When to Discontinue Antipsychotics? Reviewing the Evidence

Last updated: October 4, 2018

 

Today’s question is: When is the right time to discontinue an antipsychotic in the treatment of schizophrenia? We reviewed the evidence as well as consulting Dr. Ira Glick to help us answer this question.

Here is the summary of the podcast:

  • The APA guidelines (2004, updated 2009) recommend indefinite antipsychotics for patients with multiple episodes or two episodes within 5 years.
  • The WFSBP 2013 guidelines recommend antipsychotic maintenance for least 1 year in first-episode psychosis and 2 to 5 years treatment for multiple episodes.
  • Antipsychotic treatment should be lifelong in patients with serious suicide attempts, violent behavior and frequent relapses.
  • The longer the duration of antipsychotic treatment, the higher the risk of treatment failure when patients stop.
  • Mortality and rehospitalization rates are lower among patients continuing antipsychotics.
  • The discontinuation paradox could be due to medication-induced build up of excess of dopamine receptors or supersensitivity psychosis.

 

Transcript

Hello everyone and welcome to the Psychopharmacology Institute podcast. I’m your host, Dr. Wegdan Rashad. In this series we will be discussing topics that matter to you in your clinical practice, sharing expert opinions and latest research.

So this episode’s question is “When is the right time to discontinue an antipsychotic in the treatment of schizophrenia?” Today, we will venture into some of the evidence to answer this.

But first, I posed this question to Dr Ira Glick, Professor Emeritus of Psychiatry and Behavioral Sciences at Stanford Medical School and Director of the Schizophrenia Research Clinic at Stanford Hospital.

He told us the following;

Dr. Glick:

Well, right now, the controlled data is six years. Stefan Leucht, John Davis and I have actually, Leucht, the main one, six years.
But I’m suggesting that you have to treat over a lifetime for most patients, not all, but most.

Dr. Glick’s suggestion is based on his finding from a naturalistic study that patients who adhered to antipsychotic medication had better long-term global outcomes than those who had poor adherence. This naturalistic study followed 35 patients with chronic schizophrenia examining antipsychotic medication adherence from 8 to 50 years (average, 21 years) after onset of antipsychotic treatment.

As you probably know, antipsychotics are the cornerstone in the acute and long-term management of psychosis. In schizophrenia therapeutics there are typically three stages; the first is the period of acute psychosis often found at the acute phase of hospitalization. The second is the 2 to 3 year period after the acute phase and the third is the period from 3 years onwards.

So when to stop? We checked the latest APA guideline which was issued in 2004 with a guideline watch in 2009 and it states:

“Indefinite maintenance antipsychotic medication is recommended for patients who have had multiple prior episodes or two episodes within 5 years.”

But wait, there’s a problem with these guidelines, these were published 9 years ago. So, we continued our search for a more recent guideline.

The World Federation of Societies of Biological Psychiatry (WFSBP) issued more recent guidelines in 2013. They stated that patients with first-episode psychosis should continue antipsychotics for at least 1 year and those with multiple episodes, maintenance treatment should continue for at least 2 to 5 years.

In severe cases, lifelong treatment should be taken into consideration. Of course, we should keep into account the patient’s motivation, psychosocial situation and additional care they receive.

They recommended that antipsychotic treatment to be lifelong in patients with a history of serious suicide attempts, violent, aggressive behavior, and very frequent relapses.

So, that’s what the 2013 WFSBP guidelines say about long-term schizophrenia treatment.

Now, we have more recent data from a study published in 2018. This was a national study conducted in Finland. The study used electronic databases to assess risk of treatment failure with antipsychotic discontinuation after first episode schizophrenia (3). They found that most of the patients who stopped antipsychotics did so in the first year and nearly 40% of them experienced treatment failure compared with 30% of matched antipsychotic users.

And now comes the interesting part; they found that the longer the duration of antipsychotic treatment, the higher the risk of treatment failure when they stop. Let me repeat their finding just in case you weren’t paying attention: the longer the duration of antipsychotic treatment, the higher the risk of treatment failure when they stop.

This sounds a bit puzzling, right? One potential explanation is that long-term antipsychotic exposure modifies brain homeostasis, making discontinuation more difficult. In support of this; patients who discontinued antipsychotics after more than 5 years were 7 times more likely to experience treatment failure compared with matched antipsychotic users!

So, it seems that there is no “safe” time point for discontinuation. If antipsychotic treatment has been used continuously for several years, it is risky to discontinue treatment.

However this isn’t the case for all patients; there is a selected subgroup of patients specified as “good prognosis schizophrenia” who left their antipsychotics for several years and still showed favorable outcomes, but this is not for everyone (5).

Some may be concerned about the potential adverse effects of antipsychotic medications like metabolic syndrome for example, but a 2018 commentary concluded that mortality and rehospitalization rates were lower among patients continuing medication, strongly supporting the value of maintenance antipsychotics for patients with first-episode schizophrenia (4).

There is a growing body of literature that speaks about the so-called “discontinuation paradox”. Which is: within the first 10 months after discontinuation, up to more than half of the patients relapse (6,7). However, those who remain stable in those first 10 months, rates of relapse are considerably lower (7,8).

What could explain this? One possible theory is that antipsychotics generate a build-up of excess dopamine receptors, or the prior build-up of supersensitive dopamine receptors and precipitate supersensitivity psychosis (8,9).

So, that’s what the current literature says.

Still, from a more practical standpoint, I wondered “How does Dr. Glick approach this medication discussion with the patient and family members?”

Dr. Glick:

What I say to patients – and I learned this from one of my students in New York who runs the outpatient and emergency room, sees acute patients with schizophrenia-. “You have to think of schizophrenia, bipolar, depression and anxiety disorders like cancer”. The main thing is to help patients get efficacy.

And you have to think of psychiatric illness the same way.

So what I say to them is first, we’re going to try to help you with the medication. You may get side effects. We know almost positively there are no long-term bad side effects but there are side effects, weight gain, blurred vision, nausea. Each person is different. I’ll help you with the side effects. So yes, we get them but the first thing is to help you feel better.

So, as you can see, Dr. Glick approaches this discussion from an efficacy standpoint.

Key Points:

  • According to the APA 2004+2009 guidelines, indefinite antipsychotics are recommended for patients with multiple episodes or two episodes within 5 years.
  • The World Federation of Societies of Biological Psychiatry (WFSBP) 2013 recommended antipsychotic maintenance for least one year in first episode psychosis and 2 to 5 years treatment for multiple episodes.
  • Also, antipsychotic treatment should be lifelong in patients with serious suicide attempts, violent behavior and frequent relapses.
  • The longer the duration of antipsychotic treatment the higher the risk of treatment failure when they stop.
  • Mortality and rehospitalization rates are lower among patients continuing antipsychotics.
  • The discontinuation paradox could be due to medication-induced build up of excess of dopamine receptors or supersensitivity psychosis.

The following people participated in this episode: Dr. Flavio Guzman as the general editor, Andy Rhode as the audio engineer, Pamela Gonzalez as the project manager and myself Dr. Wegdan Rashad as the host.

Thank you for joining us in today’s podcast until the next episode, goodbye!

References:

1. Takeuchi H et al. (2012). Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res;134:219–225.
2. Robinson D et al. (1999). Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry;56:241–247.
3. Tiihonen J et al. (2018) 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia. Am J Psychiatry;175:765-773.
4. Yager J. (2018). Discontinuing Antipsychotic Medication in Patients with Schizophrenia is Risky. NEJM journal watch psychiatry.
5. Harrow M et al. (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. J Nerv Ment Dis. 2007; 195: 406–414
6. Gilbert PL et al. (1995) Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry; 52: 173–188.
7. Viguera AC et al. (1997) Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry; 54: 49–55.
8. Moncrieff J. (2006). Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand;114: 3–13.
9. Samaha AN et al. (2007) “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci; 27: 2979–2986.

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