Review
Copyright ©The Author(s) 2015.
World J Neurol. Mar 28, 2015; 5(1): 17-38
Published online Mar 28, 2015. doi: 10.5316/wjn.v5.i1.17
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
Table 2 Classification, mechanism of action and dosage range of antidepressants
ClassMechanism of actionGeneric name (trade name)Dose range (mg/d)
Older antidepressants
Mixed serotonin and norepinephrine reuptake inhibitors
First-generation tricyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninAmitriptyline (elavil) Clomipramine (anafranil) Doxepin (adapin) Imipramine (tofranil) Trimipramine (surmontil) Protriptyline (vivactil) Lofepramine100-300 100-250 100-300 50-300 100-300 75-200 15-60
Second-generation tricyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninDesipramine (norpramin) Nortriptyline (pamelor)100-300 50-150
Tetracyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninMaprotiline (ludiomil)100-200
Amoxapine (asendin)50-300
Heterocyclic agents TriazolopyridinesMixed serotonin effects: Serotonin (5-HT2A) receptor blockade with serotonin reuptake inhibitionTrazodone (desyrel)150-400
Monoamine oxidase inhibitorsNonselective inhibitor of monoamine oxidase A and BPhenelzine (nardil) Tranylcypromine (parnate) Selegiline (eldepryl)60-90 20-60 5-10
Newer antidepressants
Selective serotonin reuptake inhibitorsSelectively inhibit the reuptake of 5HT at the presynaptic neuronal membrane. Sertraline also markedly inhibits dopamine reuptakeFluoxetine (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 InhibitorsPotent inhibitors of 5HT and norepinephrine uptake; weak inhibitors of dopamine reuptakeVenlafaxine (effexor) Milnacipran (savella) Duloxetine (cymbalta)75-350 12.5-100 60
Norepinephrine reuptake inhibitorsNoradrenaline reuptake inhibitor. Inhibits norepinephrine reuptake without inhibiting serotonin reuptakeViloxazine Reboxetine (edronax) Atomoxetine (strattera)150-300 4-8 40-80
Reversible inhibitors of monoamine oxidase ASelective, reversible inhibitors of monoamine oxidase A: resulting in increased concentrations of NE, 5-HT, and dopamine in synapseMoclobemide Brofaromine300-600 75-150
5HT2 receptor antagonists/reuptake inhibitor serotonin modulatorsMixed serotonin effects. Inhibition of the reuptake of serotonin and selective postsynaptic 5-HT2A blockadeNefazodone (serzone) Desvenlafaxine (pristiq) Ritanserin300-600 50 mg once daily 5-10
5HT1a receptor agonistsPartial agonist of serotonin 5-HT1aGepirone, ipsapirone, tandospirone, felsinoxan
α2-noradrenergic antagonistsComplex action on serotonin and noradrenaline via Serotonin (5-HT2A and 2C) receptor blockade and presynaptic α2-receptor blockadeMirtazapine (remeron)15-45
GABA-mimeticsGABAA and GABAB receptor agonistsFengabine900-1800
Dopamine reuptake inhibitorsIncreases activity of norepinephrine and dopamine only; no significant effect on serotoninBuproprion (wellbutrin)200-450
Melatonin receptor agonistsMelatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonistAgomelatine (valdoxan)25-50
Herbal remedy: Hypericumperforatum/ St. John’s wortUnclear: inhibits the reuptake of several neurotransmitters, including 5HT, NE, dopamine, and γ-aminobutyric acidHypericum perforatum300-900
Table 3 Prevalence of depressive symptoms in subjects with Parkinson’s disease in different studies
Stage of PD/type of patientsNo. of patients/Prevalence of depression/ depressive symptomsPrevalence of other neuropsychatricRef.
sample sizesymptoms
Outpatients, non-fluctuating (21 de novo, 69 treated with levodopa or dopamine agonists)90Major 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 PD100Major depression in 35%[35]
Patients with PD presenting with non-motor symptoms. Retrospective study of pathologically-proven PD91Depression in 2.5%Anxiety in 3.9%[33]
Outpatients with established PD50Major depression in 42% (vs 10% of geriatric patients)[28]
Nondemented patients with moderate to severe PD111Depression in 26.1% Subthreshold depression in 28.8%[27]
Early untreated PD175Depression in 37%Apathy in 27% Sleep disturbance in 18% Anxiety in 17%[29]
New-onset PD patients685Depression in 72% (developed depression within ten years of symptomatic PD onset)[36]
Outpatients with established PD1086Major depression in 15.6%[37]
Outpatients with established PD Outpatients with established PD Outpatients with established PD1449 1449 150Depression 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 subjects10538% borderline depression Major depression in 4.8%[30]
Non-demented PD subjects450Depressive symptoms in 40% (vs 10% of controls)Probable anxious signs in 51% (vs 29% of controls)[41]
Patients with established PD256Minor depression in 36.3% Major depression in 12.9%[42]
Patients with established PD360Depression in 41.3%Only apathy in 23% Apathy + depression in 36.9%[43]
Patients with established PD202Depression in 37.3%Anxiety in 31.3%, Dementia in 25.3% Excessive daytime sleepiness in 59.4%[31]
Patients with established PD513Depression in 8.6%Anxiety alone in 22.0% Anxiety + depressive symptoms in 8.6%[44]
Outpatients with established PD158Depression in 11% to 57% (depending on the definition of depression)[45]
Outpatients with established PD New-onset PD patients639 221Depression in 66% Major depression in 9.9% (developed depression over 3-4 yr)[34] [46]
Outpatients with established PD1449Depression in 18.8%Dementia in 13.9% had Dementia + depression in 14.3%[47]
Non-demented PD subjects Early stage PD95 36Depression in 28% Depression in 36.1%Anxiety in 27% Obsessive-compulsive symptoms in 52.8% Somatization in 66.7%[48] [49]
Outpatients with established PD117Depression in 56%Anxiety in 55%[50]
Patients with established PD (ambulatory and home residents)886Depression in 24.4%28.4% dementia (20.6 % of ambulatory and 85.7 % of home residents)[51]
PD patients with mild cognitive impairment104Depression in 40.4% (vs 16.6% in controls)Subjective memory complaints 16.3% (vs 7.7% of controls)[32]
Non-demented PD subjects115Major depression in 28.7% Subthreshold depression in 26.10%[52]
Table 4 Studies on the effect of antidepressant drugs on depressive symptoms in Parkinson’s disease subjects with depression
DrugStudy designSample sizeStudy objectivesOutcomesAdverse effectsRef.
Fluoxetine23Effects of fluoxetine (up to 40 mg/d) on motor performance20/23 patients experienced no worsening of parkinsonism[167]
Fluoxetine, fluvoxamine, citalopram, and sertralineOpen-label prospective study62 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/amitriptylineRandomized study77 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 symptomsAmitriptyline better controlled depression at 3, 6, 9 and 12 mo, respectively15% abandoned amitriptyline because of side effects[137]
FluoxetineProspective, controlled, open-label study18 patients with PD and mild depression without dementiaInfluence of fluoxetine (20 mg/d) on motor functionsSignificant improvements in scores of depression and Parkinson’s disability[174]
ParoxetineTo assess the tolerability of paroxetine (20 mg once per day)Improved depression UPDRS scores ↓↑Reversible worsening of tremor in one patient[171]
Paroxetine65 outpatients with PD and depressionTo assess the tolerability of paroxetine (10-20 mg once per day)Improved depression20% stopped paroxetine because of adverse reactions Increased “off” time and tremor in 2 patients (reversible)[170]
Paroxetine CR/nortriptylineRandomized, placebo controlled trial52 patients with PD and depressionTo evaluate the efficacy of paroxetine CR and nortriptyline in treating depressionNortriptyline was superior to placebo for the change in depressive scores Paroxetine CR was not[140]
Paroxetine/venlafaxineRandomized, double-blind, placebo-controlled trial115 subjects with PDTo compare efficacy and safety paroxetine and venlafaxine extended release in treating depression in PDBoth paroxetine and venlafaxine XR significantly improved depression UPDRS scores ↓↑[173]
Citalopram46 non-demented patients with PD. 18 depressed and 28 non-depressedEffect of citalopram on motor and nonmotor symptoms of depressed and nondepressed patients with IPDImprovement in mood in 15/16 patients Motor performance ↓↑ Improved bradykinesia and finger taps in patients with and without depression[169]
CitalopramProspective, open label trial10 patients with PD and major depression, without dementiaEffects of citalopram on depressive symptomsSignificant improvement in depression and in anxiety symptoms and functional impairment[175]
EscitalopramOpen-label study14 Parkinson’s disease patients with major depressionEffects of escitalopram on depressive symptoms↓ in depressive symptomatology score (response and remission rates were only 21% and 14%)[176]
SertralineOpen-label pilot study15 patients with PD and depressionTo evaluate the safety and efficacy of sertraline to treat depression in PDSignificant improvement in depression UPDRS scores ↓↑Side effects in 1/3 2 patients discontinued sertraline[177]
Sertraline Sertraline54 PD patients with depressive disorders 374 PD patients with depressive symptomsComparing efficacy of sertraline in the usual formulation and in the liquid oral concentrate Long-term effects of sertraline on motor statusImproved depression on both formulations Improved clinical global impression-severity of illness scale Improved UPDRS ↓ Anxiety ↓ Depression8% discontinued medication for adverse events (gastrointestinal) Worsening of tremor in some patients[179] [178]
Sertraline/amitriptylineProspective single-blind randomized study31 patients with PD and depressionAssessment 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/pramipexoleRandomized trial67 outpatients with PD and major depression but no motor fluctuations and/or dyskinesiaTo compare pramipexole with sertralineBoth sertraline and pramipexole improved depression Pramipexole caused more recovery compared to sertraline (60.6% vs 27.3%) Pramipexole improved UPDRS motor subscore14.7% withdrew from the sertraline group[99]
Nefazodone/fluoxetineA pilot randomized trialDepressed patients with PDTo assess the effect of nefazodone on extrapyramidal symptoms in depressed PD patientsNefazodone significantly improved UPDRS score Both nefazodone and fluoxetine were equally effective in treating depression[185]
TrazodoneRandomized trial20 PD patients with and without depressionTo test the ability of trazodone to improve depression and motor functionSignificantly improved depression Improves motor function in depressed patients[186]
VenlafaxineProspective study14 non-fluctuating PD patients with depressionTo investigate the therapeutic efficacy of venlafaxineImproved depression scores UPDRS scores ↓↑[195]
Atomoxetine, a SNRIRandomized placebo- controlled study55 subjects with PD depression atomoxetine or placeboTo assess efficacy of atomoxetine (80 mg/d) in treating depressionFailed to improved depression Improved global cognition Improved daytime sleepiness[196]
DuloxetineNon-comparative, open-label, multi-center study151 patientsTo evaluate the tolerability, safety, and efficacy of duloxetine 60 mg once daily in PD patients with major depressive disorderImproved depressive scores Improved activities of daily living Tremor ↓↑ Rigidity ↓↑8.6% discontinued the study due to side effects[197]