Wednesday, October 21, 2020


Editor’s note: This is a review of existing formal and informal guidance on psychiatric drug withdrawal protocols. This piece should not be interpreted as medical advice or as an instruction to approach withdrawal in a particular way.

Important: Tapering guides advise that unless there is a risk of immediate serious illness from continuing, psychiatric drugs should never be stopped abruptly.

 

Antipsychotic drugs are dopamine receptor blockers, also known as dopamine receptor agonists and they were first developed in the 1950s from antihistamine drugs such as promethazine. The use of dopamine receptor blockers was associated with the overly-simplistic dopamine theory of psychosis.

According to the RxISK website, antipsychotics were the first of the modern psychotropic drugs to be linked to severe withdrawal, but even so few doctors today are aware that there can cause dependence and withdrawal or how bad the problems can be.

The problems associated with the use of first-generation dopamine receptor blockers was reported as early as 1968.

General Issues

Lack of formal research

In common with other classes of psychiatric drug, there is very little official research into withdrawal or discontinuation despite neuroleptics first being prescribed in the 1950s. Part of the reason for this seems to be the strongly held belief that ‘relapse’ and re-emergence of psychosis are near-certain consequences of stopping antipsychotic drugs.

The paradox is that longer treatment with antipsychotic drugs seems to increase the likelihood of withdrawal-induced psychosis, yet remaining relapse-free is identified as the biggest factor in successfully stopping antipsychotic drugs. Writing in 2018 in JAMA psychiatry, Christy L. M. Hui, PhD, from the department of psychiatry, University of Hong Kong, and colleagues observed:

“In a 10-year follow-up study of more than 100 patients with first-episode psychosis, researchers found that remaining relapse-free was the most significant predictor of successful long-term antipsychotic medication discontinuation.”

 

There are some projects underway that specifically focus on antipsychotic withdrawal. One such project is the RADAR study led by Professor Joanna Moncrieff in the UK.

Experiences using antipsychotics drugs

In February 2020 paper, Professor John Read and colleagues presented the results of a study of people’s experiences taking antipsychotic drugs. It is the largest survey to date and was published in the journal Schizophrenia Bulletin. 650 people, from 29 countries, responded, in an online survey, to the open question: ‘Overall in my life, antipsychotic medications have been ……….?’

“14% reported purely positive experiences, 28% had mixed experiences, and 58% reported only negative ones.

Thematic analysis identified three main negative themes: ‘adverse effects’, ‘unhelpful interactions with prescriber’ and ‘withdrawal/difficult to get off them’. Adverse effects included: weight gain, emotional numbing, cognitive dysfunction, sedation, akathisia, effects on relationships, and suicidality. Unhelpful interactions with prescribers included lack of information, support, or discussion of alternatives.

The two positive themes were ‘symptom reduction’ and ‘sleep’. The only mixed theme was ‘short-term good, long-term bad’.”

Regarding withdrawal, 65% of those responding to the survey question reported withdrawal effects and 58% reported suicidal thoughts.

 

Re-emergence of psychosis following antipsychotic withdrawal

The withdrawal or discontinuation of antipsychotic drugs is thought to be a risk factor for the re-emergence of psychosis. In a 2006 paper, Professor Joanna Moncrieff sought to review the likelihood and ascertain whether withdrawal-induced psychosis could be different to that arising from an underlying illness. She observed that withdrawal-induced psychosis was rapid onset and is known as ‘supersensitivity psychosis’.

“Evidence for a rapid onset psychosis (supersensitivity psychosis) following clozapine withdrawal was found and weaker evidence that this might occur with some other antipsychotic drugs. Some cases were reported in people without a psychiatric history. It appears that the psychosis may be a feature of drug withdrawal rather than the re-emergence of an underlying illness, at least in some patients. Meta-analyses of withdrawal studies have suggested that antipsychotic discontinuation may also increase the risk of relapse over and above the risk because of the underlying disorder, but not all individual studies show this effect. Mechanisms may relate to brain adaptations to long-term drug use but data are sparse.”

 

Supersensitivity psychosis is thought to occur because the use of antipsychotic drugs ‘upregulates’ the affected dopamine receptors. Upregulation is defined as an increase in the number or sensitivity of dopamine receptors. When the antipsychotic drug is stopped, this upregulation is not compensated for by the action of the drug.

Antipsychotic Withdrawal

Factors influencing withdrawal difficulty

In common with other classes of psychotropic drug, there are factors which may influence how difficult someone may find withdrawal from antipsychotics. These include, but are not limited to:

Length of time taking the drugs (those who have been on longer may need to take longer to withdraw).

  • The dosage taken (higher dosages can mean longer needed to withdraw safely).
  • The half-life of the drug in question (drugs that are quickly eliminated from the body tend to make withdrawal felt more quickly or more severely).
  • The age of the person (often, but not always, younger people find withdrawal easier than older people). This may be particularly true for children.
  • The general health of the person coming off (since withdrawal can be physically taxing, those who are fitter seem to fare better).
  • The use of other prescribed or street drugs (polypharmacy can complicate withdrawal, as can use of street drugs).
  • Prior failed withdrawal attempts (trying and failing to come off previously can make the psychological hurdle more challenging).

Justification for using slow tapering methods

In a 2018 paper, Miriam Larsen-Barr, Fred Seymour, John Read and Kerry Gibson described research which compared gradual withdrawal with abrupt cessation. This research was covered in-depth on Mad in America. 105 participants were involved and unwanted withdrawal effects were reported by 61.9% of the group.

“Half of the participants reported gradual withdrawal, while the other half reduced their medication abruptly (one month or less). Those who gradually withdrew did not report relapse, described successfully stopping, and were not currently using antipsychotics.

Gradual withdrawal over one month was positively associated with successful discontinuation and no current use. There was also a significant positive association between following a gradual withdrawal method and consulting a doctor. However, 47% of those who asked a doctor withdrew abruptly, while 52% withdrew gradually.

Unsurprisingly, relapse was negatively associated with discontinuation and no current use.

Withdrawal Effects

Two-thirds reported unwanted withdrawal effects, 18% reported no withdrawal effects, and 13% reported positive effects. Some of the adverse emotional withdrawal effects included: anxiety and fear, low mood, sadness and depression, irritability and agitation, suicidality, and mood swings. On the physical side, withdrawal effects included: nausea, diarrhea, vomiting, headaches, unpleasant bodily sensations, appetite, and rapid weight loss, insomnia or disturbed sleep, shaking, sweating, and one person reported seizures.

Relapse

Twenty-seven percent of the sample reported relapse of psychosis or mania during withdrawal. Thirteen percent of those who discontinued gradually reported relapse while 34% of those who stopped abruptly reported relapse.”

 

Antipsychotic withdrawal methods

Perhaps the most comprehensive antipsychotic withdrawal guidelines are those described in the German National Guidelines for Schizophrenia.

In March 2019, the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) published new guidelines for the treatment of schizophrenia. In December 2019, the DGPPN published an abbreviated English translation.

In their detailed recommendations, they advise adopting a shared-decision-making approach between the prescriber and the person wishing to withdraw and that this must be supported by adequate psychosocial support, regular follow-up of the symptoms and it must be ensured that there is no evidence of danger to the person withdrawing or to others. In all cases, they note, the person withdrawing should be informed about the increased risk of relapse from discontinuation.

Regarding the amount to reduce, the German guidelines advise that reduction steps may be larger in the early stages of withdrawal and smaller in the later stages. They give a percentage of between 5% and 20% of the current dosage, achieving this through the use of liquid forms of the drug where possible.

In relation to the intervals between reductions, they advise waiting for 6 to 12 weeks in between dosage reductions and that the selection of the next dosage reduction should be informed by the experience of the previous one.

They note that there should be a period of several weeks of symptom stability before considering the next reduction step. Following the complete withdrawal of the antipsychotics, as part of the overall treatment plan, they recommend continuous monitoring of clinical signs and symptoms of recurrence for at least two years.

Extracts from the German National Guidelines for Schizophrenia

Table 12. Possible reduction or withdrawal phenomena

Withdrawal symptoms can usually become evident within days to weeks of dose reduction or occur after rapid discontinuation of antipsychotics:

  • Cognitive disorders of concentration, attention and memory
  • Vegetative disorders: gastrointestinal disturbances (such as nausea, vomiting and diarrhea), sweating, dizziness, tachycardia, hypertension, tremor, collapse, flu-like symptoms, excessive sensitivity to pain, headache, delirium (e.g., rapid withdrawal from clozapine)
  • Emotional instability, anxiety, restlessness, depression, irritability, aggressiveness and maniform symptoms. Also, these symptoms usually arise within days or weeks after reducing or discontinuing the drug
  • Abnormal involuntary movement of the face, lips, jaw, tongue, arms, wrists, hands, fingers, legs, knees, joints, toes, neck, shoulders, hips (withdrawal dyskinesia). These symptoms often occur in the first few weeks after withdrawal and may persist for months
  • Psychotic and other behavioral symptoms that cannot always be distinguished from the original psychotic disorder. They usually develop within days to about six weeks after the reduction and often only improve after weeks. In particular, clozapine should be reduced and discontinued only slowly, as it is assumed that there is an increased risk of a rebound.

Recommendation 26 [KKP]: Discontinuation of antipsychotics

The reduction and possibly the discontinuation of antipsychotics in all stages of the disease can be offered in the sense of participative decision-making between the patient and the attending physician, provided sufficient stability, adequate psychosocial support and regular follow-up of the symptoms are ensured and there is no evidence of danger to self or others. In any case, should be informed about the increased risk of relapse from discontinuation. Suggestions for dose reduction and discontinuation can be found in the background text (5.5.3)

5.5.3 Controlled dose reduction

Controlled dose reduction is usually clinically justifiable in the course of relapse prevention for one or more of the following reasons:

  • Reduction of high doses given in acute treatment, which are unnecessary for long-term relapse prevention
  • Finding the individual lowest possible dosage in the prevention of relapse with a most favorable effect-adverse effect relationship
  • Minimize the frequent dose-related adverse drug reactions of antipsychotics
  • Patient request for the lowest possible dosage
  • Correction and reduction of existing polypharmacy by discontinuation of additional preparations.
  • Dose reduction after an unsuccessful escalation attempt with a higher dose to a previous lower dose

Tab 11 Prerequisite for a dose reduction

Good preparation before the reduction process, individual reduction steps, and close psychiatric-psychotherapeutic support

  • Check if there have already been successful or unsuccessful guided dose reduction trials in earlier stages (not in first episode)
  • Definition of clear goals (e.g., reduction of adverse drug reactions, future goals, tolerability, more independent lifestyle) of dose reduction beyond the desire to reduce the medication.
  • Prepare a contingency plan with early warning signs and therapeutic strategies or take other precautionary planning measures
  • Treatment in a multi-professional team and, if desired, peer support and participation in support groups
  • With the consent of the service user, including as many important professional and private caregivers as possible, as well as information on weaning phenomena and early warning signs
  • Ensure good social support with a stable social environment
  • Consideration of disease severity and individual symptom burden due to psychotic illness

Recommendation 25 [KKP] 

After deciding to reduce the dose of antipsychotics, it should be monitored, taking into account the recommended duration of treatment (recommendations 36 and 37) in minimal dose increments at 6 to 12 week intervals, according to the preference of the patient, including trusted individuals, overall treatment plan, history of treatment and the tolerability of existing antipsychotic medication.

Table 12. Basic ideas regarding the reduction steps of a controlled dose reduction

  • Patients and other involved people should be informed about withdrawal symptoms, but also about the high recurrence rates (see statements 2 and 3)
  • At each reduction step withdrawal phenomena should be observed during the first few weeks and classified accordingly. There should be a period of several weeks with adequate stability before the next reduction step
  • Reduction steps should be done at the beginning in larger steps and at the end in smaller steps. They should be between about 5-20% of the current dose, whereby a pragmatic approach can also be used in the absence of appropriate dosages (for example, liquid form, extended dosing, individual dosing).
  • Reduction intervals should be between 6 to 12 weeks, and the selection of the next reduction time should include the experience of the last reduction step and the total duration of treatment with antipsychotics since the last psychotic episode
  • Care should be taken to ensure adequate sleep duration and quality. Reduction-related sleep disorders can be treated in the short term by means of sedatives according to the guidelines of sleep medicine
  • In case of emergent relapse, the dose previously used should be reinstated, if necessary 10% or more above the previous dose, and other crisis management measures should be used
  • Very small reduction steps have to be taken before final discontinuation, taking into account the feasibility

Recommendation 27 [KKP]: Monitoring after discontinuation

Following discontinuation of antipsychotics, as part of the overall treatment plan, there should be continuous monitoring of clinical signs and symptoms of recurrence for at least two years.

Special considerations

Akathisia is important to watch for both during withdrawal and for some time afterwards. Akathisia is described as an intense urge to move which can be felt internally where someone observing doesn’t see movement, or externally in which case an observer will see movement or agitation. Akathisia is more commonly associated with coming off antipsychotic drugs, although has been associated with coming off antidepressant drugs too. There is some evidence that rapid withdrawal is more likely to trigger akathisia, but for some people, it can be felt even after a carefully managed gradual reduction.

Post-acute Withdrawal Syndrome (PAWS) is the name given to unremitting symptoms that persist long after the drug has been stopped. Due to the lack of research and inability to agree on an appropriate definition, PAWS is not listed in the Diagnostic and Statistical Manual of Psychiatric Disorders. It is also unrecognised by most medical associations. The concept of PAWS has, however, been adopted by drug and alcohol rehabilitation services.

Such protracted symptoms, which may persist for months or even longer, are thought to be due to the fact that the drug exposure alters brain physiology (increasing or reducing the density of neurotransmitter receptors, for example), and it may take an extended period for such brain physiology to renormalize.

Six-week ‘detox’ programs: These programs may (or may not) have merit for stopping street drugs, but they are likely to be inappropriate for psychiatric drug withdrawal, given that any withdrawal regimens need to be personalized, with tapering speeds adjusted in response to individual withdrawal experiences.

Tardive Dyskinesia

Tardive dyskinesias (TD) are uncontrollable movements of the tongue, lips, face, body or arms and legs that occur after treatment with antipsychotic drugs. Tardive means ‘delayed onset’, as these issues usually arise after long-term treatment. Though more common with long-term use of neuroleptics, they have been seen after as little as a single dose of the drug. For some people, tardive dyskinesia may continue even after withdrawing from the antipsychotic.

TD can cause stiff, jerky, irregular movements such as lip-smacking or jaw movements.

Dystonic reactions

Dystonia is a movement disorder where muscles spasm or clench, sometimes painfully. This is thought to be because of interruption in the control of the muscles by the brain resulting from the use of dopamine receptor blockers. Where dystonia is caused by the adverse effects of antipsychotic it is called tardive dystonia.

According to the Dystonia Society, dystonic symptoms do disappear but unfortunately this is rare (around 1 in 10 cases). Research suggests that, if the drug causing the tardive dystonia has been taken for only a short period of time, remission of symptoms is more likely than if the drug has been taken for a longer period.

Key Papers and References

Moncrieff J. A critique of the dopamine hypothesis of schizophrenia and psychosis. Harv Rev Psychiatry. 2009;17(3):214‐225. doi:10.1080/10673220902979896

Remaining relapse-free key to long-term antipsychotic discontinuation, Hui CLM, et al. JAMA Psychiatry. 2018;doi:10.100/jamapsychiatry.2018.3120.

Crane GE. Tardive dyskinesia in schizophrenic patients treated with psychotropic drugs. Agressologie. 1968;9(2):209‐218.

Larsen-Barr, M., Seymour, F., Read, J., & Gibson, K. (2018). Attempting to discontinue antipsychotic medication: withdrawal methods, relapse, and success. Psychiatry research. https://doi.org/10.1016/j.psychres.2018.10.001.

Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. https://www.ncbi.nlm.nih.gov/pubmed/16774655

German Association for Psychiatry, Psychotherapy and Psychosomatics, DGPPN, S3 Guideline for Schizophrenia, abbreviated version (English). https://www.dgppn.de/_Resources/Persistent/b794e84f9cbdf0d761b26cb1bd323b65188cb9e6/038-009e_S3_Schizophrenie_2019-03.pdf

Research compiled by James Moore

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