Introduction
Motor slowness, rigidity, tremor, postural dysfunction and good reaction to levodopa are significant for diagnosing Parkinson's disease (PD). Depression is a frequent psychiatric complication in PD. Anxiety, dementia, drug-induced psychosis and hallucinations not associated with medication may also occur.
In the etiology of depression in PD, both psychological and neurobiological factors are important (Veazey et al., Reference Veazey, Aki, Cook, Lai and Kunik2005). According to Remy et al. (Reference Remy, Doder, Lees, Turjanski and Brooks2005), specific loss of dopamine and noradrenaline innervation of cortical and subcortical components of the limbic system play a key role in the pathogenesis of both PD and depression in PD. Depression may precede or co-exist with symptoms of PD (Shiba et al., Reference Shiba2000). As some symptoms of PD and depression overlap, it is difficult to differentiate comorbid depressive disorder and depression caused by PD (Veazey et al., Reference Veazey, Aki, Cook, Lai and Kunik2005).
According to a recent Cochrane Review (Ghazi-Noori et al., Reference Ghazi-Noori, Chung, Deane, Rickards and Clarke2009) and a practice guideline issued by the American Psychiatric Association (Karasu et al., Reference Karasu, Gelenberg, Merriam and Wang2000), there is no evidence favoring any particular antidepressant medication in patients with depression in PD. Usually serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are considered to be well tolerated. Clinical data on improvement during such treatment is, however, limited (Ghazi-Noori et al., Reference Ghazi-Noori, Chung, Deane, Rickards and Clarke2009). Other commonly used drugs are monoamine oxidase inhibitors, amoxapine, mirtazapine, venlafaxine and bupropion (noradrenaline and dopamine reuptake inhibitor) (Karasu et al., Reference Karasu, Gelenberg, Merriam and Wang2000). According to three clinical reports, response to bupropion was superior to SSRIs, TCA with lithium and mirtazapine (Stein and Read, Reference Stein and Read1997; Leentjens et al., Reference Leentjens, Verhey and Vreeling2000; Gebhardt et al., Reference Gebhardt, Röttgers, Bäcker, Schu and Krieg2008). Moreover, in two reports, a distinct antiparkinsonian effect of bupropion was noted (Goetz et al., Reference Goetz, Tanner and Klawans1984; Leentjens et al., Reference Leentjens, Verhey and Vreeling2000).
Case presentation
The patient gave written informed consent to the publication of this report in International Psychogeriatrics.
A 78-year-old right-handed female was hospitalized in 1999 with a depressive episode and recovered on imipramine. In 2008, due to a mood decrease with a deterioration of motor abilities and episodic visual hallucinoids (flowers on walls), she underwent ambulatory treatment with fluoxetine, doxepin and risperidone (2mg/day) for several weeks. She was referred to a psychiatric hospital due to the ineffectiveness of therapy and suicidal ideation.
There was no family history of dementia, depression, psychosis nor PD. Since she lost her biological mother at the age of two, she was raised by a step-mother. She was divorced over 25 years ago. She worked as a dressmaker and retired at the age of 60. She lived alone on the third floor, with no elevator, and she benefited from the help of her children and social worker.
She had been on the following medications for several years: ramipril, metoprolol, furosemide, spironolactone, acenocoumarol, simvastatine and piracetam for arterial hypertension, coronary disease with heart insufficiency and pulmonary embolism. She had not left her home apart from seeking medical treatment for almost two years. She denied smoking or excessive drinking.
At admission she was depressed, complained of apathy, motor difficulties, irritability, insomnia, suicidal thoughts as well as loss of interest, appetite and weight. Psychomotor retardation with bradykinesia and postural dysfunction, poor physical condition and dyspnea were noticeable.
Head computed tomography (CT) revealed features of angiogenic multifocal brain lesions with foci of leukoaraiosis and slight cortical atrophy within frontal and parietal lobes. She scored 23 on the 17-item Hamilton Depression Rating Scale (HDRS) which indicated depression and 25 on the Mini-mental State Examination (MMSE), which was above the diagnostic range for dementia. Motor examination with the Unified Parkinson's Disease Rating Scale (UPDRS) revealed 24 points.
After withdrawing doxepin and continuing fluoxetine (40 mg/day) with mianserin (30 mg/day), there was no improvement in her depressed mood. Withdrawing risperidone evoked no psychotic symptoms, but extrapyramidal symptoms did not improve either. Finally, fluoxetine was withdrawn and levodopa with benserazide (187.5 mg/day) and sulpiride (100 mg/day) were introduced. During the three weeks of this treatment, the patient's motor functions significantly improved (UPDRS motor: 15) but she was still depressed (HDRS: 18). Thus, instead of sulpiride and mianserin, extended-release bupropion (150 mg/day) was introduced. Levodopa was continued. After ten days there was a significant improvement in mood, activity, sleep and appetite. At discharge she was calm, active and denied suicidal thoughts. Her HDRS score was 7.
At one year follow-up, the patient was still in remission of depressive symptoms, but her cognitive functions had worsened slightly (MMSE: 22) indicating possible early-stage dementia. She continued treatment with bupropion and levodopa. She still lived alone, but she was going out for strolls on a regular basis.
Discussion
Extrapyramidal symptoms in the patient could be connected with vascular brain lesions revealed on CT and caused by cardiovascular disease. They could also be induced by dopamine blocking with risperidone. However, there was no improvement after discontinuing risperidone and a good response to levodopa was noted together with the typical symptoms during physical examination indicating primary PD of postural instability and gait difficulty type. Her depressive episode, which was successfully treated with imipramine nine years prior to the current episode, as well as the presence of psychosocial factors predisposing her to depression (early deprivation of her mother's care, divorce and loneliness) may suggest the diagnosis of recurrent depression with co-morbid PD.
However, her depression could also be a prodromal syndrome of PD (Shiba et al., Reference Shiba2000) as well as of dementia (Brommelhoff et al., Reference Brommelhoff, Gatz, Johansson, McArdle, Fratiglioni and Pedersen2009). Slight worsening of cognitive functions with no escalation of depressive symptoms at one-year follow-up could indicate an early stage of developing dementia. Progression of common neurobiological processes postulated by Remy et al. (Reference Remy, Doder, Lees, Turjanski and Brooks2005), as described above, is supposedly responsible for development of depression, PD and dementia in the patient.
In this case, a significant improvement in motor functions and remission of depression was achieved after introducing dopaminergic agents: levodopa and bupropion. As the former treatment with serotoninergic and dopamine blocking agents (fluoxetine, mianserin, risperidone, sulpiride) was ineffective, it indicated that dopamine not serotonin deficiency played a crucial role in the common pathogenesis of depression and PD in the patient.
Hallucinatory episodes in anamnesis could be interpreted as hallucinations with preserved insight in PD or as psychotic episodes caused by a cardiovascular insufficiency or drug interaction. No psychotic symptoms were observed in the patient during the hospitalization and treatment with bupropion. Although psychotic symptoms associated with bupropion are rare, most researchers have attributed psychosis to bupropion's dopaminergic action (Bailey and Waters, Reference Bailey and Waters2008).
According to Medline resources, this is the fifth report on effective treatment of depression with bupropion in a PD patient (Goetz et al., Reference Goetz, Tanner and Klawans1984; Stein and Read, Reference Stein and Read1997; Leentjens et al., Reference Leentjens, Verhey and Vreeling2000; Gebhardt et al., Reference Gebhardt, Röttgers, Bäcker, Schu and Krieg2008). In these reports, as in our study, bupropion was more effective than TCA, SSRI or mianserin. It suggests that some patients with PD and depression could benefit from introducing bupropion. However, the quality of evidence for bupropion to treat depression in PD is still very poor. No properly controlled double-blind studies have been conducted. A case report is more a type of anecdotal evidence. Moreover, the effect of bupropion on depression in PD might be incidental despite the noradrenergic and dopaminergic agonist properties to improve both depression and PD. There also exist some reports on bupropion-induced parkinsonism (Grandas and López-Manzanares, Reference Grandas and López-Manzanares2007).
Clinicians should therefore be cautious and consider both the risks (i.e. seizure, psychosis, motor worsening) and benefits when prescribing bupropion in PD. Large randomized controlled trials should be conducted to assess bupropion's usefulness in treating depression in PD.
Conflict of interest
None.
Description of authors' roles
M. Załuska was a supervising clinician, designed the study and wrote the theoretical sections of the paper. A. Dyduch was an attending physician, wrote the case report and revised the paper.
