Table 1 Results from selected original articles

Ahn, 2018 [29]

Asia (Korea)

Case report

1 pt. (86 yo female), with early-stage PD and depression and comorbid mixed dementia (Alzhei-

mer’s disease and vascular).

Depression,

150 mg/day.

Not reported.

Pt developed propriospinal myoclonus (PSM) a few days after BUP introduction and Memantine increase that improved after discontinuation of both drugs.

BUP was suspected to cause PSM considering its effect on suppression of the transport of signals across the synapse in both sympathetic and parasympathetic pathways by antagonizing nicotinic-type acetylcholine receptors, inducing disturbance of autonomic ganglia signals.

Co-administration of Memantine might be responsible for PSM.

Benincasa, 2011 [30]

Europe (Spain)

Case report

3 females (mean age 53.7 years) with PD who developed compulsive eating after dopaminergic medications (ropinirole and pramipexole) with comorbid depressive symptoms (HAMD mean score: 14.7).

Compulsive behavior + depressive symptoms

150 mg/day.

Drastic reduction of food intake within 3–4 weeks and weight loss.

Mild improvement on depressive symptoms (HAMD mean score 11.4) at 3-month follow-up.

No significant side-effects nor worsening of parkinsonian motor symptoms (as measured on the UPDRS).

Therapeutic efficacy of BUP on compulsive behaviours may depend on inhibition of dopamine reuptake in the ventral striatum and, consequently, stabilization of dopaminergic transmission in the mesolimbic system + inhibition of norepinephrine reuptake in the prefrontal cortex.

Case report.

Chen, 2007 [31]

North America (the USA)

Original research

National sample of 7868 pts. (mean age 74.4 ± 7.8 years) with depression and comorbid PD compared with pts. without PD, investigated for 12 months after the first visit for depression.

Depression, dose not reported.

Not reported.

Not reported.

Prescription of BUP in patients with depression and comorbid PD: 6.8%.

No data on BUP efficacy and tolerability.

Gebhardt, 2008 [32]

Europe (Germany)

Case report

1 pt. (57 yo female) with PD and comorbid panic disorder, agoraphobia, disabling somatic symptoms (HAMA: 42) and depression (HAMD: 32).

Anxiety and depression, 150 mg/day.

At 16-week follow-up:

- improved anxiety (HAMA:19) and depressive (HAMD:17) symptoms

- improved global

clinical condition (CGI from 6 to 5, GAF from 40 to 52).

No BUP related side effects.

Impaired dopaminergic function due to loss of dopaminergic neurons in the substantia nigra, the limbic system, the prefrontal projections and other brain areas, may contribute to the development of both anxiety and depression in PD.

Case report.

Pt started

CBT concomitant BUP.

Pt on different medications (Levodopa, Benserazide, Rotigotine, Pramipexole, Rasagiline, Mirtazapine).

Reduction of anxiety symptoms might be a consequence of the antidepressant effect of BUP.

Goetz, 1984 [21]

North America (the USA)

Original research

20 pts. with PD (mean age 62.3 years, females n = 9), of whom 12/20 with comorbid depression.

Study design: 14 patients enrolled in a double-blind parallel protocol, 8 receiving BUP in the first phase and 6 receiving placebo +12 patients received BUP in an open label fashion, 6 as crossovers from the double-blind placebo group and 6 treated outside the double-blind protocol.

Primarily as adjunctive therapy for motor symptoms in PD, secondarily measuring the effect on depression.

Mean maintenance daily dose from 340 to 400 mg/day.

At 9 weeks, all patients statistically improved on motor symptoms (NUDS or NYUPDS).

5 of the 12 depressed pts. showed reduction of depression (on “global impression scales for both parkinsonism anddepression”).

Side effects: nausea/vomiting in 8/20 pts., excitement 9/20, restlessness 4/20, postural tremor 1/20, dyskinesia hallucinations 3/20, confusion 3/20.

Antiparkinsonian and antidepressant effects were independent.

No comparison with placebo in all patients.

Depression diagnostic criteria and rating scale not specified.

Not reported if concurrent antiparkinsonian medication was prescribed at fixed dosage is.

Honkanen, 2019 [33]

Europe (Finland)

Case report

1 pt. (52 yo male) with long history of depression who developed parkinsonism (mild bradykinesia in the left hand, mild slowness in foot-tapping rate, reduced stride length).

Depression, 150 mg/day.

Not reported.

Not reported.

Brain imaging ([123I]FP-CIT SPECT) after 4-weeks discontinuation of BUP resulted normal compared with imaging after 1-week BUP discontinuation. BUP may cause misdiagnosis in brain dopamine transporter imaging, therefore longer (>1 week) washout of BUP may be needed.

Case report.

Other concurrent medications: Venlafaxine 225 mg/day, Levodopa 450 mg/day started after the first scan, Agomelatine 25 mg/day started to replace BUP.

Kate, 2013 [34]

Asia (India)

Case report

1 pt. (75 yo male) with PD and comorbid MDD + blood hypertension.

Depression, 300 mg/day.

Not reported.

Hyponatremia (119.5 mEq/L) occurred 18 days after BUP introduction and normalized by 7 days after BUP stop.

-

Case report.

Kaur, 2012 [35]

North America (the USA)

Case report

1 pt. (58 yo female) with PD and comorbid MDD + obesity, hypertension, and hypothyroidism.

Depression, 300 mg/day.

After BUP increase (from 150 to 300 mg/day) and Rasagiline (1 mg/day) introduction, over the period of one year:

- significant improvement in neurovegetative symptoms of depression

- limited improvement in PD symptoms.

Therapeutic combination was well tolerated without side effects.

Rasagiline in combination with two antidepressants seem a successful approach.

No standardized scale used to measure improvements in depressive or PD symptoms.

Additional concurrent medications (venlafaxine 225 mg/day and implantation with deep brain stimulation).

Kim, 2009 [36]

Asia (Korea)

Original research

15 pts. (mean age 57.2 years, 8 females) with PD and comorbid MDD (DSM-IV criteria), treated with BUP for 12 weeks.

Depression, 300 mg/day.

The mean HAMD score was significantly reduced after the 12-week trial (11.12 ± 6.51) compared with baseline (23.11 ± 5.05).

No significant change in UPDRS score.

Most common side effects: dizziness, nausea.

No pts. reported significant adverse effects including hallucinations and any other confusional symptoms.

-

Open-label study.

Small sample size.

No full text published (poster conference).

Kim, 2012 [37]

Asia (Korea)

Original research

9 pts. with PD and freezing of gait (FOG), treated with BUP for 12 weeks.

FOG,

300 mg/day.

Mean GABS total score was reduced after the 12-week trial (30.4 ± 3.5) compared with baseline (34.5 ± 5.0), but not at a significant level.

Not reported.

-

Open-label study.

Small sample size.

No full text published (poster conference).

Kummer, 2006 [38]

South America (Brazil)

Case report

1 pt. (67 yo male) with PD who developed compulsive use of Levodopa and comorbid mood fluctuations (exacerbated during off-episodes) and increased writing activity suggestive of stereotype behaviours + back pain (exacerbated during off-episodes).

Depression,

150 mg/day.

BUP was started after an unsuccessful 12-week trial with sertraline (100 mg): after 8-weeks no changes in depressive symptoms or craving for Levodopa.

Not reported.

-

Case report.

Depressive symptoms were strongly correlated to on-off episodes, therefore strictly associated with PD instead of a comorbid depressive symptoms/disorder.

Leentjens, 2000 [17]

Europe (the Netherlands)

Case report

1 pt. (70 yo female) with PD (UPDRS at baseline: 16) and treatment-resistant depression (HAMD: 25).

Depression,

started at 150 mg, then 300 mg/day.

Quick and complete remission of depressive symptoms:

HAMD at 1 week: 9, at 4 weeks:7, at 7 months: 6.

No changes in motor symptoms (UPDRS at follow-up: 7 months, 16), but subjective improvement in hypokinesia.

Self-limitating nausea reported as the only side effect.

-

Case report.

Article in Dutch.

Ritter, 1997 [39]

North America (the USA)

Original research

28 pts. (all males, mean age 68 years) with PD treated with Selegiline in association with different antidepressants (including 3 pts. on BUP), aimed to find the safety of different combinations.

BUP indication not specified

Dosage range 150–300 mg/day, mean dose 217 ± 76.4 mg/day.

Not reported.

40 Selegiline-antidepressant drug combinations were found (BUP:3, TCAs:25, SSRI:7, trazodone:5).

Only one case of serotonin syndrome was reported (with fluoxetine).

No patients on BUP discontinued the drug secondary to adverse effects.

BUP is an appropriate first choice with Selegiline therapy.

Retrospective study.

Stein, 1997 [18]

North America (the USA)

Case report

1 pt. (65 yo female) with late-stage PD, severe recurrent depression, psychosis, and chronic pain (diffuse and burning pain at the lower limbs).

Depression,

300 mg/day.

Switching from Paroxetine to BUP and to sustained-release Carbidopa/Levodopa reduced fluctuations in mood and mobility and improved overall functioning but had no effect on pain that was reduced after tramadol introduction.

Not reported.

-

Complex case-report considering policomorbidity.

No standardized measure of BUP effect on depression.

Trivedi, 2002 [40]

Asia (India)

Original research

Double-blind randomized controlled study, 23 pts. treated with BUP and 23 with Sertraline.

Depression,

300 mg/day.

After 6 weeks, pts. on BUP showed a significant improvement in depressive (HAMD), global (CGI) and motor symptoms of PD, compared with patients on Sertraline.

Side effect profile with both the drugs was approximately equal.

-

No full text published (poster conference).

The effect of important information (e.g., comorbidities, concomitant medications) cannot be ruled out.

Vasile, 2013 [41]

Europe (Romania)

Original research

20 pts. (mean age 64.9 yrs., 8 females) with PD and comorbid MDD (DSM IV-TR), treated with BUP for 6 months.

Depression,

150–300 mg/day.

Compared to baseline, pts. showed a significant improvement in:

- depressive symptoms severity (MADRS: −17.6)

- global functioning (GAF: +22.1, and CGI-I: −3.5)

- severity of PD symptoms

(‘non-motor experiences of daily living’

dimension of UPDRS: −13.2)

- quality of life (SF-36: total score) and on ‘mental health’ (+12.3), ‘general health’ (+8.2), ‘vitality’ (+7.7), and ‘social functioning’ (+6.2) subscales.

Good tolerability: mild (n = 4) and moderate (n = 3) side effects. The most frequently reported side effects were anxiety, insomnia, and sweating.

-

Open-label study.

Small sample size.

No full text published (poster conference).

Vegda, 2020 [42]

Asia (India)

Case report

1 pt. (78 yo female) with PD and comorbid depression + comorbid hypertension.

Depression,

150 mg/day.

Not reported.

Pt developed dyskinesias and dystonia (bilateral upper and lower extremity dystonia, buccolingual crisis, left laterocollis, pseudo-macroglossia and severe laryngeal dystonia) 2 days after BUP start that reduced and disappeared after BUP stop.

Dystonia developed after BUP can be considered similar to dopamine-induced peak dose dystonia by its mechanism of increasing the availability of dopamine.

Severe stage of PD (UPDRS:148) with significant motor and non-motor on-off symptoms.

Załuska, 2011 [19]

Europe (Poland)

Case report

1 pt. (78 yo female) with clinical symptoms of PD and depression + possible cognitive impairment (MMSE score 25 and 22 in two subsequent evaluations) + brain imaging suggestive for features of angiogenic multifocal brain lesions and slight cortical atrophy +

several comorbid conditions.

Depression,

150 mg/day.

Improvement of depressive symptoms (HAMD from 18 to 7) after 10 days after BUP introduction, in remission after 1-year follow up.

Levodopa contributed to the improvement of motor functions (UPDRS

motor from 24 to 15 after 3-week treatment).

No psychotic symptoms associated with BUP treatment.

-

Complex case-report considering policomorbidity and brain lesions.