Introduction

Drug-induced parkinsonism (DIP) is a clinical syndrome characterized by bradykinesia, tremor, stiffness, and postural instability. Idiopathic Parkinson’s disease (PD) and DIP represent the two main causes of parkinsonism in the world¹. In the 50s, the first DIP descriptions were made, and they linked the syndrome to the use of chlorpromazine and reserpine, drugs that were used at the time as antipsychotic and antihypertensive, respectively². In later years, parkinsonism was recognized as a frequent adverse effect related to different antipsychotic drugs and later to other numerous drugs of other pharmacologic groups (Table 1).

Objective

The purpose of this article is to contribute to a bigger understanding and recognition of DIP through an updated description about clinical and therapeutic aspects, etiology, and physiopathology, diving into key concepts and situations for the psychiatrist.

Methodology

A literature research in the PubMed database was made, using a combination of the following key words: “DIP,” “parkinsonism AND neuroleptics,” “parkinsonism AND antidepressants,” “parkinsonism AND mood stabilizers,” “parkinsonism and psychiatry,” and “parkinsonism and drugs.” Additional articles used as references from the obtained articles of the mentioned research were also included. We selected publications in English and Spanish. We reviewed the articles and chose the ones that enabled to reach the aim of the present study.

Epidemiology

Savica et al. found 11,9% of parkinsonism in the Olmstead county, Minnesota, between 1976 and 2005, corresponded to DIP and the estimated incidence rate was 3,3/100,000 persons-year¹. Furthermore, they identify a tendency toward a decrease in the rate of DIP incidence of the 68,6% from 1976 to 2005¹. In Korean population, the reported incidence has been greater than the one described in American population and in contrast to America, the Korean records showed an increase of DIP incidence from 7,1 to 13,9/100,000 persons-year in 2012 and 2015, respectively (p < 0,0001)³.

Among Latin-American population, some studies evaluated the epidemiology behavior of DIP. The Pietà study made in Brazil found that DIP represents the 12,3% of parkinsonism cases with a raw prevalence of 1300 cases/100,000 people⁴. This estimate was lower compared to the one reported in the previous studies in Brazilian population as well⁵. In specific scenarios, such as neurology and movement disorders consult, studies report that between 6,8% and 56% of evaluated patients for parkinsonism correspond to DIP⁶,⁷. Despite the described studies, the incidence and prevalence of DIP remains unknown due to a lack of record of this syndrome and the frequent confusion between DIP and idiopathic PD⁷,⁸.

Risk factors

The OMS pharmacovigilance database analysis (Vigibase^®) showed that people over 75 years old are at the highest risk of developing this disorder (reporting odds ratio [ROR] = 2,12; IC 95% 1,98-2,26)⁹. Some factors may explain the risk in this population, such as higher exposure to drugs for behavior disorders, higher polypharmacy, higher risk for cognitive impairment, and less nigrostriatal integrity¹⁰,¹¹.

Many studies have reported a higher DIP frequency among women¹¹. However, Germany et al. found the risk for DIP was higher in men compared to women (ROR = 1,39, IC 95%: 1,31-1,47)⁹, when they adjusted the total ratio of pharmacological adverse effects reports. Furthermore, genetic factors have been associated with higher predisposition to parkinsonism development, therefore not everyone exposed to antipsychotics develop this disorder¹⁰,¹².

Key elements for definition

DIP is defined as a parkinsonian syndrome secondary to the use of drugs, which alters the dopaminergic function in persons without previous parkinsonism history¹. A key aspect when drugs are linked with parkinsonism development is the existence of a temporal relationship between the use of a drug to the emergence of symptoms¹³. However, the gap between the initiation of a drug and the parkinsonism manifestation is variable, going from a few days to months¹⁴,¹⁵. The French pharmacovigilance database analysis enabled to identify two peaks in the emergence of symptoms. The initial peak occurred in the first 3 months of drug use and it was mainly associated to D2 receptor blockers and antidepressants. The second peak occurred between 9 and 12 months and it was especially associated to calcium channel blockers¹⁴,¹⁵. On the other hand, it is considered that the parkinsonian syndrome resolution must come in the first 6 months after the drug suspension, although this time is also variable and controversial¹⁵-¹⁷.

Physiopathology

Movement control involves many cortical and subcortical regions. The planning and movement performance starts in the premotor and motor areas of the cerebral cortex; while the basal nuclei, the substantia nigra, the subthalamic nucleus, and the red nucleus among others also play a fundamental role in the reception, integration, and regulation of the information coming from the cerebral cortex, cerebellum, and other nervous system regions¹⁸. A great number of neurotransmitters interact in these cerebral regions, including monoamines, acetylcholine, glutamate, and gamma-aminobutyric acid (GABA)¹⁸.

The main central dopaminergic pathways are the nigrostriatal, mesolimbic, and mesocortical, which emerge from the substantia nigra, the ventral tegmental area, and the retrorubral region¹⁹. The substantia nigra regulates the basal ganglia and its effect is mediated by dopamine. Until now, five types of dopamine receptors have been described, from D1 to D5, grouped in two families, D1-like and D2-like²⁰. The D1-like family includes D1 and D5 and they are characterized by Gs protein coupled receptors, they stimulate adenylyl and increase the intracellular cAMP levels, in general, they lead to an excitatory effect. The D2-like family includes D2-D4 receptors, they are Gi protein coupled receptors and their stimulation induces opposite effects to the ones described for the D1-like receptors family¹⁸,²⁰.

The antipsychotics block the D2 receptors in the mesolimbic and mesocortical pathways. In the corpus striatum, the D2 receptor stimulation, the inhibitory kind, regulates the GABA release in the striatal neurons, avoiding the excess of an inhibitory tone in the indirect pathway and maintaining a balance with the direct pathway²¹. Drugs that alter the nigrostriatal pathway may modify the dopamine mediated negative feedback toward the corpus striatum, which induce a deeper activation and an increase of the inhibitory tone coming from the striatum¹⁹. It has been estimated that the emergence of parkinsonian symptoms comes when more than 80% of the D2 receptors are blocked²². However, not only the percentage of occupied receptors is important but also the drug-receptor union. Drugs like aripiprazole may reach more than 90% of blockage without producing parkinsonian symptoms, it seems to be explained by a high drug-receptor clearance rate²³.

The hyperkinetic symptoms observed in DIP, such as oromandibular dyskinesia, may be also explained by the prolonged blockage of dopaminergic receptors; but in this case, the dyskinesia is due to the compensatory hypersensitivity they develop²⁴. Other implicated mechanisms include type 2 vesicular monoamine transporter 2 blockage and the modification of calcium channels at the presynaptic terminal²⁵.

Drugs associated with parkinsonism

Numerous drugs from different pharmacological groups frequently used in the neurology and psychiatric practice have been associated to parkinsonism emergence.

Antipsychotics

Up to 60% of DIP cases have been attributed to the psychopharmaceutic drugs, especially antipsychotics²⁶. In general, a higher risk is attributed to typical antipsychotics because these drugs have a greater affinity and minor speed of clearance over the D2 receptors, while the atypical antipsychotics may have a more restricted effect over the 2A serotonin receptors²⁷. However, the risk of parkinsonism with atypical antipsychotics is variable and, in general, when high dosage is used, their risk is comparable to the risk of typical antipsychotics²⁸. Gomez et al. evaluated this risk among patients with schizophrenia, who frequently get high dosage of this drugs and they found that the DIP prevalence was similar among patients, who got both types of antipsychotics²⁹.

Risperidone, an atypical antipsychotic, has a dosage-dependent action on D2 receptors, therefore, their effect at a high dosage emulates a typical antipsychotic action²⁷. Olanzapine is another atypical antipsychotic that has shown a high potential to induce parkinsonism and other extrapyramidal effects²⁷. On the other hand, aripiprazole is an atypical antipsychotic, with a novel mechanism of action and a fast speed of clearance from the receptor. Initially, there was considering that aripiprazole had a low risk of inducing parkinsonism, although this has been controversial in recent publications²³. The two antipsychotics with the lowest risk for parkinsonism are clozapine and quetiapine²⁷,³⁰.

Antidepressants

Although rare, the association between antidepressants and parkinsonism has also been reported. A retrospective study of pharmacovigilance reported that 8% of DIP cases have been associated with the use of antidepressants¹⁵. Among these drugs, serotonin reuptake inhibitors and dual-action antidepressants stand out, especially sertraline and escitalopram¹⁵. Hawthorne et al. found that parkinsonism was the most frequent extrapyramidal reaction associated with antidepressants and 80,2% of all the extrapyramidal effects were associated with serotonin reuptake inhibitors³¹. It is believed that the mechanism by which the antidepressants may induce parkinsonism is because of the increase of the serotoninergic activity at the raphe nucleus, which generates an inhibitory action over the striatal and tegmental dopaminergic pathways³¹.

Mood stabilizers

Mood stabilizers may also induce extrapyramidal effects³². Among this group, the valproic acid is the drug which associates the most with tremor and parkinsonism³²-³⁴. This drug has several mechanisms of action, the blockage of voltage-dependent sodium channels and the inhibition of GABA-metabolizing enzymes generate an increase of GABA in the striatum nuclei, this mechanism may explain its parkinsonian effects³³,³⁴. Strikingly, it has been described that there is no direct relationship between serum valproic acid levels and the development of parkinsonism; furthermore, the emergence of symptoms may appear even years after the start of the drug³³,³⁴. Zadikoff et al. reported parkinsonism in 10% of patients taking valproic acid³².

Persistent DIP: DIP or idiopathic PD?

Up to 30% of the patients with DIP may present a persistent or progressive parkinsonian syndrome³⁵. The persistence or the deterioration of parkinsonian syndrome, as well as a complete remission with posterior symptom recurrence after the suspension of the drug, may indicate the existence of a preclinical idiopathic PD state, which was uncovered by the drugs³⁵. In fact, it has been reported that just 43% of patients with DIP presented normal activity in the nigrostriatal system, which may indicate that a great amount of DIP patients really corresponded to PD uncovered by drugs more than a pure DIP³⁶,³⁷.

Although clinical manifestations alone are not sufficient to differentiate PD and DIP, some authors have reported semiologic differences that may orient the differentiation³⁵. The presentation of idiopathic PD is slow and progressive, while DIP has usually a subacute start and the evolutions tend to be stationary³⁸. In addition, Yomtoob et al. reported that patients with more than main two manifestations of parkinsonism have a greater probability of having PD than DIP²⁶. Several studies have described a greater asymmetric parkinsonian prevalence among PD uncovered by drugs than a pure DIP³⁶,³⁹. Pieters et al. found 20,8% of DIP patients presents with asymmetric parkinsonian symptoms and the asymmetric presentation was associated with a greater severity of symptoms, especially cognitive behavioral symptoms and psychopathology⁴⁰. However, even one-third of pure DIP patients may also exhibit asymmetric parkinsonian symptoms³⁹. Other more frequent characteristics of DIP are hypomimia, akinetic-rigid phenotype, upper extremities impairment, and higher frequency of postural tremor⁴¹.

Non-motor symptoms may also be crucial for the differentiation of these two types of parkinsonism. Morley et al. found that non-motor symptoms such as constipation (p = 0,02) and erectile dysfunction (p = 0,05) were significantly more frequent in PD than in DIP. On the other hand, cognitive complains and psychopathology were higher in DIP. Although hyposmia was frequent in DIP and PD (88% vs. 57%), it was significantly more frequent in DIP (p = 0,003)⁴¹. The evaluation of the olfactory function is a tool with a good performance for this differentiation and the result of the olfactory test may predict with great accuracy if patients with parkinsonism could recover after the suspension of the involved drug⁴¹,⁴². Kim et al. evaluated other symptoms using the non-motor symptoms scale in patients with PD, DIP, and healthy controls, they found that symptoms such as urinary and sleep impairment, attention deficit, and hyposmia were associated with PD, even after adjusting confounding variables⁴³.

Treatment

The management of DIP includes prevention, early recognition, and modification of the pharmacological therapy that is potentially causing parkinsonism⁷. Because DIP is an iatrogenic manifestation, doctors must be aware of the safety profile of the drugs they prescribe and the characteristics of the patients, especially older patients. Patients with high risk for developing DIP receiving drugs that alter dopaminergic function must be evaluated regularly with the intention to detect early parkinsonian symptoms⁴⁴.

The main DIP treatment is the suspension of the involved drug. In some cases, there is no need to change the drug for another. For example, some patients with migraine treated with valproic acid or flunarizine, who have achieved good symptoms control, do not need to continue the drug nor change it. However, in other cases, a change of the drug is needed, such as patients receiving typical antipsychotics, who may benefit from a change to an atypical antipsychotic. Patients using an atypical antipsychotic such as risperidone may improve with a change to another atypical antipsychotics with lower parkinsonism risk such as clozapine or quetiapine. Patients cannot change the implicated drug because of their illness, the drug must be reduced to the minimum possible dosage⁴⁴.

Amantadine and anticholinergics, including biperiden, benztropine, or trihexyphenidyl, have been used for the control of symptoms but they lack strong evidence to support their use²⁵,⁴⁴.

Prognosis

The majority of DIP cases are reversible with the suspension of the drug, that is, why DIP prognosis is usually benign. However, up to 30% of patients with DIP may develop a persistent or progressive parkinsonian syndrome and there is the hypothesis that many of these patients have another cause of parkinsonism. Yoo et al. reported that patients, who reach a full recovery, showed greater functional connectivity in prefrontal and cerebellar regions⁴⁵. On the other hand, there is a possibility that DIP behaves as a risk factor for PD. For example, a cohort study showed that the long-term risk for PD increased 2,3 times after the exposure to neuroleptics⁴⁶.

It seems that the complete remission of parkinsonian symptoms after the suspension of the drug is not an accurate indicator of DIP diagnosis. A study of autopsies found pathological findings matching PD in two patients who have had DIP diagnosis and have reached a complete remission of symptoms after the drug suspension⁴⁷.

Functional imaging has shown a good performance predicting the evolution of parkinsonism with great diagnostic utility. However, patients with DIP and normal activity of the dopamine transporter may also present persistence of parkinsonism⁴⁸.

Conclusion

DIP is one of the main causes of parkinsonism in the world and this syndrome will continue to be an important cause of morbidity, especially in older population. In most cases, DIP is a pure syndrome without dysfunction of the nigrostriatal system. However, a variable but significant percentage of patients presents previous disturbances in the nigrostriatal system, which allows to think that in these cases the drug uncovers a previous neurodegenerative disease. In both cases, parkinsonism has an important morbidity for patients, therefore, it is important to prevent it and to recognize it in early stages to limit its clinical impact.