Vermeulen,K; Staal, WG; Bokhoven, H van ; Egger, JMI; Kleefstra,T
2017, Article/Letter to editor (Clinical Neuropharmacology, 40, 4, (2017) pp. 185-188)

Doi link to publisher: https://doi.org/10.1097/WNF.0000000000000226

This is a Kleefstra Syndrome UK summary of this research from 2017. For the full information, please see the link above.

Background information

Psychosis is severe mental condition in which thought and emotions are so affected that suffers lose contact with reality. They may see and hear things that do not exist (hallucinations) and believe things that are not actually true (delusions). It may also involve confused (disordered) thinking and speaking. A person experiencing symptoms of psychosis is often referred to as having a psychotic episode. Antipsychotic drugs are used to relieve the symptoms of psychosis

What this paper is about

This is a letter to a journal in which Prof. Kleefstra’s team report on 3 individuals with KS who suffered from regression after developing sleep disturbance. The team suggests that a change in how antipsychotic medication is used in this situation may be beneficial.

Introduction to the paper

The EHMT1 gene which is linked to Kleefstra Syndrome (KS) is also associated with some cases of schizophrenia.

Prof K’s group is studying a subset of KS individuals who show progressive intellectual deterioration (regression). At puberty or early adulthood some people with KS may demonstrate severe sleep disturbance which precedes severe psychiatric disturbance and loss of function.

Adolescence is a critical period for development of major psychiatric disorders such as psychotic disturbance, bipolar disorder or depression. These require urgent treatment with adequate doses of antipsychotic drugs.

Individuals with intellectual disability (ID) may be more at risk of the side effects of antipsychotic drugs so generally they are started at lower doses and doses are increased more slowly than when treating the general population.

The case reports

The paper describes the clinical course of 3 individuals who each experienced severe sleep disturbance and psychiatric symptoms and who subsequently developed regression. Each person had a psychiatric diagnosis in addition to KS. In each case treatment following the usual principles for the use of antipsychotic in individuals with ID (start with a low dose and increase slowly) was unsuccessful. However, introduction of a high/normal dose led to rapid resolution of the sleep disturbance, halted the regression and allowed some recovery of function.

Case 1

Female aged 19, also has ADHD and ASD
She experienced a gradual onset of sleep disturbance after an episode of pneumonia until eventually she was awake for 72 hours straight, hyperactive, aggressive, not eating and required acute psychiatric admission. Low dose benzodiazepine treatment was ineffectual, but her sleep normalised in 24 hours following a larger dose of olanzepine (an antipsychotic drug).
When she was aged 12 her developmental level was 2 years, six months after this episode she had a developmental age of 17 months. She had lost the ability to talk in sentences, had become incontinent and demonstrated more self-injuring behaviours.

Case 2

Female aged 23, also ASD
She developed a major depressive episode aged 18 and had severe sleep disturbance. She was started on low dose aripiprazole (antipsychotic drug) but this made her sleepy, so the dose was reduced to 2mg. Over the next 2 years she lost the ability to dress herself, to read and write and to talk in sentences. Her personal hygiene also deteriorated. When she was treated with a much larger (15mg) dose of aripiprazole her sleep recovered, the depression resolved and the regression stopped. She also re-learned some skills so was able to speak in short sentences and had some awareness of personal hygiene. At the age of 19 her developmental age was 3 years 10 months, one year after the episode it was 2 years 5 months.

Case 3

Female aged 23, also had ASD
Aged 20 she developed psychotic symptoms after the death of her grandfather. She stopped sleeping and developed delusions and hallucinations. Several antipsychotic drugs were tried at low to normal doses, but none were effective. Over the course of 2 years she suffered a major regression of function. She lost the ability to talk, to read and write, to dress herself, to swim and became incontinent.
At the age of 22 she spent several months as a psychiatric inpatient. When the dose of her antipsychotic drugs was increased her sleep recovered and her psychiatric symptoms resolved. Her developmental age was 15 moths, having been 3 years at the age of 16.

The authors’ comments

1. Sleep disturbance is common in KS, especially in adolescence or early adulthood, and may be followed by rapid regression. This occurs at a time when psychiatric disorders may also develop.
2. The cases show the benefits of immediate treatment with adequate doses of second-generation antipsychotic drugs. Clozapine is the most effective of these, but it has the potential for some serious side-effects. The second choice is olanzapine. This is useful in patients with ID as it comes in a preparation which melts in the mouth. Both drugs are most effective when use in a high-normal dose.

Their take home message

Instead of following the usual pattern of using lower than normal doses of antipsychotic drugs to treat acute psychosis in patients with ID treatment should be as that in the non-ID population with psychosis. This may help to reduce/prevent episodes of severe regression and contribute to quality of life in these individuals.