Prevalence, clinical features and treatment of depression in Parkinson’s disease: An update

Table 1 Diagnostic criteria for major depressive episode

Depressed mood most of the day, nearly every day

Markedly diminished interest or pleasure in all or almost all activities

Significant weight loss when not dieting or weight gain

Insomnia or hypersomnia nearly every day

Psychomotor agitation or retardation

Fatigue or loss of energy

Feelings of worthlessness or excessive or inappropriate guilt

Diminished ability to think or concentrate, or indecisiveness

Recurrent thoughts of death or suicidal ideation

Five or more of the symptoms must have been present during the same 2-wk period, represent a change from previous functioning and cause significant distress or impairment in social, occupational or other functioning. One of the symptoms should be either depressed mood or loss of interest or pleasure, significant weight loss or weight gain. Symptoms should be present nearly every day, most of the day are not due to drug or a general medical condition. Criteria adapted from Diagnostic Statistical Manual of Mental Disorders[15].

Table 2 Classification, mechanism of action and dosage range of antidepressants

Class	Mechanism of action	Generic name (trade name)	Dose range (mg/d)
Older antidepressants
Mixed serotonin and norepinephrine reuptake inhibitors
First-generation tricyclic antidepressants	Inhibit neuronal reuptake of norepinephrine and serotonin	Amitriptyline (elavil) Clomipramine (anafranil) Doxepin (adapin) Imipramine (tofranil) Trimipramine (surmontil) Protriptyline (vivactil) Lofepramine	100-300 100-250 100-300 50-300 100-300 75-200 15-60
Second-generation tricyclic antidepressants	Inhibit neuronal reuptake of norepinephrine and serotonin	Desipramine (norpramin) Nortriptyline (pamelor)	100-300 50-150
Tetracyclic antidepressants	Inhibit neuronal reuptake of norepinephrine and serotonin	Maprotiline (ludiomil)	100-200
		Amoxapine (asendin)	50-300
Heterocyclic agents Triazolopyridines	Mixed serotonin effects: Serotonin (5-HT2A) receptor blockade with serotonin reuptake inhibition	Trazodone (desyrel)	150-400
Monoamine oxidase inhibitors	Nonselective inhibitor of monoamine oxidase A and B	Phenelzine (nardil) Tranylcypromine (parnate) Selegiline (eldepryl)	60-90 20-60 5-10
Newer antidepressants
Selective serotonin reuptake inhibitors	Selectively inhibit the reuptake of 5HT at the presynaptic neuronal membrane. Sertraline also markedly inhibits dopamine reuptake	Fluoxetine (prozac) Fluvoxamine (luvox) Paroxetine (paxil) Sertraline (zoloft) Citalopram (celexa) Escitalopram (lexapro)	20-60 100-300 20-50 50-200 20-40 5-20
Serotonin and noradrenaline reuptake Inhibitors	Potent inhibitors of 5HT and norepinephrine uptake; weak inhibitors of dopamine reuptake	Venlafaxine (effexor) Milnacipran (savella) Duloxetine (cymbalta)	75-350 12.5-100 60
Norepinephrine reuptake inhibitors	Noradrenaline reuptake inhibitor. Inhibits norepinephrine reuptake without inhibiting serotonin reuptake	Viloxazine Reboxetine (edronax) Atomoxetine (strattera)	150-300 4-8 40-80
Reversible inhibitors of monoamine oxidase A	Selective, reversible inhibitors of monoamine oxidase A: resulting in increased concentrations of NE, 5-HT, and dopamine in synapse	Moclobemide Brofaromine	300-600 75-150
5HT2 receptor antagonists/reuptake inhibitor serotonin modulators	Mixed serotonin effects. Inhibition of the reuptake of serotonin and selective postsynaptic 5-HT2A blockade	Nefazodone (serzone) Desvenlafaxine (pristiq) Ritanserin	300-600 50 mg once daily 5-10
5HT1a receptor agonists	Partial agonist of serotonin 5-HT1a	Gepirone, ipsapirone, tandospirone, felsinoxan
α2-noradrenergic antagonists	Complex action on serotonin and noradrenaline via Serotonin (5-HT2A and 2C) receptor blockade and presynaptic α2-receptor blockade	Mirtazapine (remeron)	15-45
GABA-mimetics	GABAA and GABAB receptor agonists	Fengabine	900-1800
Dopamine reuptake inhibitors	Increases activity of norepinephrine and dopamine only; no significant effect on serotonin	Buproprion (wellbutrin)	200-450
Melatonin receptor agonists	Melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist	Agomelatine (valdoxan)	25-50
Herbal remedy: Hypericumperforatum/ St. John’s wort	Unclear: inhibits the reuptake of several neurotransmitters, including 5HT, NE, dopamine, and γ-aminobutyric acid	Hypericum perforatum	300-900

Clomipramine, nefazodone and venlafaxine are potent non-selective serotonin reuptake inhibitors. Citalopram S-enantiomer, escitalopram, is the most active isomer and is a more potent and more selective serotonin reuptake inhibitor than citalopram. Extracts of Hypericum perforatum (St. John’s Wort) are used in many countries to treat depressive disorders. GABA: Gamma aminobutyric acid; NE: Norepinephrine; 5HT: 5-hydroxytryptamine.

Table 3 Prevalence of depressive symptoms in subjects with Parkinson’s disease in different studies

Stage of PD/type of patients	No. of patients/	Prevalence of depression/ depressive symptoms	Prevalence of other neuropsychatric	Ref.
	sample size		symptoms
Outpatients, non-fluctuating (21 de novo, 69 treated with levodopa or dopamine agonists)	90	Major depression in 21.1% (vs in 3.3% controls)	Panic disorders in 30% (vs 5.5% in controls) Dystimia in 18.8% (vs 4.4% in controls)	[26]
Outpatients with established PD	100	Major depression in 35%		[35]
Patients with PD presenting with non-motor symptoms. Retrospective study of pathologically-proven PD	91	Depression in 2.5%	Anxiety in 3.9%	[33]
Outpatients with established PD	50	Major depression in 42% (vs 10% of geriatric patients)		[28]
Nondemented patients with moderate to severe PD	111	Depression in 26.1% Subthreshold depression in 28.8%		[27]
Early untreated PD	175	Depression in 37%	Apathy in 27% Sleep disturbance in 18% Anxiety in 17%	[29]
New-onset PD patients	685	Depression in 72% (developed depression within ten years of symptomatic PD onset)		[36]
Outpatients with established PD	1086	Major depression in 15.6%		[37]
Outpatients with established PD Outpatients with established PD Outpatients with established PD	1449 1449 150	Depression in 25% Depression in 33.6% Depression in 43% Depression without apathy in 13%	Anxiety in 20% Dementia in 29% Psychotic syndromes in 12.7% Sleep disturbances in 49% Apathy only in in 17% Apathy + depression in 43%	[38] [39] [40]
Non-demented PD subjects	105	38% borderline depression Major depression in 4.8%		[30]
Non-demented PD subjects	450	Depressive symptoms in 40% (vs 10% of controls)	Probable anxious signs in 51% (vs 29% of controls)	[41]
Patients with established PD	256	Minor depression in 36.3% Major depression in 12.9%		[42]
Patients with established PD	360	Depression in 41.3%	Only apathy in 23% Apathy + depression in 36.9%	[43]
Patients with established PD	202	Depression in 37.3%	Anxiety in 31.3%, Dementia in 25.3% Excessive daytime sleepiness in 59.4%	[31]
Patients with established PD	513	Depression in 8.6%	Anxiety alone in 22.0% Anxiety + depressive symptoms in 8.6%	[44]
Outpatients with established PD	158	Depression in 11% to 57% (depending on the definition of depression)		[45]
Outpatients with established PD New-onset PD patients	639 221	Depression in 66% Major depression in 9.9% (developed depression over 3-4 yr)		[34] [46]
Outpatients with established PD	1449	Depression in 18.8%	Dementia in 13.9% had Dementia + depression in 14.3%	[47]
Non-demented PD subjects Early stage PD	95 36	Depression in 28% Depression in 36.1%	Anxiety in 27% Obsessive-compulsive symptoms in 52.8% Somatization in 66.7%	[48] [49]
Outpatients with established PD	117	Depression in 56%	Anxiety in 55%	[50]
Patients with established PD (ambulatory and home residents)	886	Depression in 24.4%	28.4% dementia (20.6 % of ambulatory and 85.7 % of home residents)	[51]
PD patients with mild cognitive impairment	104	Depression in 40.4% (vs 16.6% in controls)	Subjective memory complaints 16.3% (vs 7.7% of controls)	[32]
Non-demented PD subjects	115	Major depression in 28.7% Subthreshold depression in 26.10%		[52]

PD: Parkinson’s disease.

Table 4 Studies on the effect of antidepressant drugs on depressive symptoms in Parkinson’s disease subjects with depression

Drug	Study design	Sample size	Study objectives	Outcomes	Adverse effects	Ref.
Fluoxetine		23	Effects of fluoxetine (up to 40 mg/d) on motor performance	20/23 patients experienced no worsening of parkinsonism		[167]
Fluoxetine, fluvoxamine, citalopram, and sertraline	Open-label prospective study	62 depressed patients with PD (without dementia or motor fluctuation) (15 patients received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline)	Effects of SSRIs on motor performance and depressive symptoms	↓↑ UPDRS scores Significant improvements in depression with all SSRIs		[168]
Fluoxetine/amitriptyline	Randomized study	77 patients with PD (37 received fluoxetine and 40 received amitriptyline)	Comparing fluoxetine (20-40 mg/d) and amitriptyline (25-75 mg/d) at low doses on depressive symptoms	Amitriptyline better controlled depression at 3, 6, 9 and 12 mo, respectively	15% abandoned amitriptyline because of side effects	[137]
Fluoxetine	Prospective, controlled, open-label study	18 patients with PD and mild depression without dementia	Influence of fluoxetine (20 mg/d) on motor functions	Significant improvements in scores of depression and Parkinson’s disability		[174]
Paroxetine			To assess the tolerability of paroxetine (20 mg once per day)	Improved depression UPDRS scores ↓↑	Reversible worsening of tremor in one patient	[171]
Paroxetine		65 outpatients with PD and depression	To assess the tolerability of paroxetine (10-20 mg once per day)	Improved depression	20% stopped paroxetine because of adverse reactions Increased “off” time and tremor in 2 patients (reversible)	[170]
Paroxetine CR/nortriptyline	Randomized, placebo controlled trial	52 patients with PD and depression	To evaluate the efficacy of paroxetine CR and nortriptyline in treating depression	Nortriptyline was superior to placebo for the change in depressive scores Paroxetine CR was not		[140]
Paroxetine/venlafaxine	Randomized, double-blind, placebo-controlled trial	115 subjects with PD	To compare efficacy and safety paroxetine and venlafaxine extended release in treating depression in PD	Both paroxetine and venlafaxine XR significantly improved depression UPDRS scores ↓↑		[173]
Citalopram		46 non-demented patients with PD. 18 depressed and 28 non-depressed	Effect of citalopram on motor and nonmotor symptoms of depressed and nondepressed patients with IPD	Improvement in mood in 15/16 patients Motor performance ↓↑ Improved bradykinesia and finger taps in patients with and without depression		[169]
Citalopram	Prospective, open label trial	10 patients with PD and major depression, without dementia	Effects of citalopram on depressive symptoms	Significant improvement in depression and in anxiety symptoms and functional impairment		[175]
Escitalopram	Open-label study	14 Parkinson’s disease patients with major depression	Effects of escitalopram on depressive symptoms	↓ in depressive symptomatology score (response and remission rates were only 21% and 14%)		[176]
Sertraline	Open-label pilot study	15 patients with PD and depression	To evaluate the safety and efficacy of sertraline to treat depression in PD	Significant improvement in depression UPDRS scores ↓↑	Side effects in 1/3 2 patients discontinued sertraline	[177]
Sertraline Sertraline		54 PD patients with depressive disorders 374 PD patients with depressive symptoms	Comparing efficacy of sertraline in the usual formulation and in the liquid oral concentrate Long-term effects of sertraline on motor status	Improved depression on both formulations Improved clinical global impression-severity of illness scale Improved UPDRS ↓ Anxiety ↓ Depression	8% discontinued medication for adverse events (gastrointestinal) Worsening of tremor in some patients	[179] [178]
Sertraline/amitriptyline	Prospective single-blind randomized study	31 patients with PD and depression	Assessment of the effect of sertraline (50 mg) or low-dose amitriptyline (25 mg) on depression and quality of life	↓ Depression by both drugs Sertraline improved quality of life ↓↑ UPDRS scores		[138]
Sertraline/pramipexole	Randomized trial	67 outpatients with PD and major depression but no motor fluctuations and/or dyskinesia	To compare pramipexole with sertraline	Both sertraline and pramipexole improved depression Pramipexole caused more recovery compared to sertraline (60.6% vs 27.3%) Pramipexole improved UPDRS motor subscore	14.7% withdrew from the sertraline group	[99]
Nefazodone/fluoxetine	A pilot randomized trial	Depressed patients with PD	To assess the effect of nefazodone on extrapyramidal symptoms in depressed PD patients	Nefazodone significantly improved UPDRS score Both nefazodone and fluoxetine were equally effective in treating depression		[185]
Trazodone	Randomized trial	20 PD patients with and without depression	To test the ability of trazodone to improve depression and motor function	Significantly improved depression Improves motor function in depressed patients		[186]
Venlafaxine	Prospective study	14 non-fluctuating PD patients with depression	To investigate the therapeutic efficacy of venlafaxine	Improved depression scores UPDRS scores ↓↑		[195]
Atomoxetine, a SNRI	Randomized placebo- controlled study	55 subjects with PD depression atomoxetine or placebo	To assess efficacy of atomoxetine (80 mg/d) in treating depression	Failed to improved depression Improved global cognition Improved daytime sleepiness		[196]
Duloxetine	Non-comparative, open-label, multi-center study	151 patients	To evaluate the tolerability, safety, and efficacy of duloxetine 60 mg once daily in PD patients with major depressive disorder	Improved depressive scores Improved activities of daily living Tremor ↓↑ Rigidity ↓↑	8.6% discontinued the study due to side effects	[197]

PD: Parkinson’s disease; SNRI: Selective norepinephrine reuptake inhibitor; UPDRS: Unified Parkinson’s disease Rating Scale.