Drug-induced Parkinsonian tremor

Pharmacological disruption of striatal dopaminergic neurotransmission can duplicate virtually all of the clinical features of PD [8], [9]. This includes resting tremor in the limbs and lips at 4–8 Hz and which can be unilateral, bilateral, symmetrical, or asymmetrical. This form of tremor tends to be more prevalent in women than men and often arises at an older age than typical PD. A coarse, flapping tremor or a tremor initiated during action has also been described from the use of dopamine blocking medications [10], [11]. Tremor caused by dopamine blocking medications can evolve shortly after the start of the drug or at weeks to months later. Though this group of drugs reduces dopaminergic neurotransmission as a dose-related and reversible effect, the resting tremor and other Parkinsonian features have been known to persist for varying periods of time long afterwards (in some instances, up to several weeks).

Drugs responsible for inducing resting tremor and other clinical features of PD include a large number of compounds mostly targeted to the D-2 dopamine receptor family (which includes the D-3 dopamine receptor). These drugs, which form the mainstay of pharmacological treatment for schizophrenia and other psychoses, have been classified as “typical” and “atypical” neuroleptics. The drugs regarded as “typical” neuroleptics have been in use since the late 1950s, beginning with chlorpromazine. Among the later generation of compounds with similar psychiatric uses were fluphenazine, perphenazine, pimozide, mesoridazine, promazine, trifluoperazine, loxapine, sulpiride, and haloperidol, among many others used worldwide. A later generation of neuroleptics were modeled after the improved side effect profile of clozapine and received the term “atypical” because of their reduced propensity to produce extrapyramidal side effects such as Parkinsonism or acute dystonic reactions. Most researchers consider the only genuinely “atypical” neuroleptic to be clozapine, a drug that does not cause tardive dyskinesia or Parkinsonism (and which uniquely can block PD tremor [12]). Quetiapine, although not capable of diminishing Parkinsonian tremor, has a pharmacological profile that is closest to the actions of clozapine with respect to extrapyramidal reactions. In recent years, a number of antipsychotic drugs that have been promoted in marketing as “atypical” neuroleptics—among them olanzapine, risperidone, ziprasidone, and aripiprazole—are widely known to behave otherwise and commonly induce Parkinsonian side effects like resting tremor. One of the older neuroleptic drugs, thioridazine (now discontinued) possessed an additional anticholinergic property which would simultaneously provide some symptomatic effects against Parkinsonian resting tremor.

Two drugs in common use also can produce typical neuroleptic drug side effects such as tremor. These include the antinausea drug prochlorperazine and a drug used to enhance gastric motility, metoclopramide. Each of these drugs can enter the brain to antagonize striatal D-2 dopamine receptors and so can induce features of Parkinsonism. Another pharmacological way that dopaminergic neurotransmission can be disrupted is by depletion of presynaptic vesicular dopamine stores as occurs with reserpine (an antihypertensive drug no longer used in Western medicine) and tetrabenazine [13]. Each of these ways to diminish striatal dopaminergic neurotransmission can induce the full spectrum of Parkinsonian features, including resting tremor.

Drug-induced tremor caused by dopamine depletion or receptor blockade can respond to anticholinergic drugs or amantadine, and tends to be rapidly reversible. Some drug formulations, such as depot injections, can deliver drugs for long periods of time and as a result, tremor can persist long after discontinuation of therapy. Another outcome of neuroleptic drug use is a rare condition termed “tardive tremor.” Tardive tremor arises when the long-term use of a neuroleptic medication induces a persisting resting tremor. This condition is akin to the phenomena of other tardive movement disorders such as dyskinesia or dystonia [14], [15]. There has been little further reporting of this condition, which potentially can be confused with the unmasking or simultaneous development of PD. One distinguishing feature of tardive tremor is that, unlike the tremor of PD, it is dampened by the reinstitution of a dopamine blocking or depleting drug.

A rare movement disorder termed “orthostatic tremor” also has been reported to occur as an outcome from use of dopamine blocking medications. Orthostatic tremor most commonly is a disorder of unknown etiology that develops spontaneously in otherwise healthy individuals. While localization of its origin in the brain or spinal cord is not well understood, it lies presumably within the central nervous system. It is characterized by a tremor that affects the legs and lower trunk exclusively during upright posture. Patients described as developing drug-induced orthostatic tremor during exposure to metoclopramide, sulpiride, and thiethylperazine experienced full remission in three of four reported cases and marked improvement in the fourth case [16].

Tremor induced by anticonvulsant drugs

Drugs with anticonvulsant properties are widely used, in some instances for other approved or off-label indications in psychiatry and other fields of medicine. The use of these drugs as mood stabilizers for bipolar disorder may occur in patients previously treated with lithium salts, also a drug that commonly leads to drug-induced action tremor. Tremor is not produced by most of the anticonvulsant class drugs, however. Several of them, such as primidone, phenobarbital, and clonazepam, can be useful for treating essential tremor. However, among drugs often utilized for seizure control (and migraine prophylaxis), valproate is the one most likely to induce action tremor [17], [18]. An action tremor of the limbs is produced in up to one-quarter of all patients treated with conventional doses of valproate, and an even greater fraction of them will show the induction of tremor on sensitive recordings [19]. The tremor can be in the range of typical physiological tremor or up to 15 Hz and can also be associated with titubation of head, neck, and trunk [18]. In addition to action and postural tremor of the limbs, sometimes a resting tremor can be produced. Tremors caused by valproate can be suppressed by coadministration of other drugs including acetazolamide [20], amantadine, or propranolol [18]. In one report, a markedly asymmetrical tremor was described in a valproate-treated patient [21].

Other drugs with anticonvulsant properties also can produce relatively mild tremor in small fractions of patients receiving conventional doses. Among these are gabapentin, tiagabine, carbamazepine and related derivatives such as oxazepine, and lamotrigine. Reporting of tremor in placebo-controlled clinical trials has the potential for confounding by the not infrequent incidence of essential tremor and the target population of anticonvulsant therapy which commonly includes patients with injury to the nervous system (which can be another source of tremor). The properties of the various anticonvulsants vary substantially and so no clear mechanism of tremor induction can be gleaned from their pharmacological actions. In fact, the anticonvulsants topiramate and primidone can confer suppression of action and postural tremor in many patients affected with essential tremor.

Tremor induced by lithium salts

One of the most common sources of drug-induced tremor is lithium, generally formulated as lithium carbonate and administered today primarily for bipolar disorder. The tremor produced by lithium affects up to a third or more of patients receiving conventional doses (particularly in men and older patients) [22]; sometimes, the tremor is a dose-limiting side effect. Over time, the intensity of tremor can lessen [23] and the dosing can be adjusted in its timing and quantities to minimize the problems it can cause. The tremor can be both action and postural in affecting the limbs [24] and has shown a higher frequency (8–12 cycles per second) than in essential tremor [25]. In some instances, chronic use of lithium has resulted in enduring tremor even after discontinuation of the drug [26].

Tremor induced by antidepressant medications

Among drugs developed for treatment of depression, the idiosyncratic and dose-related generation of tremor has become well recognized as a side effect. These drugs can also exacerbate physiological tremor as well as preexisting with PD and essential tremor. Up to half of all patients treated with a member of this drug class experience a postural or action tremor. Some studies have suggested that tremor due to these drugs may have an origin in increased noradrenergic activity in the brain, and find that drugs with beta-receptor blocking properties can attenuate them [27]. Postural tremor rather than action or resting tremor has been emphasized as a predominant clinical feature in many of the reports describing the older class of antidepressant medications (such as amitriptyline, nortriptyline, and imipramine). The second generation of antidepressant medications, which includes compounds classified as selective serotonin reuptake inhibitors and selective serotonin-norepinephrine reuptake inhibitors, also are prone to causing dose-related tremor in many treated patients. Generally, the severity is no more than mild and its clinical manifestations resemble those of essential tremor, although its frequency may be greater in some cases. Persistence of the tremors has been described for several months after discontinuation of fluoxetine in one report [28].

Tremor induced by stimulant drugs

Drugs with sympathomimetic properties are well known to cause tremors either as a feature of excessive medication or even in therapeutic dosage. Since physiological tremor may also be driven in part by endogenous catecholamine actions similar to the effects of drugs like amphetamine, the mechanisms of tremor may be similar. Conventional therapy with the various drugs used for attention deficit disorder and hyperactivity syndrome does not generally lead to problematic occurrence of tremor in children or adults. Withdrawal of stimulant-class drugs for those individuals who were taking them in excess can result in markedly tremulous states.

Short- and longer-acting beta-adrenergic receptor agonists and various xanthine-structure compounds are routinely used in asthma therapeutics. These drugs share a structural similarity to caffeine, which also increases physiological tremor for some individuals (although not to the extent that popular myth sometimes implies [29]. Postural and action tremors are regularly encountered as dose-related effects of these drugs [30], possibly enhanced in some instances by a patient’s endogenous release of epinephrine and norepinephrine due to the stress of breathing difficulty. Whether these effects originate in the central nervous system or skeletal muscle (or both) is not fully understood. Hypokalemia may also be a risk factor for tremor [31]. The synergistic role of a substituted xanthine (aminophylline) in exacerbating action tremor has been demonstrated in essential tremor patients treated with this drug [32]. Another commonly-used class of drugs for obstructive pulmonary disease, beta-adrenergic receptor agonists, also are routinely observed to produce enhancement of physiological or essential tremor. Since the use of beta-adrenergic receptor blocking medications is contraindicated in their management, this side effect needs to be balanced by the effectiveness of the drug in each patient using them. With beta-2-adrenergic receptor agonists, up to 4% of treated asthma patients report the side effect of tremor. Fortunately, tolerance to repeated use of beta-2-adrenergic agonists rarely is a reason for discontinuation of this form of treatment [31].