Clinical Consequences of Motor Behavior as Transdiagnostic Phenomenon

The paper of Walther and Mittal contains important new insights of motor behavior in psychosis and other severe mental illness (SMI) research. They discuss the role of motor abnormalities, eg, dyskinesia, parkinsonism, bradykinesia, motor coordination problems, neurological soft signs, stereotypies, hand gesture defects, and catatonia, as transdiagnostic markers directly linked to psychopathology in psychosis and other SMI. That motor abnormalities were inherent in psychotic disorders had been known for more than a hundred years and several meta-analyses confirm an increased risk of dyskinesia, parkinsonism, and neurological soft signs in antipsychotic-naive patients with schizophrenia compared to healthy controls.^1,2 Over the years, several systematic reviews have demonstrated the clinical relevance of motor abnormalities, as they have been related to psychotic symptoms, negative symptoms, and cognitive deficits in psychosis.^2,3 For clinical practice, the most important question is the diagnostic and treatment value of motor abnormalities in psychosis. Thus, elucidating the relation between motor behavior and the psychotic illness course is highly relevant for prediction and intervention. A recent systematic review showed that movement abnormalities have a prognostic value for clinical and functional outcome in psychosis. The review (68 studies, total of 23 630 subjects) showed that increased levels of movement abnormalities (in particular neurological soft signs, parkinsonism, and dyskinesia) were related to deteriorating symptomatic and poor functional outcome over time. This was found by individuals at clinical high risk for psychosis, patients with first-episode psychosis, and patients with chronic schizophrenia.⁴ Thus, motor abnormalities have prognostic value in psychotic disorders, justifying the important clinical questions in the Walther and Mittal paper, namely who will develop mental disorders among high-risk clinical patients, who will have favorable outcomes in the face of an existing mental disorder, and who benefits most from specific treatments?

The most innovative part of the paper is that Walther and Mittal are expanding the scope of motor behavior to other diagnostic categories. They argue that motor behavior or movement abnormalities merit a transdiagnostic approach, making movement abnormalities a transdiagnostic symptom/sign. This view is in line with the current developments in psychosis research, where transdiagnostic tools are used for psychosis prediction.^5–7 A recently published study demonstrated that clinical-neurocognitive machine learning models could lead to more precise prediction of psychosis in young patients with affective and clinical high-risk syndromes.⁷ Adding motor behavior to these individualized clinical risk calculators can help identifying those at risk for psychosis, thus offering potential individualized intervention targets. Peralta and Cuesta⁸ have addressed these transdiagnostic perspectives on motor abnormalities. They found that motor abnormalities represent true diagnostic markers as they were directly related to symptom severity and/or disease progression in neurodevelopmental (autism spectrum disorders, schizophrenia, obsessive compulsive disorders), functional (psychotic and affective disorders), and neurodegenerative disorders.⁸

The key role of motor abnormalities in different diagnostic categories is in line with Obeso’s paper showing that the basal ganglia are closely linked to the cortex through several separate but parallel loops.⁹ These loops are divided 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 cause movement abnormalities, behavioral disturbances, cognitive abnormalities, or mood swings. Typically, symptoms that are present in various psychiatric illnesses.

Instrumental Measurement

Instrumental measurements are ideal for quantifying movement abnormalities. These tools are evolving rapidly and the revolution in technology and information science offers new approaches. Instruments are objective, accurate, and sensitive and can detect motor signs below the threshold. In addition, wearable devices enable long-term real-world evaluation. With the large number of sensors available in a smartphone and smartwatch, it is realistic to expect that continuous measurement will play a key role in psychiatric diagnostic processes.

Sensors can simultaneously measure movement abnormalities (pedometer, accelerometer, gyroscope), environment (barometer, temperature, humidity), location (GPS), sleep (breathing and movement pattern), and speech analysis (microphone). The way the user performs activities on their smartphone can also be analyzed.^10,11 Subtle aspects of typing and scrolling, such as the latency between space and character or the interval between scrolling and clicking, are related to cognitive traits and affective states.¹² In combination with the Experience Sampling Method (ESM) a motor-mental-cognitive-sleep ecological real-world assessment may be possible.^12,13 Actigraphy devices allow for continuous and passive monitoring of motor activity over an extended timeframe, mostly several days, and can also measure a range of sleep-related parameters (eg, sleep duration, sleep onset latency, and circadian rhythms). It is found that motor activity measures can be related to clinical features (such as psychotic symptoms, cognitive functioning) and also to movement disorders.¹⁴ A recent study found that decreased activity and increased sedentary behavior were associated with parkinsonism.¹⁵

Ongoing assessments create large-individualized datasets. Using machine learning and network analysis, interactions between variables and underlying causal relationships of psychomotor functioning can be unraveled. Systems utilizing artificial intelligence powered by data and algorithms that include motor symptoms, can further contribute to evidence-based and personalized clinical decisions. If programs are available that can interpret these data, then instrumental screening of movement abnormalities can be done, at low costs, as a routine in diagnostic processes. This may reveal clinical and prognostic relevant relationships between movement abnormalities and symptoms in other diagnostic categories.

Drug-Induced Motor Abnormalities

The article pays little attention to the influence of medication on motor symptoms while in clinical practice medication induced motor abnormalities/disorders are an important topic. The assumption of this article is that motor abnormalities are intrinsic to psychiatric disease. However, it is clear that dopamine blocking agents can cause movement disorders.¹⁶ Many reports of dopamine blocking agents, such as the antiemetic metoclopramide, given to patients without psychiatric disorder, can induce all movement disorders classified in the DSM-5.^17–20

In addition, the cause-effect relationship seems clear for akathisia as a side effect, akathisia may develop immediately after initiation of the offending drug and disappear after drug withdrawal and reappear after a rechallenge. Also, acute dystonia is directly related as it almost always occurs within 96 h of starting antipsychotic treatment or after a large dose increase.²¹ However, for tardive dyskinesia that starts after months or years of treatment with dopamine blocking agents the relationship is less clear.²² Without a test to distinguish tardive drug-induced dyskinesia from dyskinesia as a symptom of the psychiatric illness, the controversy remains.

It may be possible to overcome this controversy by thinking in a network in which movement abnormalities are considered one of the symptoms of a psychiatric disorder and that antipsychotics or other drugs are other nodes in the network that have a major influence on the incidence, severity, and course of motor abnormalities and psychiatric symptoms.²³ Such a model is very attractive because it may explain the interaction between many variables, such as the predictive value of movement abnormalities, the persistence of parkinsonism even after discontinuation of the offending drugs.

This brings us back to the 3 questions in the introduction. In studies to who will develop mental disorders among high-risk individuals, movement abnormalities should be added. This has been omitted in a recent meta-analysis about risk factors related to the onset of psychosis in this vulnerable group.²⁴ The prognostic question about who will have favorable outcomes, is clinical highly relevant and with movement abnormalities may predict poor functional outcome, and in psychotic disorders a less favorable effectiveness of antipsychotics, clinicians should be aware of these symptoms.⁴

The final question is the most important one for clinicians: who will benefit most from specific treatments? Cohort studies comparing patients with movement abnormalities vs those without are needed to answer this question. It may be very interesting to study the role of clozapine in such studies, as movement abnormalities are related to less effectiveness of antipsychotics and treatment resistance is the primary indication for clozapine.²⁵