• anxiety;
  • dopamine;
  • dopaminergic;
  • generalized anxiety disorder


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Abstract  The authors describe a 31-year-old woman who developed persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Independently of that, she had experienced a panic attack followed by dystonias, shortly after a single dose of that drug, 17 years before. Both temporal association and recurrence of anxiety symptoms after re-challenge with metoclopramide suggest a causal relationship. The case might provide an initial piece of evidence that dopaminergic neurotransmission can be involved in the pathogenesis of generalized anxiety disorder.


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Studies in animals,1–3 healthy volunteers,4,5 and patients6 suggest that the dopaminergic system is involved in the pathogenesis of anxiety. Little is known, however, about its potential role in generalized anxiety disorder.5

The dopamine antagonist metoclopramide is widely used as an antiemetic and prokinetic drug. Although its antipsychotic efficacy was found to be comparable to that of haloperidol7 it is not commonly used as an antipsychotic.8

Metoclopramide has been implicated in the induction of anxiety symptoms in a single case report so far in the literature.8 In the patient described there, panic and agoraphobia occurred several weeks after taking metoclopramide subsequent to an akathisia. The authors report a patient who developed persistent generalized anxiety following brief exposure to metoclopramide and who had experienced a panic attack after a single dose of that drug 17 years before. Informed consent for publication was given by the patient.


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During a long-distance trip, the patient, a 31-year-old woman, developed free-floating anxiety, breathlessness, agitation, epigastric discomfort, thirst followed by polydipsia and polyuria, severe sleep disturbances, intermitting dizziness, and difficulty concentrating, 2 h after taking metoclopramide 10 mg because of nausea due to a gastrointestinal infection. These symptoms continued for 6 days and were more pronounced at night-time. Symptoms were aggravated by taking metoclopramide 10 mg, 4 and 5 days after onset. When returning to her home country, thirst, polydipsia and polyuria spontaneously stopped. A water deprivation test was normal. Sleep disturbances ceased under treatment with mirtazapine 15 mg/day. However, anxiety, agitation, epigastric discomfort, intermitting breathlessness and dizziness as well as difficulty concentrating persisted. In addition, the patient worried about the future and not getting healthy again. Therefore, the patient was admitted to the Psychiatric Clinic of the Max Planck Institute of Psychiatry, Munich, Germany, 3.5 weeks later (about 5 weeks after onset of the complaints). On admission, other clinically relevant psychiatric symptoms (e.g. depressive symptoms) were not present. Physical (including neurological) examination, laboratory parameters (except bilirubin (1.7 mg/dL) and thyroid-stimulating hormone (4.69 μU/mL), electroencephalogram, and magnetic resonance imaging of the brain were without pathologic findings. Within 3 weeks, anxiety and accompanying physical symptoms largely remitted after increasing mirtazapine to 60 mg/day. However, subsequently, depressive symptoms (depressed mood, lack of energy, hopelessness) emerged. Mirtazapine 90 mg/day and transientadministration of lorazepam 2 mg/day were associated with a remission of the depressive symptoms within 3 weeks.

A total of 17 years before that, at age 14 years, the patient abruptly developed agitation, palpitations, breathlessness, fear of going crazy, sweating, dry mouth, and dizziness 2 h after taking a single dose of metoclopramide because of nausea due to a gastrointestinal infection. Some 60 min later, dystonic movements (retrocollis, oculogyric crisis) additionally occurred. Another 30 min later, symptoms ceased after administration of biperiden. The next day, an electroencephalogram was normal.

Apart from the two episodes described, the patients' remaining psychiatric history was negative for any affective, anxiety, psychotic, or substance abuse disorder. Her past medical history was unremarkable. Family psychiatric history was negative.


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  2. Abstract

The patient developed persistent free-floating anxiety, worry about the future and not getting healthy again, autonomic overactivity such as epigastric discomfort, and difficulty concentrating, consistent with the diagnosis of a generalized anxiety disorder as defined in the International Classification of Diseases 10th edition,9,10 shortly after brief exposure to metoclopramide. Independently of that, she had experienced anxiety and physical symptoms, judged as a panic attack followed by dystonias, after a single dose of this benzamide drug. Temporal association between anxiety symptoms and drug exposure, recurrence of anxiety symptoms after re-challenge with metoclopramide, and lack of a personal or family history of psychiatric diseases strongly suggest a causal relationship. These findings appear surprising, as other benzamides such as sulpiride or amisulpride have been shown to have antidepressant,11–13 and anxiolytic14 effects.

The reason why anxiety symptoms actually emerged in this patient and why they persisted for several weeks after last exposure to metoclopramide is not fully clear. Apart from a conceivable vulnerability of the patient, the gastrointestinal infection being present in both cases when anxiety symptoms emerged, might be of importance. Gastroenteritis can lead to a secretion of cytokines as part of the immune response.15,16 Cytokines in turn have been suggested to be mediators of psychiatric conditions such as depression17 or anxiety.18 However, this hypothesis is highly speculative. While drug-induced symptoms mostly disappear after drug discontinuation, some can last markedly longer, such as tardive dyskinesias19 or psychiatric symptoms (e.g. anxiety or depression).8 Those effects can be possibly explained by neural plasticity.17,20

Generalized anxiety was followed by depressive symptoms, fulfilling International Classification of Diseases 10th edition criteria of a depressive episode. Comorbidity of anxiety disorders with depression is very common. In generalized anxiety disorder, up to 50% of patients have been reported to concomitantly suffer from major depression.21 In the majority of those patients, generalized anxiety disorder preceded the major depression.22 Also, the patient reported here, developed depressive symptoms following generalized anxiety. Therefore, depression might well be considered sequela of the anxiety disorder. Otherwise, depression associated with metoclopramide has been repeatedly reported, however, mostly with chronic treatment.8

As yet, there is very little information suggesting an involvement of the dopamine system in generalized anxiety disorder.5 In contrast, several lines of evidence indicate that dopaminergic neurotransmission is relevant in social anxiety disorder (social phobia), which has been reported to co-occur in up to 59% of patients with generalized anxiety disorder.23 Various findings suggest a decreased dopamine function:

  • • 
    social anxiety was triggered in patients treated with dopamine antagonists;5
  • • 
    the dopamine metabolite homovanillic acid in cerebrospinal fluid was lower in patients with panic disorder who concomitantly suffered from social phobia than in those who did not;5
  • • 
    an association between social anxiety and subsequent risk of Parkinson's disease has been suggested;5
  • • 
    functional imaging studies showed a reduced density of dopamine reuptake sites5 and a lower striatal D2 receptor binding in patients with social phobia compared to healthy controls.6

Similarly, generalized anxiety in the patient described here, might have also been induced by dopaminergic hypofunction. This could also explain the beneficial effect of mirtazapine what has been repeatedly shown to increase dopaminergic neurotransmission.24–26

In conclusion, the case might provide an initial piece of evidence that the dopamine system can be involved in the pathogenesis of generalized anxiety disorder.


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  • 1
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    Mejia NI, Jankovic J. Metoclopramide-induced tardive dyskinesia in an infant. Mov. Disord. 2005; 20: 8689.
  • 20
    Hayase T, Yamamoto Y, Yamamoto K. Persistent anxiogenic effects of a single or repeated doses of cocaine and methamphetamine: Interactions with endogenous cannabinoid receptor ligands. Behav. Pharmacol. 2005; 16: 395404.
  • 21
    Stein DJ. Comorbidity in generalized anxiety disorder: Impact and implications. J. Clin. Psychiatry 2001; 62 (Suppl. 11): 2934.
  • 22
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  • 24
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  • 26
    Millan MJ, Gobert A, Rivet JM et al. Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: A comparison with citalopram. Eur. J. Neurosci. 2000; 12: 10791095.