Most clinicians relate parkinsonism and dyskinesia directly to acute and tardive drug-induced
movement disorders. However, parkinsonism and dyskinesia are also present in antipsychotic-naïve
patients with psychotic disorders. In this paper, we want to highlight the clinical
value of these spontaneous movement disorders and want to discuss the concept of “non-mental
signs.”
Acute Drug-Induced Movement Disorders
Acute drug-induced movement disorders, such as acute dystonia, parkinsonism, and akathisia,
are very common side effects of dopamine blocking agents. A causal relationship between
these movement disorders and antipsychotics is beyond any doubt if (i) antipsychotic-naïve
psychotic patients without movement disorders receive antipsychotics and develop these
side effects, (ii) they disappear after dose reduction or cessation of the antipsychotics,
and (iii) this on–off mechanism can be repeated.
Tardive Syndromes
The relationship between tardive syndromes and antipsychotics is far more complex
because they start after months to years of treatment with antipsychotics and can
also be suppressed by antipsychotics. Tardive suggests drug induced, and also spontaneous
hyperkinetic dyskinesias, such as “grimacing” and “irregular movements of tongue and
lips” (and also parkinsonism), are prevalent in antipsychotic-naïve psychotic patients
and have been described by Kraepelin and Bleuler more than a 100 years ago (1).
In patients with long-term use of antipsychotics, there is no test to differentiate
between drug-induced tardive and spontaneous movement disorders. The prevalence of
drug-induced tardive dyskinesia is substantial and increases with age, the same counts
for spontaneous movement disorders such as dyskinesia, bradykinesia, and soft neurological
signs related to schizophrenia (2–15). Also, a meta-analysis showed that in antipsychotic-naïve
patients with schizophrenia the risk of dyskinesia and parkinsonism are three and
five times higher than in healthy controls, respectively (16). Furthermore, another
study in antipsychotic-naïve patients showed a prevalence of dyskinesia and parkinsonism
of 13 and 18%, respectively, with the use of clinical rating scales, which increased
to 20 and 28%, respectively, with the use of instrumental assessment (17).
On the other hand, several findings suggest a direct relationship between antipsychotics
and tardive dyskinesia. First, non-psychiatric patients may also develop tardive dyskinesia
after long-term use of dopamine blocking agents, e.g., long-term use of metoclopramide
to treat nausea, or antipsychotics for insomnia (18, 19). Furthermore, in older patients
receiving first-generation antipsychotics for the first time the yearly incidence
of tardive dyskinesia is extremely high, over 20%, which is much higher than the incidence
of spontaneous dyskinetic movement in older patients (12, 13). Also, tardive dyskinesia
may disappear after cessation of antipsychotics or after a switch to clozapine. These
findings suggest a direct relationship between antipsychotics and tardive dyskinesia.
Based on the studies mentioned above, it is clear that the assumption that antipsy-
chotics are responsible for tardive dyskinesia is at least incomplete. Indeed, movement
disorders can be considered an intrinsic feature of the disease process and implicate
dysfunction in cortical–basal ganglia-cortical circuitry (11). The role of the antipsychotics
may be modification of the disease-based motor disorder and anti- psychotics can both
improve and unmask primary motor abnormalities (10).
The clinical importance of spontaneous movement disorders is also emphasized by the
relationship between spontaneous parkinsonism and cognitive dysfunction. In a prospective
study in antipsychotic-naïve patients with first-episode psychosis, spontaneous parkinsonism
at baseline showed high 6-month predictive values for cognitive impairment (9).
Pathophysiology
The pathogenesis of tardive dyskinesia remains unresolved. Several hypotheses have
been proposed such as dopamine 2 (D2)-receptor hypersensitivity, striatal neurodegeneration,
maladaptive synaptic plasticity, and enhanced serotonin 2 (5-HT2)-receptor signaling
and recently up regulation of striatal D3 receptors had been suggested in a primate
model (20). Although none of these models have been confirmed sufficiently they have
in common the disturbance of the balance in the motor circuit of the basal ganglia
in which dopamine plays a central role. The dopamine (and possibly also the acetylcholine)
dysregulation in the basal ganglia-thalamo-cortical loops may result in hyper or hypokinetic
movements whereas dopamine dysregulation in other brain areas may result in the development
of psychosis (21).
Another model is based on synaptic dysregulations in which the core hypothesis is
that non-functional astrocytic receptors may cause an unconstrained synaptic information
flux, such that glia lose their modulatory function in glial–neuronal interaction
(tripartite synapses) (22). Dysregulation of tripartite synapses would occur with
dopamine synapses throughout the brain and may be related to both motoric and mental
symptoms.
Clinical Relevance
The clinical relevance for measuring dyskinesia and/or parkinsonism in first-episode
psychotic disorders is based on several follow-up studies showing that they predict
poor prognosis, increased cognitive impairment, poorer response to antipsychotics,
and an increased risk for drug-induced movement disorders (9, 11, 23).
Also, in individuals at ultra-high risk for psychosis (UHR group) the assessment of
spontaneous movement disorders may be highly relevant. Several studies suggest that
subtle abnormal movements are predictive for conversion to psychosis later. The current
screening strategy focuses on mental symptoms and has a limited conversion rate to
psychosis, around 20–40%, giving to many false positives. It could be that adding
measurement of movement disorders to the screening strategy will reduce the number
of false positives. Indeed, studies show (i) more abnormal movements in the UHR group
than in the control group, (ii) a relationship between the severity of the abnormal
movements and the severity of prodromal signs (positive, negative, and total) at baseline,
(iii) a relationship between an increase in severity of the abnormal movements with
an increase of prodromal signs during follow-up, and (iv) a higher risk to convert
to psychosis at follow-up in the UHR groups with abnormal movements at baseline than
those without (24, 25).
Detection of those in the UHR group who will convert to psychosis is relevant as a
meta-analysis showed the effectiveness of some interventions to prevent or postpone
a first-episode of psychosis (26).
Relationship between Movement, Cognitive, and Emotional Disorders
Obeso et al. describe that the basal ganglia are intimately connected with the cortex
through several segregated but parallel loops. These loops are subdivided into motor,
associative (cognitive), and limbic (emotional) domains and are related to the control
of movement, behavior and cognition, and reward and emotions, respectively. When one
or more of these circuits become dysfunctional they can generate movement disorders,
behavioral, cognitive abnormalities, or mood changes. They suggest, for example that
the combination of nigrostriatal denervation and dopaminergic drugs, as seen in Parkinson’s
disease, may induce behavioral disorders such as impulse control disorders and that
this may be the behavioral counterpart of hyperkinetic disorders such as dyskinesia
(27). Similar with this idea is the concept that dysregulation of dopaminergic activity
in dopaminergic related brain areas lead to positive and negative symptoms in psychotic
disorders and that these symptoms are the behavioral counterpart of dyskinesia and
bradykinesia, respectively. It has been suggested that psychotic patients with abnormal
movements, compared to those without, have a more severely dysregulated dopamine system
(28). This may explain the clustering of abnormal movements with cognitive and negative
symptoms and the relationship with poor prognosis. Also, a correlation has been found
between tardive dyskinesia and cognitive symptoms (29). It could be that drug-induced
movement disorders are related to a more vulnerable dopamine system and subsequently
to an increased risk for dyskinesia and negative and cognitive symptoms. In line with
the vulnerability concept is the relationship found between early extrapyramidal symptoms
such as parkinsonism and an increased risk for developing tardive dyskinesia in the
future (30, 31). However, the underlying dysfunction(s) that provoke(s) spontaneous
movement abnormalities, tardive dyskinesia, cognitive impairment, negative symptoms,
and emotional disturbances remains unclear. It is unlikely that one neurotransmitter,
i.e., dopamine is responsible. Although, dysfunction of the modulatory activity of
dopamine plays an important role in the clinical manifestations mentioned above, also
acetylcholine, which is released across the entire striatal network by striatal cholinergic
interneurons, has neuromodulatory properties in the basal ganglia. Furthermore, other
neurotransmitters are involved, such as glutamatergic inputs from the cerebral cortex
and thalamus to striatal spiny projection neurons (21).
Non-Mental Signs
Based on the presence of motor, associative (cognitive), and limbic (emotional) loops
in the basal ganglia, we want to introduce the concept of non-mental signs (dyskinesia
and parkinsonism) in psychotic disorders. This concept is the equivalent of non-motor
signs (mood disorders, apathy, anxiety, etc.) in Parkinson’s disease (32). The severity
of non-mental signs may have a direct relationship with the severity of dysregulation
of the dopamine system. An advantage of non-mental signs is the possibility to measure
them objectively and several research groups have developed instruments to measure
these non-mental signs instrumentally. Instrumental assessment of movement disorders
is sensitive, valid, and reliable and a motor test battery that will quantify the
main motor functions has been suggested (33–38). In addition, instrumental measurement
can also detect subclinical movement abnormalities and these assessments may be used
to predict the course of a (pre)psychotic disorder and can be used to develop preventive
strategies.
In conclusion, we suggest classifying movement disorders in psychotic disorders or
in UHR groups as non-mental signs. Instrumental measurements of these non-mental signs
are objective and have clinical implications for prognosis, diagnosis, and treatment
of psychotic disorders. In UHR groups adding non-mental signs to the screening strategy
may reduce the number of false positives. Non-mental signs could become one of the
first biomarkers in psychiatric screening programs.
Conflict of Interest Statement
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.