Is late dyskinesia permanent
Neuroleptics cause brain atrophy
Critical commentary on an article in the Frankfurter Allgemeine Zeitung
On January 26th, 2015 an article appeared in the Frankfurter Allgemeine Zeitung (FAZ) under the title “Neuroleptics - When psychopills make the brain shrink”. In this article, brain atrophy as a result of (long-term) use of neuroleptics and possibly associated cognitive deficits was described. Reference was made to the importance of alternative treatment options and the need to select the smallest possible (initial treatment, but also maintenance) dose of an antipsychotic medication.
Neuroleptics, also called antipsychotics, are the only group of drugs that act on psychotic symptoms such as hallucinations or delusions. What they have in common is an antagonistic effect on dopamine receptors, through which they presumably develop the antipsychotic effect. Most of the substances in this group of drugs also influence numerous other neurotransmitters. Even beyond the brain atrophy discussed here, they have serious undesirable effects, for example in the form of extrapyramidal motor side effects, a metabolic syndrome with cardiovascular consequences, cardiac arrhythmias, sexual dysfunction, depressive syndromes and anhedonia and changes in the blood count.
Neuroleptics are widely used for common diseases such as schizophrenia (lifetime prevalence: 1%) or schizoaffective psychosis, but are now also used for bipolar affective illness and unipolar depression. In view of this very broad indication and approval area and the increase in prescriptions (from 234 million defined daily dosages (DDD) at the expense of the statutory health insurance in 2004 to 321 million DDD in 2013) (1), the risks of this group of substances must be taken even more seriously and still be to illuminate more critically.
After an initial illness, the S3 guideline for schizophrenia recommends treatment with a neuroleptic for one year from remission, after which a doctor-accompanied attempt at tapering off can be considered. In the case of recurrence of the disease, two to five years of drug maintenance therapy or relapse prophylaxis is currently recommended (2).
Neuroleptics cause brain atrophy
The FAZ is correct. It can now be assumed with certainty that the consumption of neuroleptics leads to a reduction in brain volume. Ho et al. presented a high-quality and demanding study in 2011 in which they examined 211 patients with schizophrenia who had had little or no neuroleptic pretreatment over a period of up to 14 years (mean: 7.2 years) with regular cerebral MRI. There was a decrease in the total brain volume and an enlargement of the liquor spaces over time, which could initially be due to the underlying disease. It is known that people with schizophrenia have, on average, lower brain volumes than healthy people. However, the decrease in brain volume (gray and white matter) was clearly associated with the cumulative dose of neuroleptics taken over the observation period, even if statistical corrections were made for disease severity and comorbid addictions (3).
An animal study in which macaques (monkeys) were administered haloperidol, olanzapine or placebo for 17 to 27 months (in doses that led to plasma concentrations such as are present in patients) showed that the monkeys in the two groups of neuroleptics were highly significant had 8 to 11% less brain volume than the placebo-treated monkeys (4). Combining the results of the two studies allows the relationship between brain shrinkage and cumulative neuroleptic dose in the clinical study by Ho et al. to be regarded as causal.
A current meta-analysis (5) of 30 longitudinal MRI studies in a total of 1046 schizophrenic patients and 780 healthy controls confirms the findings by showing that the patients already had significantly lower brain volumes and enlarged lateral ventricles at the start of the study, but only in those with In the course of the study, patients treated with neuroleptics showed a further enlargement of the lateral ventricles and a decrease in the volume of gray matter. This was significantly correlated with the cumulative neuroleptic dose.
The review by Aderhold et al. (6), which is referred to in the FAZ article, also provides a comprehensive overview of the relevant studies on this topic and confirms the findings. Overall, however, it should also be noted that the studies reviewed in the article sometimes come to very inconsistent results that are difficult to explain in terms of their heterogeneity.
The complex topic requires a differentiated approach. The consequences of brain atrophy and what this means for the prescription of neuroleptics is still unclear. The mere assumption "the less brain, the worse" certainly falls short here. The reduction in brain volume is possibly at least partially reversible and not an expression of an irretrievable loss of substance, but the regression of dopaminergic projection paths and synapses as long as dopamine transmission is neuroleptically blocked. The brain is subject to constant changes in its plasticity depending on current requirements and influences. The observed reduction in brain volume could thus represent the mechanism of action of the neuroleptics: There was evidence that a reduction in brain mass in the frontal lobe was accompanied by a reduction in productive psychotic symptoms (6).
There are no uniform study results that the reduction in volume is also associated with cognitive deficits. In some studies there are indications of a correlation between the degradation of brain matter and the loss of cognitive abilities, but elsewhere there were also cognitive deficits that did not correlate with the drug intake and also cases in which a decrease in brain volume did not result in cognitive deficits seemed.
A case-control cross-sectional study with patients with schizophrenic primary illness has just been published in JAMA Psychiatry. In this study, too, the cerebral cortex was significantly narrowed in various regions in a medicated patient group (n = 23) compared to an unmedicated patient group (n = 22), while the unmedicated patients did not differ in this regard from healthy controls (n = 37). However, the group of neuroleptically treated patients sometimes performed better than the group of unmedicated patients in neuropsychological tests and showed higher activity in functional imaging (fMRI) in some regions of the prefrontal cortex than the unmedicated patients. The authors conclude that purely morphological results should be interpreted with caution (7).
The statement made at the beginning of the FAZ article that the prognosis of schizophrenia would be improved by discontinuing the medication (even against medical advice) cannot be confirmed in this simplification by studies. The authors of the study cited by Aderhold in the neurologist in this regard, that discontinuation of neurolepsy would lead to more than twice as high a recovery rate, express themselves rather cautiously in their assessment: “Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice. ”(“ Only a limited number of patients can successfully discontinue the medication. High relapse rates prevent discontinuation from becoming a common practice ”) (8).
Prescribing the lowest possible dose, as called for in the FAZ article, is a medical matter of course. For all medications, the minimum dosage should be selected that still ensures sufficient improvement of the symptoms or adequate protection against relapse. A higher dosage would only increase the risk of side effects. This is also required in the national S3 guideline for schizophrenia from 2005 (which has now expired and is being updated): “The dosage of antipsychotics should generally be selected as low as possible. High dosages are not superior to standard dosages. An optimal dosage can be assumed if a good effect is achieved on the entire spectrum of psychotic symptoms with a different focus in the respective phase of the disease with few side effects. ”(2).
Regardless of the discussion about brain atrophy, antipsychotic monotherapy should be prescribed whenever possible, as there is no evidence for the superiority of combination therapy (9; 10). It is also unreservedly in favor that non-drug therapy options (psychotherapy, sociotherapy) should be prescribed on an equal footing and that the range of such therapies should be expanded. The S3 guideline also recommends this: "Pharmacotherapy should be embedded in an overall treatment concept including general and special psychotherapeutic, sociotherapeutic and occupational therapy measures and psychiatric treatment care depending on a differential indication." (2).
With regard to the statement in the FAZ article that the so-called atypical neuroleptics would not have a better potential for side effects, it should be noted that overall it could not actually be shown that these drugs have fewer side effects. However, they are very likely to have fewer extrapyramidal motor side effects and are also likely to cause fewer tardive dyskinesias. The article writes about this side effect: “These manifest themselves in involuntary jerks, tics and noticeable movement anomalies on the tongue, face and in the area of the neck and trunk muscles. They can reach such an extent that those affected are stigmatized for that very reason. ”A reduction in these side effects is of great importance for those affected. It would be too short to say that neuroleptics differ little from one another. This was confirmed in 2013 by a study published by Leucht et al. Methodologically high-quality meta-analysis published in the Lancet, in which the data from more than 40,000 patients from more than 200 blinded studies were included: "Antipsychotics differed substantially in side-effects" ("The antipsychotics differed considerably in their side effects") (11 ).
Numerous studies have shown that neuroleptics are effective and prevent disease recurrence (e.g. (12)). Schizophrenia or other psychosis is a serious illness from which the patient suffers severely, which represents an acute danger to the patient and / or others and in which every recurrence of the disease can have serious psychosocial consequences (e.g. loss of job, breakdown of a Relationship). As with all other (psychiatric and somatic) therapies, the advantages and disadvantages of neuroleptics must also be carefully weighed up. In addition to brain atrophy, these are mainly extrapyramidal, cardiac and metabolic side effects. This weighing should be done together with the patient and, if necessary, his relatives in the sense of a participatory decision-making.
Brain atrophy is a serious side effect of antipsychotic medication, although it cannot be said with certainty to what extent this correlates with impaired function and to what extent the atrophy is reversible after discontinuation. These as well as other side effects should be assessed together with the patient when prescribing in terms of a risk-benefit assessment. From this it follows that neuroleptics should only be prescribed if there is a clear indication and predominance of the advantages over the disadvantages and that if possible, a neuroleptic should be monotherapy in the lowest effective dose. The recommendation to generally refrain from or to discontinue neuroleptics very early cannot be derived from this.
Conflicts of Interest
P. Nordhues denies a conflict of interest.
T. Bschor ended all financial relationships with pharmaceutical manufacturers since April 2014. He had previously accepted lecture fees from Lilly, BMS, esparma (Aristo), Servier, AstraZeneca, Sanofi and Lundbeck as well as reimbursement of conference participation fees and travel and accommodation expenses from Lundbeck and AstraZeneca. He denies any other conflicts of interest.
1 Schwabe U, Paffrath D (Ed.): Drug Ordinance Report 2014. Berlin, Heidelberg: Springer-Verlag, 2014.
2 German Society for Psychiatry, Psychotherapy and Neurology DGPPN (Ed.): S3 Practice Guidelines in Psychiatry and Psychotherapy. Volume 1 - Schizophrenia Treatment Guideline. Darmstadt; Steinkopff Verlag, 2006.
3 Ho BC, Andreasen NC, Ziebell S et al :. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128-137.
4 Dorph-Petersen KA, Pierri JN, Perel JM et al .: The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys. Neuropsychopharmacology 2005; 30: 1649-1661.
5 Fusar-Poli P, Smieskova R, Kempton MJ et al .: Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013; 37: 1680-1691.
6 Aderhold V, Weinmann S, Hägele C, Heinz A: Frontal brain volume reduction through antipsychotics? Neurologist 2015; 86: 302-323.
7 Lesh TA, Tanase C, Geib BR et al .: A Multimodal Analysis of Antipsychotic Effects on Brain Structure and Function in First-Episode Schizophrenia. JAMA Psychiatry 2015; 72: 226-234.
8 Wunderink L, Nienhuis FJ, Sytema S et al .: Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68: 654-661.
9 Barbui C, Nosè M, Mazzi MA et al .: Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol 2006; 21: 355-362.
10 Pandurangi AK, Dalkilic A: Polypharmacy with second-generation antipsychotics: a review of evidence. J Psychiatr Pract 2008; 14: 345-367.
11 Leucht S, Cipriani A, Spineli L et al .: Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951-962.
12 Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM: Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379: 2063-2071.
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