symptoms coming off clozapine.
    I hope that your insomnia you are experiencing will be transient.

    I have also read many of the medical journal articles you have quoted.

    I certainly agree with you that the management of clozapine discontinuation is an area that needs careful consideration.

    Liked by 1 person

    • Hi – thank you very much for your comments!

      I’m sorry to hear about the rough time you experienced on clozapine and during the period afterwards. It’s good hear that you’re doing better on the olanzapine. I hope things (including the ‘voices’) continue to improve for you.

      I was on clozapine for over two years, got up to 500mg/day but most of the time was spent on 350mg/day. I was a rapid metaboliser of clozapine though (and a smoker for most of my time on it), so getting to therapeutic levels was a challenge.

      I had ‘voices’ before starting clozapine but even the high doses didn’t seem to do much for them… Surprisingly, they have dramatically improved off it (it could be the aripiprazole finally working). One of the beneficial effects the clozapine did have was reducing suicidal ideation and that’s one effect that was needed during a rough time in my life. Happy to say I can work through those thoughts much better and with less distress these days.

      I’m finally getting a decent sleep doxylamine (37.5mg) and melatonin (10mg). That said, I’m really quite agitated still and even the slightest stress causes me to start pacing and get quite uptight. I don’t seem to be quite so ‘OCD’ off clozapine, which is nice.

      Thanks again for taking the time to share your experiences and for having a look around my site.

      All the best!


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