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Regular Article   |    
Clinical Features and Comorbidity of Mood Fluctuations in Parkinson's Disease
Brad A. Racette, M.D.; Johanna M. Hartlein, R.N., B.S.N.; Tamara Hershey, Ph.D.; Jonathan W. Mink, M.D., Ph.D.; Joel S. Perlmutter, M.D.; Kevin J. Black, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2002;14:438-442. doi:10.1176/appi.neuropsych.14.4.438
View Author and Article Information

Parkinson's Disease

Received July 10, 2001; accepted September 18, 2001. From the Departments of Neurology & Neurological Surgery (b.a.r., j.w.m., j.s.p., k.j.b.), Anatomy & Neurobiology (j.w.m., j.s.p.), Pediatrics (j.w.m.), and Psychiatry (j.m.h., t.h., k.j.b.) and the Mallinckrodt Institute of Radiology (j.s.p., k.j.b.), Washington University School of Medicine, St. Louis, Missouri; and the American Parkinson Disease Association Advanced Center for Parkinson Research (all authors). Address correspondence to Dr. Racette, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110. E-mail: racetteb@neuro.wustl.edu.

Parkinson's disease (PD) patients commonly develop fluctuations in their motor responses to levodopa within several years of initiation of treatment; some also develop nonmotor fluctuations. The authors performed a case-control study comparing the frequency of comorbid symptoms in 70 PD patients who experienced clinically apparent mood changes during their motor "on" or "off" states with two control groups with no mood fluctuations. Mood fluctuators had significantly younger age at onset and longer disease duration and were significantly more likely to have dementia, psychosis, clinical depression, and motor complications. This association remained after removing effects of age and disease duration.

Abstract Teaser
Figures in this Article

Initially, treatment of Parkinson's disease (PD) with levodopa ameliorates the symptoms of bradykinesia, tremor, rigidity, and postural instability.1 However, complications often accompany progression of disease and continued treatment. One such complication is increasingly shorter duration of motor benefit from each dose of levodopa, leading to frequent "off" periods with increased parkinsonian symptoms during the course of the day.

Although fluctuations in response to levodopa are typically defined by changes in motor signs, autonomic and psychological fluctuations may occur.2,3 Some degree of sadness during times of motor dysfunction is not surprising, and many patients with motor fluctuations report worse mood when "off" than when "on."410 However, a minority of patients develop clinically significant off-period depression.26,11,12 Akathisia or anxiety may accompany these brief periods of depression,3,7,8,13,14 and some patients also have on-period manic symptoms.2,4,5,12,15 These more severe mood fluctuations may produce more disability than motor fluctuations for some patients.16

Although mood fluctuations in PD have been reported for decades, our understanding of them remains limited.17 Many authors describe mild changes that remain within the normal range.6,9,18,19 Most reports of clinically significant mood changes do not allow an estimate of prevalence.24,11,12 Although mood fluctuation can be distinguished phenomenologically from the typical persistent sadness of major depression or the steady high of mania,20 it is not clear whether levodopa-related mood fluctuation occurs more frequently in patients who have had major depression. In addition, there is little information about neuropsychiatric or motor comorbidity associated with mood fluctuations; the existing literature consists almost exclusively of small studies.13,21

As a first step toward addressing some of these questions, we reviewed our experience at the Washington University School of Medicine Movement Disorders Center. We looked for evidence from existing clinical records that would address the relationship of clinically apparent mood fluctuations to other psychiatric illness and to parkinsonian motor features.

+

Procedures

The Washington University School of Medicine Human Studies Committee approved these studies. Movement disorders specialists at the Washington University Movement Disorders Center examined all patients and recorded all clinical information, including medical history and general and neurological examinations, in an electronic records system. Between 1996 and 2000, we evaluated 1,063 new parkinsonian patients, including both unselected (self-referred) and physician-referred patients.

In 1996, the authors began recording diagnoses of "PD with motor fluctuations" or "PD with mood fluctuations" in patients' medical records. For this report, we carefully reviewed the complete medical records of all patients with either of these diagnoses, together with all medical records in which the following words occurred in the history, assessment, or recommendation sections: "mood fluctuations," depression, anxiety, or hypomania. From this sample we identified patients with clinically significant mood fluctuations. Because the data were obtained for clinical purposes and reviewed retrospectively, the phenomenology of anxiety, depression, or mania is not always recorded in detail. Thus for many patients it is not known whether the patient experienced 5 of 9 criterion A symptoms of the DSM-IV major depressive syndrome during "off" periods,22 or the corresponding syndromal criteria for anxiety or mania. For the purpose of this study, we diagnosed "clinically significant mood fluctuations" only in patients with depressive, anxious, or manic symptoms that were a focus of clinical concern and were consistently associated with expected peaks or nadirs of levodopa dosing. In each case, 1) the treating physician believed the mood complaints were clinically meaningful, and 2) the reviewing physician agreed that the patient's symptoms corresponded to DSM-IV diagnoses of "anxiety disorder due to a general medical condition" or "mood disorder due to a general medical condition" (with depressive or manic features).23 Mood fluctuations were classified by the reviewing physician as "on-" or "off-period" depending on the association with levodopa dose schedule and the motor symptoms experienced by the patient at the time of the mood symptoms.

We defined disease severity with the modified Hoehn and Yahr scale24 at the most recent rating; dementia (of any etiology) according to DSM-IV;23 and psychosis as one or more episodes of visual or auditory hallucinations. The age at onset of parkinsonism was defined as the age at which patients developed their first symptoms. Clinical depression refers to steady (not fluctuating with levodopa) sadness or anhedonia that was severe enough to require antidepressant treatment.

Two control groups were compared with the mood fluctuators. The first control group consisted of 100 consecutively ascertained PD patients selected only for the absence of mood fluctuations. The second control group consisted of 70 consecutively ascertained PD patients with motor fluctuations but no mood fluctuations. All control subjects were evaluated in a similar manner to the cases. The first 44 subjects in the motor fluctuator control group were included in the consecutively ascertained control group.

+

Statistical Analysis

Age at onset and duration of disease were compared in the mood fluctuators and control subjects with a two-tailed, unpaired t-test. The distributions of the Hoehn and Yahr stage in the three groups were compared by using a Mann-Whitney U test. We used a chi-square analysis to compare the frequency of individual clinical features between control subjects and mood fluctuators. A Bonferroni correction was applied to correct for multiple comparisons: all P-values obtained from comparison of clinical features were multiplied by 9 in the comparison of mood fluctuators and sequentially ascertained control subjects and by 4 in the comparison of mood fluctuators and motor fluctuators. To compute logistic regression models in the comparison of motor and mood fluctuators, we used SPSS version 7.5 (SPSS, Inc., Chicago, IL), using as dependent variables presence or absence of psychosis, dementia, or clinical depression. Age at onset and duration of illness were entered first, and the question of interest was the statistical significance of the residual effect of group (mood fluctuators vs. motor-only fluctuators), reported as estimated odds ratios and 95% confidence intervals.

We identified 70 patients with clinically significant mood fluctuations corresponding to their motor "off" or "on" states. This represented 6.6% of all parkinsonian patients evaluated during the five-year period covered by the study.

Patients with mood fluctuation developed PD symptoms earlier than the sequentially ascertained control subjects but not the motor fluctuator control subjects, and they had a longer duration of disease than either control group (t1). There were no differences between mood fluctuators and either control group in gender or in disease severity as measured by the modified Hoehn and Yahr scale.

There was no significant difference in the frequency of tremor, rigidity, or bradykinesia between the mood fluctuators and consecutively ascertained control subjects. There was a trend toward increased frequency of postural instability in the mood fluctuators, but this difference was not significant after accounting for multiple comparisons (t2).

All 70 patients with mood fluctuations also had fluctuations of motor response to levodopa. Mood fluctuations occurred in either the "on" or "off" states and included off-period anxiety (81%), off-period depressive symptoms (63%), and on-period hypomania (24%). There was a significant association between motor and mood fluctuations in the mood fluctuators when compared with the sequentially ascertained control subjects. (t3). Dementia, nonfluctuating clinical depression, and psychosis were significantly associated with mood fluctuations in the mood fluctuators when compared with sequentially ascertained control subjects (t4).

To determine if the presence of motor fluctuations accounted for the association of dementia, depression, and psychosis in patients with levodopa-related mood fluctuations, we compared the frequency of these neuropsychiatric complications in mood fluctuators with their frequency in the group of PD patients having only motor fluctuations. Dyskinesias occurred more frequently in mood fluctuators compared with motor fluctuator control subjects (t3). Dementia, nonfluctuating clinical depression, and psychosis were significantly associated with mood fluctuators when compared with motor fluctuator control subjects (t4). These associations remained significant after correcting for age at onset and duration of disease, as shown by the following odds ratios (and 95% confidence intervals) for presence of each syndrome in patients with mood fluctuations versus patients with only motor fluctuations: psychosis, 2.45 (1.18—5.09); dementia, 3.24 (1.35—7.81); and clinical depression, 12.33 (5.32—28.56). Thus, even after we accounted for age at onset, duration of illness, and presence of motor fluctuations, patients with clinically important mood fluctuations were substantially more likely than other patients with PD to have experienced psychosis, dementia, or nonfluctuating clinical depression.

Our study provides a reasonable estimate of the prevalence of clinically significant mood fluctuations (7%) in a general, clinical PD population. The patients we diagnosed with mood fluctuations were those with clinically apparent change in mood associated with individual levodopa doses; these methods likely underestimate the role of levodopa in persistent mood changes in PD. One study using intravenous levodopa found "off-period" depressive symptoms in 18 of 20 patients after discontinuation of intravenous infusion.5

We found that mood fluctuations occurred more frequently in patients with younger age at onset. This finding may be due to the more frequent association of young-onset disease with motor fluctuations,25 as supported by our finding that mood fluctuations were strongly associated with motor fluctuations. We also found a strong association between mood fluctuations and psychosis, dementia, and nonfluctuating clinical depression, even when mood fluctuators (who all had motor fluctuations) were compared with other motor-fluctuating patients. This association suggests that mood fluctuations may occur more commonly in patients in whom the PD pathology involves cortical or mesolimbic areas.26

The timing of mood responses to levodopa infusion, the lack of mood fluctuations with placebo infusion, and the lack of similar mood fluctuations in arthritic patients with similar severity of motor fluctuations all suggest that mood fluctuation can be a direct effect of dopamine denervation and levodopa therapy on mood rather than a secondary change associated with relief of motor symptoms.79,27 There is substantial support for the idea that dopamine-influenced neuronal pathways can affect mood.

The most common type of mood fluctuation in our patients was off-period anxiety.13 Several lines of evidence implicate abnormal dopamine function in anxiety.28 School phobia is associated with a dopamine transporter allele.29 Patients with social phobia have decreased binding of striatal dopaminergic ligands, whether assessed with presynaptic or postsynaptic markers,30,31 despite similar striatal volume.32 Clinically, acute impairment of dopaminergic neurotransmission produces anxious discomfort as part of akathisia and can cause school phobia in patients with Tourette syndrome.33 Steady anxiety is common in Parkinson's disease; one study (presented as a conference paper) reported a 58% prevalence of lifetime DSM-IV anxiety disorders in Parkinson's disease patients, compared with 33% in neurological control subjects.34 Our findings provide additional support for the relevance of dopamine to the control of anxiety.

Dopamine also has well-known effects on the core behavioral symptoms involved in major depression, such as appetitive approach and the association of specific activities with pleasurable reward.35,36 Animal models of "depression" demonstrate deficient dopaminergic transmission.37,38 In humans, links between dopamine and idiopathic major depression are modest.39,40 However, factors related to parkinsonism, prolonged dopaminergic treatment, or both may constitute a permissive state allowing acute decreases in dopaminergic transmission to depress mood. Major depression is common in PD41,42 and is accompanied by preferential loss of neurons in ventral tegmental area26 and by defects in prefrontal cortex blood flow and metabolism.43,44

One-quarter of patients with mood fluctuations had clinically significant on-period manic features, including abnormally elevated mood, grandiosity, hypersexuality, impulsivity, or decreased need for sleep. All but one of these patients also had levodopa-induced dyskinesias. These findings are consistent with previous reports associating mania with excess dopaminergic stimulation or hyperkinetic movement disorders.15,45 PD and its treatment result in a unique combination of a dopamine-deficient untreated state and therapeutic dopaminergic excesses, and our study demonstrates the critical balance required in dopaminergic treatment.

This work was supported by National Institutes of Health Grants NS01808 and NS01898 and by the National Alliance for Research on Schizophrenia and Depression, the American Parkinson Disease Association, the Tourette Syndrome Association, the Charles A. Dana Foundation, and the McDonnell Center for the Study of Higher Brain Function. The work was presented at the 6th International Congress of Movement Disorders, Barcelona, Spain, June 11—15, 2000.

Cotzias GC, van Woert HH, Schiffer LM: Aromatic amino acids and modifications of parkinsonism. N Engl J Med  1967; 276:374-379
[CrossRef] | [PubMed]
 
Lees AJ: The on-off phenomenon. J Neurol Neurosurg Psychiatry 1989; 52(suppl):29-37
 
Riley DE, Lang AE: The spectrum of levodopa-related fluctuations in Parkinson's disease. Neurology  1993; 43:1459-1464
[PubMed]
 
Nissenbaum H, Quinn NP, Brown RG, et al: Mood swings associated with the "on-off" phenomenon in Parkinson's disease. Psychol Med  1987; 17:899-904
[CrossRef] | [PubMed]
 
Hardie RJ, Lees AJ, Stern GM: On-off fluctuations in Parkinson's disease: a clinical and neuropharmacological study. Brain  1984; 107:487-506
[CrossRef] | [PubMed]
 
Menza MA, Sage J, Marshall E, et al: Mood changes and "on-off" phenomena in Parkinson's disease. Mov Disord  1990; 5:148-151
[CrossRef] | [PubMed]
 
Maricle RA, Nutt JG, Carter JH: Mood and anxiety fluctuation in Parkinson's disease associated with levodopa infusion: preliminary findings. Mov Disord  1995; 10:329-332
[CrossRef] | [PubMed]
 
Maricle RA, Nutt JG, Valentine RJ, et al: Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson's disease: a double-blind, placebo-controlled study. Neurology  1995; 45:1757-1760
[PubMed]
 
Maricle RA, Valentine RJ, Carter J, et al: Mood response to levodopa infusion in early Parkinson's disease. Neurology  1998; 50:1890-1892
[PubMed]
 
Richard IH, Justus AW, Kurlan R: Relationship between mood and motor fluctuations in Parkinson's disease. J Neuropsychiatry Clin Neurosci  2001; 13:35-41
[CrossRef] | [PubMed]
 
Damásio AR, Lobo-Antunes J, Macedo C: Psychiatric aspects in parkinsonism treated with l-dopa. J Neurol Neurosurg Psychiatry  1971; 34:502-507
[CrossRef] | [PubMed]
 
Keshavan MS, David AS, Narayanen HS, et al: "On-off" phenomena and manic-depressive mood shifts: case report. J Clin Psychiatry  1986; 47:93-94
[PubMed]
 
Vázquez A, Jiménez-Jiménez FJ, García-Ruiz P, et al: "Panic attacks" in Parkinson's disease. Acta Neurol Scand  1993; 87:14-18
[CrossRef] | [PubMed]
 
Siemers ER, Shekhar A, Quaid K, et al: Anxiety and motor performance in Parkinson's disease. Mov Disord  1993; 8:1-6
[CrossRef] | [PubMed]
 
Goodwin FK: Biochemical and pharmacological studies, in Manic-Depressive Illness, edited by Goodwin FK, Jamison KR. New York, Oxford University Press, 1990, pp 416-502
 
Kaphan E, Witjas T, Azulay JP, et al: Nonmotor fluctuations (NMF) in Parkinson's disease (abstract). Neurology 2001; 56(suppl 3):A121
 
Black KJ, Mink JW: Neuropsychiatry of movement disorders. Curr Opin Psychiatry  1999; 12:313-319
[CrossRef]
 
Brown RG, Marsden CD, Quinn N, et al: Alterations in cognitive performance and affect-arousal state during fluctuations in motor function in Parkinson's disease. J Neurol Neurosurg Psychiatry  1984; 47:454-465
[CrossRef] | [PubMed]
 
Henderson R, Kurlan R, Kersun JM, et al: Preliminary examination of the comorbidity of anxiety and depression in Parkinson's disease. J Neuropsychiatry Clin Neurosci  1992; 4:257-264
[PubMed]
 
Friedenberg DL, Cummings JL: Parkinson's disease, depression, and the on-off phenomenon. Psychosomatics  1989; 30:94-99
[PubMed]
 
Menza M, Forman N, Sage J, et al: Psychiatric symptoms in Parkinson's disease: a comparison between patients with and without "on-off" symptoms. Biol Psychiatry  1993; 33:682-684
[CrossRef] | [PubMed]
 
Black KJ: Diagnosing depression after stroke. South Med J  1995; 88:699-708
[CrossRef] | [PubMed]
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Fahn S, Elton RL, Members of the UPDRS Development Committee: Unified Parkinson's Disease Rating Scale, in Recent Developments in Parkinson's Disease, edited by Fahn S, Marsden CD, Goldstein M et al. New York, Macmillan, 1987, pp 153-163
 
Quinn N, Critchley P, Marsden CD: Young onset Parkinson's disease. Mov Disord  1987; 2:73-91
[CrossRef] | [PubMed]
 
Torack RM, Morris JC: The association of ventral tegmental area histopathology with adult dementia. Arch Neurol  1988; 45:497-501
[PubMed]
 
Cantello R, Gilli M, Riccio A, et al: Mood changes associated with "end-of-dose deterioration" in Parkinson's disease: a controlled study. J Neurol Neurosurg Psychiatry  1986; 49:1182-1190
[CrossRef] | [PubMed]
 
Potts NL, Book S, Davidson JR: The neurobiology of social phobia. Int Clin Psychopharmacol  1996; 11:43-48
[CrossRef] | [PubMed]
 
Rowe DC, Stever C, Gard JM, et al: The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children. Behav Genet  1998; 28:215-225
[CrossRef] | [PubMed]
 
Tiihonen J, Kuikka J, Bergstrom K, et al: Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry  1997; 154:239-242
[PubMed]
 
Schneier FR, Liebowitz MR, Abi-Dargham A, et al: Low dopamine D2 receptor binding potential in social phobia. Am J Psychiatry  2000; 157:457-459
[CrossRef] | [PubMed]
 
Potts NL, Davidson JR, Krishnan KR, et al: Magnetic resonance imaging in social phobia. Psychiatry Res  1994; 52:35-42
[CrossRef] | [PubMed]
 
Mikkelsen EJ, Detlor J, Cohen DJ: School avoidance and social phobia triggered by haloperidol in patients with Tourette's disorder. Am J Psychiatry  1981; 138:1572-1576
[PubMed]
 
Kormos TC, Meah Y, Miyawaki E, et al: Social phobia in Parkinson's disease (abstract). Mov Disord  1996; 11:601-602
 
Schultz W: Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol  1997; 7:191-197
[CrossRef] | [PubMed]
 
Jackson DM, Westlind-Danielsson A: Dopamine receptors: molecular biology, biochemistry and behavioral aspects. Pharmacol Ther  1994; 64:291-369
[CrossRef] | [PubMed]
 
Gambarana C, Ghiglieri O, Tagliamonte A, et al: Crucial role of D1 dopamine receptors in mediating the antidepressant effect of imipramine. Pharmacol Biochem Behav  1995; 50:147-151
[CrossRef] | [PubMed]
 
Willner P: Sensitization of dopamine D2- or D3-type receptors as a final common pathway in antidepressant drug action. Clin Neuropharmacol 1995; 18:S49-S56
 
Bunney WE, Janowsky DS, Goodwin FK, et al: Effect of l-dopa on depression. Lancet  1969; 1:885-886
[PubMed]
 
Währens J, Gerlach J: Bromocriptine and imipramine in endogenous depression: a double-blind controlled trial in out-patients. J Affect Disord  1981; 3:193-202
[CrossRef] | [PubMed]
 
Cummings JL: Depression and Parkinson's disease: a review. Am J Psychiatry  1992; 149:443-454
[PubMed]
 
Meah Y, Miyawaki E, Kormos TC, et al: Depression in Parkinson's disease: a meta-analysis regarding severity (abstract). Mov Disord  1996; 11:159
 
Mayberg HS, Solomon DH: Depression in Parkinson's disease: a biochemical and organic viewpoint, in Behavioral Neurology of Movement Disorders, edited by Weiner WJ, Lang AE. New York, Raven, 1995, pp 49-60
 
Ring HA, Bench CJ, Trimble MR, et al: Depression in Parkinson's disease: a positron emission study. Br J Psychiatry  1994; 165:333-339
[CrossRef] | [PubMed]
 
Black KJ, Perlmutter JS: Septuagenarian Sydenham's with secondary hypomania. Neuropsychiatry Neuropsychol Behav Neurol  1997; 10:147-150
[PubMed]
 
+

References

Cotzias GC, van Woert HH, Schiffer LM: Aromatic amino acids and modifications of parkinsonism. N Engl J Med  1967; 276:374-379
[CrossRef] | [PubMed]
 
Lees AJ: The on-off phenomenon. J Neurol Neurosurg Psychiatry 1989; 52(suppl):29-37
 
Riley DE, Lang AE: The spectrum of levodopa-related fluctuations in Parkinson's disease. Neurology  1993; 43:1459-1464
[PubMed]
 
Nissenbaum H, Quinn NP, Brown RG, et al: Mood swings associated with the "on-off" phenomenon in Parkinson's disease. Psychol Med  1987; 17:899-904
[CrossRef] | [PubMed]
 
Hardie RJ, Lees AJ, Stern GM: On-off fluctuations in Parkinson's disease: a clinical and neuropharmacological study. Brain  1984; 107:487-506
[CrossRef] | [PubMed]
 
Menza MA, Sage J, Marshall E, et al: Mood changes and "on-off" phenomena in Parkinson's disease. Mov Disord  1990; 5:148-151
[CrossRef] | [PubMed]
 
Maricle RA, Nutt JG, Carter JH: Mood and anxiety fluctuation in Parkinson's disease associated with levodopa infusion: preliminary findings. Mov Disord  1995; 10:329-332
[CrossRef] | [PubMed]
 
Maricle RA, Nutt JG, Valentine RJ, et al: Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson's disease: a double-blind, placebo-controlled study. Neurology  1995; 45:1757-1760
[PubMed]
 
Maricle RA, Valentine RJ, Carter J, et al: Mood response to levodopa infusion in early Parkinson's disease. Neurology  1998; 50:1890-1892
[PubMed]
 
Richard IH, Justus AW, Kurlan R: Relationship between mood and motor fluctuations in Parkinson's disease. J Neuropsychiatry Clin Neurosci  2001; 13:35-41
[CrossRef] | [PubMed]
 
Damásio AR, Lobo-Antunes J, Macedo C: Psychiatric aspects in parkinsonism treated with l-dopa. J Neurol Neurosurg Psychiatry  1971; 34:502-507
[CrossRef] | [PubMed]
 
Keshavan MS, David AS, Narayanen HS, et al: "On-off" phenomena and manic-depressive mood shifts: case report. J Clin Psychiatry  1986; 47:93-94
[PubMed]
 
Vázquez A, Jiménez-Jiménez FJ, García-Ruiz P, et al: "Panic attacks" in Parkinson's disease. Acta Neurol Scand  1993; 87:14-18
[CrossRef] | [PubMed]
 
Siemers ER, Shekhar A, Quaid K, et al: Anxiety and motor performance in Parkinson's disease. Mov Disord  1993; 8:1-6
[CrossRef] | [PubMed]
 
Goodwin FK: Biochemical and pharmacological studies, in Manic-Depressive Illness, edited by Goodwin FK, Jamison KR. New York, Oxford University Press, 1990, pp 416-502
 
Kaphan E, Witjas T, Azulay JP, et al: Nonmotor fluctuations (NMF) in Parkinson's disease (abstract). Neurology 2001; 56(suppl 3):A121
 
Black KJ, Mink JW: Neuropsychiatry of movement disorders. Curr Opin Psychiatry  1999; 12:313-319
[CrossRef]
 
Brown RG, Marsden CD, Quinn N, et al: Alterations in cognitive performance and affect-arousal state during fluctuations in motor function in Parkinson's disease. J Neurol Neurosurg Psychiatry  1984; 47:454-465
[CrossRef] | [PubMed]
 
Henderson R, Kurlan R, Kersun JM, et al: Preliminary examination of the comorbidity of anxiety and depression in Parkinson's disease. J Neuropsychiatry Clin Neurosci  1992; 4:257-264
[PubMed]
 
Friedenberg DL, Cummings JL: Parkinson's disease, depression, and the on-off phenomenon. Psychosomatics  1989; 30:94-99
[PubMed]
 
Menza M, Forman N, Sage J, et al: Psychiatric symptoms in Parkinson's disease: a comparison between patients with and without "on-off" symptoms. Biol Psychiatry  1993; 33:682-684
[CrossRef] | [PubMed]
 
Black KJ: Diagnosing depression after stroke. South Med J  1995; 88:699-708
[CrossRef] | [PubMed]
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Fahn S, Elton RL, Members of the UPDRS Development Committee: Unified Parkinson's Disease Rating Scale, in Recent Developments in Parkinson's Disease, edited by Fahn S, Marsden CD, Goldstein M et al. New York, Macmillan, 1987, pp 153-163
 
Quinn N, Critchley P, Marsden CD: Young onset Parkinson's disease. Mov Disord  1987; 2:73-91
[CrossRef] | [PubMed]
 
Torack RM, Morris JC: The association of ventral tegmental area histopathology with adult dementia. Arch Neurol  1988; 45:497-501
[PubMed]
 
Cantello R, Gilli M, Riccio A, et al: Mood changes associated with "end-of-dose deterioration" in Parkinson's disease: a controlled study. J Neurol Neurosurg Psychiatry  1986; 49:1182-1190
[CrossRef] | [PubMed]
 
Potts NL, Book S, Davidson JR: The neurobiology of social phobia. Int Clin Psychopharmacol  1996; 11:43-48
[CrossRef] | [PubMed]
 
Rowe DC, Stever C, Gard JM, et al: The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children. Behav Genet  1998; 28:215-225
[CrossRef] | [PubMed]
 
Tiihonen J, Kuikka J, Bergstrom K, et al: Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry  1997; 154:239-242
[PubMed]
 
Schneier FR, Liebowitz MR, Abi-Dargham A, et al: Low dopamine D2 receptor binding potential in social phobia. Am J Psychiatry  2000; 157:457-459
[CrossRef] | [PubMed]
 
Potts NL, Davidson JR, Krishnan KR, et al: Magnetic resonance imaging in social phobia. Psychiatry Res  1994; 52:35-42
[CrossRef] | [PubMed]
 
Mikkelsen EJ, Detlor J, Cohen DJ: School avoidance and social phobia triggered by haloperidol in patients with Tourette's disorder. Am J Psychiatry  1981; 138:1572-1576
[PubMed]
 
Kormos TC, Meah Y, Miyawaki E, et al: Social phobia in Parkinson's disease (abstract). Mov Disord  1996; 11:601-602
 
Schultz W: Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol  1997; 7:191-197
[CrossRef] | [PubMed]
 
Jackson DM, Westlind-Danielsson A: Dopamine receptors: molecular biology, biochemistry and behavioral aspects. Pharmacol Ther  1994; 64:291-369
[CrossRef] | [PubMed]
 
Gambarana C, Ghiglieri O, Tagliamonte A, et al: Crucial role of D1 dopamine receptors in mediating the antidepressant effect of imipramine. Pharmacol Biochem Behav  1995; 50:147-151
[CrossRef] | [PubMed]
 
Willner P: Sensitization of dopamine D2- or D3-type receptors as a final common pathway in antidepressant drug action. Clin Neuropharmacol 1995; 18:S49-S56
 
Bunney WE, Janowsky DS, Goodwin FK, et al: Effect of l-dopa on depression. Lancet  1969; 1:885-886
[PubMed]
 
Währens J, Gerlach J: Bromocriptine and imipramine in endogenous depression: a double-blind controlled trial in out-patients. J Affect Disord  1981; 3:193-202
[CrossRef] | [PubMed]
 
Cummings JL: Depression and Parkinson's disease: a review. Am J Psychiatry  1992; 149:443-454
[PubMed]
 
Meah Y, Miyawaki E, Kormos TC, et al: Depression in Parkinson's disease: a meta-analysis regarding severity (abstract). Mov Disord  1996; 11:159
 
Mayberg HS, Solomon DH: Depression in Parkinson's disease: a biochemical and organic viewpoint, in Behavioral Neurology of Movement Disorders, edited by Weiner WJ, Lang AE. New York, Raven, 1995, pp 49-60
 
Ring HA, Bench CJ, Trimble MR, et al: Depression in Parkinson's disease: a positron emission study. Br J Psychiatry  1994; 165:333-339
[CrossRef] | [PubMed]
 
Black KJ, Perlmutter JS: Septuagenarian Sydenham's with secondary hypomania. Neuropsychiatry Neuropsychol Behav Neurol  1997; 10:147-150
[PubMed]
 
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