Briefly, candidate gene studies pointed to potential involvement of genetic variants related to dopaminergic or serotonergic transmission, drug metabolism CYP enzyme family , and oxidative stress mechanisms Genetic research on other types of antipsychotic-induced movement disorders is limited. Moreover, many studies regard different forms of acute drug-induced movement disorders as a single clinical entity The Regulator of G protein signaling 2 RGS2 gene was associated with AIP 18 , 19 and supported functionally by behavioral studies of AIP like features in mice carrying a mutation leading to reduction of gene expression However, other groups have failed to validate this association.
While pharmacogenetics may have major clinical value to personalized medicine in psychiatry 26 , 27 , the aim of this hypothesis article is to put the genetics of antipsychotic-induced movement disorders in a broader context. This original hypothesis suggests that the same genes, which confer susceptibility to or protection against AIP and TD among schizophrenia patients treated with antipsychotics , may be modifier genes that influence the clinical expression of PD in those affected by this disease. AIP variants might be related to compensatory mechanisms for dopamine loss in the striatum, or influence nigrostriatal NS pathway integrity and functionality and thereby possibly modulate PD motor sub-phenotypes such as age at disease onset and rate of disease progression.
Another sub-phenotype of importance is susceptibility of PD patients to early development of a serious side effect of dopaminergic treatment, l -DOPA induced dyskinesia LID. LID may share a common genetic background with TD, with which it shares clinical features. In the following sections, we present epidemiological, imaging, and molecular data that support this line of thought.
On the other hand, there is substantial and intriguing similarity between two phenotype pairs, which is the background to our hypothesis. Although the empirical supporting evidence for our assumptions is limited at the current stage of the field as presented below and some of the underlying assumptions might be eventually wrong, the aim of this paper is to introduce a novel hypothesis and perspective, challenging future study in this direction employing more advanced genetic, genomic, and epigenetic tools , rather than to reach definitive conclusions.
Antipsychotic-induced parkinsonism, the most common manifestation of antipsychotic-induced movement disorders, is an acute, reversible side effect 28 , This substantial heterogeneity may stem from inter-study differences in medication regimens and patient demographic background. According to data from the s, most affected patients develop AIP within the first 2 months of antipsychotic exposure, or even earlier 34 , Improvement occurs within a few months.
The pathophysiology of AIP is not entirely clear. All known, antipsychotics are DRD2s blockers and are thought to reduce psychotic symptoms by blocking these receptors in the mesolimbic dopamine pathway 4. Disease manifestation includes motor and non-motor symptoms, variable clinical expression, and a slowly deteriorating course 38 , The central motor features of PD are tremor at rest, rigidity, bradykinesia, postural instability, flexed posture, and freezing of gait Indeed, there are clinical settings in which it is difficult to distinguish between the two 45 , Although AIP is considered to be more symmetric and less characterized by tremor compared than PD 48 , 49 , asymmetry, and tremor do occur frequently AIP patients 45 , 50 , Other study suggested that AIP affects the upper limbs more than the lower ones Naturally, reversibility of signs following antipsychotics withdrawal is characteristic of AIP and not PD.
Also, while AIP is essentially a motor side effects among schizophrenia or other psychotic patients, the clinical picture of PD is much broader, and includes multiple non-motor symptoms such as neuropsychiatric disturbances for example depression, anxiety, and hallucinations , cognitive decline, and autonomic dysfunction We suggest that genes associated with susceptibility to AIP may be modifier genes that influence the clinical expression of PD motor symptoms.
The hypothesis is tethered in the fact that loss of dopaminergic stimulation albeit reversible in AIP and irreversible in PD is a core feature of both clinical entities. Thus, genes that affect occurrence and severity of AIP in schizophrenia patients exposed to antipsychotic-induced loss of dopaminergic stimulation, could have a similar role in modulating severity of several clinical aspects among PD patients with neurodegenerative loss of dopaminergic NS input.
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Identification of gene variants that are protective against AIP caused by administration of dopamine antagonist could advance our understanding of the intrinsic ability of an individual to compensate for dopamine loss best manifested in the context of PD. In addition, AIP vulnerability variants may be associated with subclinical dopaminergic deficits in the striatum that are aggravated by exposure to antipsychotics. Therefore, these variants could provide clues to the genetic contribution to NS pathway integrity in schizophrenia and PD. Post-mortem analysis of Parkinsonian brains indicates that extensive loss of dopamine in the putamen and caudate nucleus can be accompanied by minor clinical manifestations only 55 , Inter-individual difference in severity of motor symptoms during early and mid-duration PD may be attributed to existence or lack of compensatory mechanisms that counterbalance dopamine loss 57 , and reduce severity of motor symptoms and progression rate Table 1.
Examples for compensatory mechanisms categories in PD. If extrapolation is made from these putative compensatory mechanisms in PD to schizophrenia patients exposed to antipsychotics, lower severity of AIP symptoms seems related to the ability of the individual to counterbalance lack of dopamine induced by exogenous block of dopaminergic transmission.
Individuals with higher compensatory potential would be less likely to develop AIP when treated with antipsychotics, due to mechanisms found at both striatal and extra-striatal levels, as mentioned above. Interpersonal differences in compensatory ability could be explained, at least partially, by genetic variants that are linked to one or more of the compensatory mechanisms, described in PD.
Therefore, the relevant compensatory mechanisms that effect AIP severity are probably more specifically related to DRD2 signaling at the striatal level, but may be more general and essentially similar to those mechanisms involved in PD at the extra-striatal level e. If taken one step further, AIP genetic variants could be relevant for etiology of some sub-phenotypes of PD motor symptoms, resulting in early or delayed disease onset, or accelerated or retarded rate of progression.
PD is a late-onset disease, and the mean age at onset AAO is approximately 60 years However, AAO of the disease is variable, ranging from early onset cases to cases in the 8th—9th decades of life 76 , 77 , and several genes have been associated with PD AAO 75 , 78 , Identification of AIP protective variants can advance understanding of the intrinsic ability of an individual to compensate for dopamine loss and delay appearance of clinical PD motor symptoms.
More specifically, we suggest that AIP susceptibility variants may be associated with earlier AAO among PD patients lower ability to compensate for dopamine loss and AIP protective variants with delayed AAO of motor symptoms better compensatory capacity. In a small pilot study Greenbaum et al.
Drug-Induced Movement Disorders: A Primer
Two nominally significant associations in the expected direction were observed in the Italian sample, but did not withstand correction for multiple testing and were not validated in the Israeli sample. The negative findings do not necessarily mean that our basic assumption is incorrect. The fact that we were unable to support our hypothesis in this pilot study may stem from the relatively small sample sizes and limited statistical power.
Alternatively, some of the AIP variants selected for this investigation may be false-positive due to spurious results in previous studies. If robust AIP risk variants are still undiscovered, lack of association with this PD sub-phenotype is understandable. Turning back to schizophrenia patients, an alternative functional explanation for the role of AIP genetic risk variants may be their influence on NS pathway integrity and therefore its ability to deliver sufficient amount of dopamine to the striatum.
Dopaminergic deficits in the NS pathway may thus be a predisposing factor for AIP since schizophrenia patients with latent subclinical deficits in NS function would be more susceptible to external blockade of dopaminergic receptor, as happens in AIP double hit model: underlying dopamine NS defect exaggerates DRD2 blockade. Thus, among AIP patients carrying the risk allele, administration of antipsychotic drugs that block DRD2s might aggravate preexisting, subclinical, pre-synaptic dopaminergic changes. The cocaine derivate [ I]-FP-CIT is a sensitive marker for degeneration of the NS pathway, due to its binding to the dopamine transporter DAT , a protein localized to pre-synaptic dopaminergic terminals 80 , By implementing this neuroimaging technique to quantify dopaminergic deficits, it is possible to study the effects of AIP risk variants on NS integrity among healthy individuals and PD or schizophrenia patients and thereby link genetic variants to pre-synaptic dopaminergic changes.
This implies that at least among PD patients, this variant may be linked to mechanisms that increase dopaminergic deficits in the NS pathway, a potential predisposing factor for AIP among schizophrenia patients. Interestingly, several neuroimaging studies in drug-induced parkinsonism patients showed that some of them manifest significantly diminished striatal binding in DAT scans 47 , 83 — According to our hypothesis, this finding might be explained by genetic factors predisposing to the subclinical NS deficits. Taken together, it is possible that AIP associated variants will provide insights into genetic factors influencing dopamine secretion capacity, related to NS integrity and function.
This information may be valuable for understanding the preclinical stages of PD in which substantial NS degeneration exist, despite few clinical motor manifestations. Combination of existing subclinical deficits at baseline state, with ongoing neurodegenerative disease, could result in earlier AAO and faster disease progression rate. Tardive dyskinesia is a chronic, severe, and potentially irreversible adverse effect of prolonged exposure to antipsychotics 36 , TD is characterized by abnormal involuntary movements of the face and extremities, and may fluctuate in severity 86 , Risk factors for TD include older age, female gender, and duration and intensity of antipsychotic treatment 91 , Genetic predisposition probably plays a role in determining individual TD susceptibility, as described in the introduction.
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The etiology of TD is unknown, and several explanations have been suggested including supersensitivity of post-synaptic dopamine D2 receptors in the NS pathway following long-lasting blockade of dopamine 93 , Other possible mechanisms are damage to striatal GABA-containing neurons and dysregulation of this system 95 , degeneration of striatal cholinergic interneurons 87 , or neuronal damage neurotoxicity due to overproduction of free radicals 96 , Moving again to PD, dopamine replacement therapy [in particular, levodopa l -DOPA ], is regarded as the pharmacological therapy of choice for the motor symptoms of this disease 37 , The majority of PD patients respond well to l -DOPA during the early years of treatment , but most will ultimately experience disabling adverse motor manifestations such as motor fluctuations and LID.
LID is involuntary movements, mostly choreiform or dystonic in nature, affecting discrete body parts Once established, LID is irreversible and appears on every administration of the dopaminergic agent Several classifications for LID have been purposed; the most common types are peak-dose and diphasic Inter-individual differences in LID susceptibility and onset-time may be explained by a combination of demographic, clinical, and genetic risk factors.
Genetic factors may contribute to LID variability in combination with clinical risk factors. The underlying etiology of LID is unclear.
LID development first requires denervation of the basal ganglia as happens in PD , which changes response to future dopaminergic medications Then, chronic consumption of l -DOPA or other dopaminergic agents causes pulsatile and non-physiological stimulation of dopamine receptors in the striatum. The result is disturbance in anatomical pathways and functional mechanisms, which are responsible for proper motor control This may be mediated by aberrant neuroplasticity and remodeling of relevant neuronal connectivity , D1 receptors and their downstream signaling cascade are considered to contribute substantially to LID pathophysiology , although other receptors are probably also relevant [e.
Nevertheless, there are also some prominent clinical features, which differentiate the two types of dyskinesia. TD is more characterized by oral, buccal, and lingual movements which are repetitive and complex , and limbs and trunk involvement is less severe Compared to TD, LID is phenomenologically more heterogeneous, and includes chorea, athetosis, dystonia, and myoclonus , Also, LID is pronounced in the extremities and neck , , and tend to start on the body side more severely affected by PD Epidemiologically, two important and interrelated risk factors for LID susceptibility are younger age at PD onset and longer disease duration — , while the most consistently established risk factor for TD is advancing age , These differences should be kept in mind.
Based on the clinical and the neurobiological similarities of the two chronic drug-induced dyskinesia phenomena, we suggest a possible common genetic background shared by TD and LID, such that particular genetic variants are associated with susceptibility to TD as well as LID same risk allele. Although the underlying disease context is different, there is a high level of clinical similarity between TD to LID, both being hyperkinetic phenotypes with uncontrolled movements.
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The two disorders are associated with an imbalance in the dopamine system, due to years of drug treatment leading to chronic, non-physiological, pulsatile stimulation LID , or blockade TD of dopaminergic receptors. Analogy between two phenotypes may also be found at the pharmacological level; for example, overactivity of the glutamatergic system , Amantadine, a glutamatergic antagonist, suppresses LID , and also improves TD among schizophrenia patients 99 , Using MRI, volumetric abnormalities in the inferior frontal gyrus were demonstrated in patients with both phenotypes , Thus, we hypothesize that factors important in the pathophysiology of TD might be insightful for understanding that of LID Actually, the potential existence of similar pathophysiological mechanisms between LID and TD is not new in the literature, and was postulated previously by several authors , , The emphasis on the genetic aspect of this hypothesis is the novelty of this manuscript.
Besides contributing to the molecular understanding of both TD and LID per se , this insight if correct may advance the field of PD pharmacogenetic as well as that of schizophrenia, due to reciprocal influences. Common genetic variants may predispose to both phenotypes. According to this risk allele sharing notion, risk variants for TD among schizophrenia patients may be relevant to early LID susceptibility in PD affected individuals, representing a pleiotropic effect. The extent of this genetic overlap is probably limited and partial, while additional genetic risk variants confer susceptibility to LID or TD, separately.
This finding was not validated in a Jewish Israeli sample LID positive and 75 negative, after 3 years of drug exposure , and did not withstand correction for multiple testing The goal of our preliminary data presentation was to demonstrate the applicability of this approach, and its possible implementation. Compared to the relatively extensive volume of pharmacogenetic studies in TD, research on the genetics of LID is limited. Several candidate gene studies were performed in small samples [for example, Ref. Findings from the more mature field of TD genetics may provide reasonable candidate genetic variants for LID research and if validated also molecular targets for further research and drug development.
Mark Edwards, Niall Quinn, and Kailash Bhatia
Analysis of novel and robust TD variants detected in the future for association with LID is indicated and may support our hypothesis. Moreover, when LID GWASs are hopefully performed and published in the future, it will be of interest to compare the top association signals from GWASs of both phenotypes, looking for overlapping risk variants and genes.
Further application of pharmacogenetic tools to antipsychotic drug therapy is greatly needed , Identification of genetic biomarkers that may assist in a priori prediction of antipsychotic-induced movement disorders manifestations such as AIP and TD among schizophrenia patients will be of great value. The aim of this article has been to broaden the context of antipsychotic-induced movement disorders genetics research. We put forward the hypothesis that extending our understanding of the genetic background of AIP and TD and applying this knowledge to PD could render pivotal insights into genetic and molecular aspects of PD, provide new targets for drug development, and assist in finding biomarkers for personalized medicine.
We have suggested that:. As an unproven hypothesis, not well supported by empirical data, caution in evaluation is required. We render only modest empirical support for our hypothesis, based on traditional pharmacogenetics association studies candidate genes and GWASs , in relatively small and probably underpowered samples. However, the aim of this paper is to raise new postulations, and stimulate direction for future research.
Due to recent advances in last decade in genetics, genomics, and epigenetics research, we are now in a better position that may enable systematic investigation of these hypotheses in detail, beyond the limited tools used to date. Larger sample GWASs will assist in this task, especially when combined with a pathway analysis approach.
Since phenotype susceptibility depend on cumulative effect of variants within multiple genes in relatively small number of functional pathways , , this method may assist in shedding light on shared molecular pathways between phenotypes of interest, beyond the contribution of specific gene.
The same sources shall also be used in investigation of shared epigenetics mechanisms to phenotypes of interest, such as DNA methylation or micro RNA e. Last, multiple rare genetic variants with large effect size discovery by whole exome sequencing may also be relevant to genetics of antipsychotic-induced movement disorders, and its intersection with PD. Currently, understanding the contribution of rare variants to pharmacogenetic traits is only at the beginning. Integration of data derived from these approaches, in addition to animal models studies available for most phenotypes discussed here , aiming to gain mechanistic insights — will assist in better understanding of the genetic architecture of the phenotypes discussed above, and the potential intersection between them.
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As novel findings and mechanisms will emerge and accumulate, it will be possible to validate the hypothesis presented, or refute it. However, if these assumptions are correct, even partially, then the incentive for deciphering antipsychotic-induced movement disorders genetic is high, with broader applications for PD and schizophrenia research. LG and BL jointly developed the concept of this article, reviewed the relevant literature, and wrote the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 12 — Stahl SM. New York: Cambridge university press Google Scholar. Pharmacogenetics of response to antipsychotics in patients with schizophrenia.