1 BMC Psychiatry 2009 Vol: 9(1):16. DOI: 10.1186/1471-244X-9-16

Bipolar disorder and dopamine dysfunction: an indirect approach focusing on tardive movement syndromes in a naturalistic setting

It has been suggested that dopamine dysfunction may play a role in bipolar disorder (BD). An indirect approach to examine this issue was developed, focusing on associations between dopamine proxy measures observed in BD (dopamine-related clinical traits using tardive movement syndromes as dopamine proxy measure of reference). 3459 eligible bipolar patients were enrolled in an observational study. Incidence rates of tardive movement syndromes (tardive dyskinesia and tardive dystonia; TDD) were examined. A priori hypothesized associations between incident TDD and other dopamine proxies (e.g. prolactin-related adverse effects, bipolar symptoms) were tested over a 2 year follow-up period. The incidence rate of tardive syndromes was 4.1 %. Incident TDD was independently associated not only with use of antipsychotics, but also with more severe bipolar symptoms, other extrapyramidal symptoms and prolactin-related adverse effects of medication. Apart from the well-known association with antipsychotics, development of TDD was associated with various other dopamine proxy measures, indirectly supporting the notion of generalised dopamine dysregulation in BD.

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References
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    • . . . Even though a number of studies suggest that bipolar patients experience higher rates of EPS (parkinsonism, dystonia, akathisia) and TD compared to patients with a diagnosis of schizophrenia 12, research within the bipolar disorder (BD) population has been limited. . . .
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    • . . . Even though a number of studies suggest that bipolar patients experience higher rates of EPS (parkinsonism, dystonia, akathisia) and TD compared to patients with a diagnosis of schizophrenia 12, research within the bipolar disorder (BD) population has been limited. . . .
    • . . . Reported incidence rates of tardive syndromes in bipolar populations vary widely in the literature, probably due to variation in use of medication (type of antipsychotic, duration of exposure to lithium, polypharmacy), tardive syndrome definitions, characteristics of patient populations, study designs and mood state dependent fluctuations 2 . . .
    • . . . The association between more severe mania and TDD incidence may be considered surprising, as the limited reports available suggest a decrease of TD severity during manic episodes 2 . . .
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    • . . . Berk and colleagues, reviewing converging data on the role of dopamine (DA) in bipolar disorder, recently postulated the Dopamine Dysregulation Syndrome 3, based on a consilience approach using research from a diversity of domains, including preclinical, genetic, neuroimaging, pharmacological and clinical research . . .
    • . . . Up and down regulation may be mediated by endogenous homeostatic mechanisms; individual vulnerabilities exist to the hyper- and hypodopaminergic state, explaining the large inter-individual variability in illness course 3. . . .
    • . . . The Dopamine Dysregulation Syndrome, as applied to BD by Berk and colleagues 3, is currently limited to DA functioning in the mesolimbic tract, focusing on mania and depression . . .
    • . . . Obviously, epidemiological research is not the appropriate methodology to investigate these underlying mechanisms; more neuroimaging and pre-clinical data are needed to shed light on the nature and extent of DA dysfunction within the framework of the hypothesized dopamine dysregulation syndrome proposed by Berk and colleagues 3 as well as the extensions proposed in the current report. . . .
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    • . . . These may include, for example, presence of (i) prolactin-related adverse effects as a proxy for alterations in the tuberoinfundibular tract 4, ii) TD and EPS as proxies for alterations in the nigrostriatal DA tract 5 whereas (iii) psychotic 56, manic 7 and depressive 8 symptoms may reflect altered mesolimbic DA neurotransmission . . .
    • . . . Using these proxy measures in a prospective study of schizophrenia patients, Tenback and colleagues showed associations between incidence of TD on the one hand and occurrence of EPS 9, prolactin-related adverse effects 4 and worsening of psychotic symptoms on the other 6, suggesting general DA dysregulation across the different DA tracts in schizophrenia. . . .
    • . . . In order to test this hypothesis, DA dysfunction was examined in a sample of patients with bipolar disorder, using the proxy measures defined by Tenback et al 46 . . .
    • . . . In line with Tenback and colleagues 46, tardive movement syndromes formed the reference outcome for the analyses . . .
    • . . . Guided by previous analyses using these measures 4, movement disorder variables were analyzed as dichotomous indicators (0 = not present versus 1 = present; the latter combining scores of '1' and '2') . . .
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    • . . . These may include, for example, presence of (i) prolactin-related adverse effects as a proxy for alterations in the tuberoinfundibular tract 4, ii) TD and EPS as proxies for alterations in the nigrostriatal DA tract 5 whereas (iii) psychotic 56, manic 7 and depressive 8 symptoms may reflect altered mesolimbic DA neurotransmission . . .
    • . . . (i) Psychotic and manic symptoms may be associated with high DA transmission in the mesolimbic pathway 57 . . .
    • . . . Depression may be associated with lower DA transmission in the same tract, even though different receptor classes or sub-regions may be involved 58 . . .
    • . . . (iii) Extrapyramidal symptoms, including TD, have been hypothesized to reflect low DA transmission in the nigrostriatal DA tract in the brain 5 . . .
    • . . . (iv) Use of antipsychotics (APs) is known to affect dopamine transmission 21 and in addition is strongly associated with TD 5 . . .
    • . . . It is widely accepted that antipsychotic use and lithium in itself are associated with an increased risk for developing movement disorders and other adverse effects 5 . . .
    • . . . The association between EPS and TDD was anticipated based on similar findings in schizophrenia 9, and the fact that extrapyramidal symptom clusters in general have been linked to low DA transmission in the nigrostriatal tract 5 . . .
    • . . . Associations between measures of sexual dysfunction and TDD are somewhat more complex as they imply the involvement of different tracts; they are, however, both associated with relatively low DA transmission 51920. . . .
    • . . . Manic symptoms, similar to psychotic symptoms, have been linked to the mesolimbic DA tract 57, suggesting that this theory may be extrapolated to the mania symptom cluster as well . . .
    • . . . Tardive dyskinesia has been reported to abate after dose increases 34, usually to reappear after some time, whereas acute dystonia often emerges following dose increases 5 . . .
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    • . . . These may include, for example, presence of (i) prolactin-related adverse effects as a proxy for alterations in the tuberoinfundibular tract 4, ii) TD and EPS as proxies for alterations in the nigrostriatal DA tract 5 whereas (iii) psychotic 56, manic 7 and depressive 8 symptoms may reflect altered mesolimbic DA neurotransmission . . .
    • . . . Using these proxy measures in a prospective study of schizophrenia patients, Tenback and colleagues showed associations between incidence of TD on the one hand and occurrence of EPS 9, prolactin-related adverse effects 4 and worsening of psychotic symptoms on the other 6, suggesting general DA dysregulation across the different DA tracts in schizophrenia. . . .
    • . . . In order to test this hypothesis, DA dysfunction was examined in a sample of patients with bipolar disorder, using the proxy measures defined by Tenback et al 46 . . .
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    • . . . These may include, for example, presence of (i) prolactin-related adverse effects as a proxy for alterations in the tuberoinfundibular tract 4, ii) TD and EPS as proxies for alterations in the nigrostriatal DA tract 5 whereas (iii) psychotic 56, manic 7 and depressive 8 symptoms may reflect altered mesolimbic DA neurotransmission . . .
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    • . . . These may include, for example, presence of (i) prolactin-related adverse effects as a proxy for alterations in the tuberoinfundibular tract 4, ii) TD and EPS as proxies for alterations in the nigrostriatal DA tract 5 whereas (iii) psychotic 56, manic 7 and depressive 8 symptoms may reflect altered mesolimbic DA neurotransmission . . .
    • . . . Depression may be associated with lower DA transmission in the same tract, even though different receptor classes or sub-regions may be involved 58 . . .
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    • . . . Using these proxy measures in a prospective study of schizophrenia patients, Tenback and colleagues showed associations between incidence of TD on the one hand and occurrence of EPS 9, prolactin-related adverse effects 4 and worsening of psychotic symptoms on the other 6, suggesting general DA dysregulation across the different DA tracts in schizophrenia. . . .
    • . . . Research indicates that EPS (defined as parkinsonism, akathisia and acute dystonia) represents a vulnerability to develop tardive movement disorders, in particular tardive dyskinesia, in patients with schizophrenia 9. . . .
    • . . . The association between EPS and TDD was anticipated based on similar findings in schizophrenia 9, and the fact that extrapyramidal symptom clusters in general have been linked to low DA transmission in the nigrostriatal tract 5 . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
    • . . . The reported incidences for tardive dystonia and TD were 0.7%, and 10.2%, respectively 13, whereas in our sample tardive dystonia had a higher incidence than TD . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
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    • . . . The rational for combining TD and dystonia comes from (i) their strong association 1213, (ii) shared risk factors and mechanisms 1415 and (iii) the fact that existing scales measuring tardive syndromes do not differentiate between TD and tardive dystonia 1617 . . .
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    • . . . (ii) Both amenorrhea and sexual dysfunction are associated with elevated prolactin levels induced by low DA transmission 1920 originating in the tuberoinfundibular DA tract . . .
    • . . . This link is likely stronger for amenorrhea, as sexual disturbances in patients with schizophrenia are of multifactorial origin, and are therefore only in part attributable to illness- or medication-related prolactin levels 1920 . . .
    • . . . Associations between measures of sexual dysfunction and TDD are somewhat more complex as they imply the involvement of different tracts; they are, however, both associated with relatively low DA transmission 51920. . . .
    • . . . For instance, use of concomitant medication or antagonism of other receptors by APs may affect sexual dysfunction 1920. . . .
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    • . . . (ii) Both amenorrhea and sexual dysfunction are associated with elevated prolactin levels induced by low DA transmission 1920 originating in the tuberoinfundibular DA tract . . .
    • . . . This link is likely stronger for amenorrhea, as sexual disturbances in patients with schizophrenia are of multifactorial origin, and are therefore only in part attributable to illness- or medication-related prolactin levels 1920 . . .
    • . . . Associations between measures of sexual dysfunction and TDD are somewhat more complex as they imply the involvement of different tracts; they are, however, both associated with relatively low DA transmission 51920. . . .
    • . . . For instance, use of concomitant medication or antagonism of other receptors by APs may affect sexual dysfunction 1920. . . .
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    • . . . (iv) Use of antipsychotics (APs) is known to affect dopamine transmission 21 and in addition is strongly associated with TD 5 . . .
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    • . . . The following confounders were introduced in the Cox regression models: social economic status (SES, expressed as educational achievement; 1 = no education, 2 = primary school, 3 = secondary school lower, 4 = secondary school upper, 5 = post-secondary vocational training, 6 = university), country, compliance (0 = no medication prescribed or always complies; 1 = never complies or 50% of the time), age per decade 2223, age of onset in years 24, gender 2325 and duration of illness in years 26 . . .
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    • . . . The following confounders were introduced in the Cox regression models: social economic status (SES, expressed as educational achievement; 1 = no education, 2 = primary school, 3 = secondary school lower, 4 = secondary school upper, 5 = post-secondary vocational training, 6 = university), country, compliance (0 = no medication prescribed or always complies; 1 = never complies or 50% of the time), age per decade 2223, age of onset in years 24, gender 2325 and duration of illness in years 26 . . .
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    • . . . The following confounders were introduced in the Cox regression models: social economic status (SES, expressed as educational achievement; 1 = no education, 2 = primary school, 3 = secondary school lower, 4 = secondary school upper, 5 = post-secondary vocational training, 6 = university), country, compliance (0 = no medication prescribed or always complies; 1 = never complies or 50% of the time), age per decade 2223, age of onset in years 24, gender 2325 and duration of illness in years 26 . . .
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    • . . . The following confounders were introduced in the Cox regression models: social economic status (SES, expressed as educational achievement; 1 = no education, 2 = primary school, 3 = secondary school lower, 4 = secondary school upper, 5 = post-secondary vocational training, 6 = university), country, compliance (0 = no medication prescribed or always complies; 1 = never complies or 50% of the time), age per decade 2223, age of onset in years 24, gender 2325 and duration of illness in years 26 . . .
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    • . . . The use of the propensity score has been suggested as a means to obtain more complete control in these circumstances 27 . . .
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    • . . . The propensity score for an individual, defined as the conditional probability of (in this case) developing TDD given the individual's covariates, can be used to balance the covariates in observational studies, and thus reduce bias 28 . . .
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    • . . . All analyses were performed using the computer package STATA, version 10.0 29. . . .
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    • . . . Consequently, misclassification of the acute form of dystonia, which usually has an onset within 5 days of new antipsychotic treatment 30, could be ruled out with even more confidence. . . .
    • . . . However, the Curacao study also reported that the incidence of tardive dystonia diminished over time, whereas the risk of TD followed an inverse pattern 30 . . .
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    • . . . Indeed, the incidence rate for tardive dystonia in the current study (3.3%; 2.3% when a stricter definition was applied), approximates the 3% incidence rate reported for patients on long-term antipsychotic treatment in a review by Van Harten et al. 31 . . .
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    • . . . One might argue that the increase in psychotic symptoms and the emergence of TDD may be occasioned simultaneously by withdrawal of APs 32 . . .
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    • . . . It may be attractive to speculate, in combination with the association found between TDD and psychotic symptoms, that this finding can be explained using the concept of 'supersensitivity psychosis', which postulates that psychotic symptoms may be produced by increased sensitivity of DA receptors in the mesolimbic tract 33 . . .
  34. H Nasrallah Focus on lower risk of tardive dyskinesia with atypical antipsychotics Annals of Clinical Psychiatry 18, 57-62 (2006) .
    • . . . Tardive dyskinesia has been reported to abate after dose increases 34, usually to reappear after some time, whereas acute dystonia often emerges following dose increases 5 . . .
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