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Clin Geriatr. Author manuscript; available in PMC 2017 May 18. Published in final edited form as: Clin Geriatr. 1998 October ; 6(11): 34–46.
Treatment of Depression in the Patient with Parkinson's Disease Tiffany W. Chow, M.D. and Jeffrey L. Cummings, M.D. From the Departments of Neurology and Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, and the Neuropsychiatry and Neurobehavior Unit, Psychiatry Service, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.
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Parkinson's disease (PD) is a common neurological illness, with a prevalence of approximately 100/100,000. Among neurological conditions, PD is the most commonly encountered extrapyramidal movement disorder. The cardinal manifestations of PD result from loss of dopaminergic neurons in the substantia nigra and include resting tremor resembling “pill-rolling,” slowing of movement (bradykinesia), poor balance due to impairment of postural reflexes, and rigidity. The natural history of the illness is long, but two-thirds of PD patients are at least partially disabled five years after onset.1
Neuropsychiatric Evaluation for Depression in Parkinson's Disease
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Depression of varying severity commonly co-occurs with PD, accounting for the majority (up to 90%) of psychiatric referrals of PD patients.2 The estimated rate of clinically important depression in PD patients (37%) is more than twice that seen in medically ill patients (18%).3 Possible risk factors for developing depression with PD include a past history of depression, younger age at onset of parkinsonism, female gender, parkinsonian symptoms predominating on the right side of the body, rigidity, increased severity of disability, anxiety, and psychosis.4-14 Depression may be difficult to recognize in the patient with PD, because the signs of the two disorders overlap. Parkinsonism limits facial expression, slows movements, and quiets the voice, giving the patient a depressed-like affect. Disability or social embarrassment causes patients to withdraw from their usual activities. Thus, parkinsonism may mask underlying depression or, alternatively, clinicians may overdiagnose depression in parkinsonian patients.
Systematic Approach Author Manuscript
Identification and management of depression in PD requires a systematic approach. Once depression has been recognized, the first step is to reevaluate the current antiparkinsonian treatment regimen; following this, sequential steps are taken to optimize antidepressant therapy. Treatment guidelines for depression in PD lack the benefit of placebo-controlled, double-blind assessment of antidepressant efficacy in this setting.
Reevaluating the Antiparkinsonian Regimen Antiparkinsonian agents comprise either dopaminergic therapy or anticholinergic therapy. Ldopa combined with carbidopa enhances dopamine synthesis by providing more substrate. L-dopa/carbidopa is available in both regular and sustained-release forms. Amantadine
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stimulates increased dopamine release and inhibits its reuptake presynaptically. Pergolide and bromocriptine are postsynaptic dopaminergic agents. Monoamine oxidase inhibitors (MAOIs) decrease catabolism of dopamine and other catecholamines. Selegiline inhibits MAO, type B (MAO-B). Entacapone inhibits catechol-O-methyltransferase (COMT), another enzyme that breaks down dopamine. Dopaminergic agents are most beneficial for rigidity and bradykinesia; anticholinergic medications (benztropine, trihexiphenidyl) decrease the resting tremor of PD.
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Mood responses to antiparkinsonian treatment have been limited with respect to dopaminergic therapies, but MAOIs show promise as antidepressants, possibly because they have a combined effect on several catecholamines. Initially, depression was believed to be related to use of L-dopa to treat parkinsonism. Precipitation or exacerbation of depression by L-dopa cannot be excluded, but in most cases, the mood changes have alternate explanations. If depression occurs as a consequence of therapy, it responds to lowering the dosage of L-dopa.11 When tested as an antidepressant, L-dopa was not effective.10,15 In one study, bromocriptine at a dose of 85 to 220 mg daily produced significant improvement in both parkinsonian and depressive symptoms, but it has at best an adjunctive role as an antidepressant.16 Amantadine and anticholinergic medications are reported to relieve depression in some PD patients but have not been proved to be effective in double-blind, placebo-controlled trials. The side effects of anticholinergic medications make them difficult to use in many elderly PD patients. Selegiline
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The catecholaminergic activity of MAOIs has shown promising antidepressant effects.17-20 Of the two types of MAOIs, MAOI-A blocks the catabolism of norepinephrine and 5-HT; MAOI-B blocks catabolism of dopamine. Selegiline is an MAOI-B. Selegiline is metabolized to amphetamine and methamphetamine, which have sympathomimetic activity with doses greater than 30 mg per day,21 but the antidepressant activity of selegiline is mainly attributed to its MAOI properties.20 Selective serotonergic reuptake inhibitors (SSRIs)
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More studies have focused on proving efficacy of tricyclic antidepressants (TCAs) than SSRIs, but SSRIs are reported to have lower side effects, supporting their use in PD patients: they do not affect cardiac conduction, decrease seizure threshold, exert significant quinidinelike effects, or alter blood pressure.22 The main contraindication is the potential competition for metabolism by the cytochrome P450 system; sertraline has relatively fewer inhibitory effects than fluoxetine and paroxetine on this system of enzymes.22 Each antidepressant medication should have a six-week trial at the maximum tolerated therapeutic dosage or at the appropriate plasma level. Table I summarizes interactions between antiparkinsonism and antidepressant medications. As seen in Table II, fluoxetine may worsen parkinsonism; all SSRIs may cause akathisia. Both side effects respond to reduction of the SSRI.22
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Tricyclic antidepressants
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TCAs have dopaminergic, noradrenergic, and serotonergic effects. TCAs are less easily used than SSRIs for PD patients because of orthostatic hypotension and anticholinergic effects. See Table III for recommended dosages. Patients unresponsive to SSRIs may improve with TCA therapy; an agent with lower anticholinergic side effects (e.g., desipramine, nortriptyline) should be chosen. Monoamine oxidase and catechol-O-methyl-transferase inhibitors Late-life depression may be modulated by age-related dopamine depletion due to increases in MAO-B activity.23 Under this assumption, MAOIs other than selegiline, such as phenelzine, bifemaline, moclobemide, and brofaromine, may prove beneficial in treatment of depression in PD.24-29
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A COMT inhibitor combined with an MAOI-A would synergistically maximize catecholamines in the central nervous system. This combination has been effective in rat models for depression but has not been tested in depressed PD patients. Coadministration of COMT inhibitors with antiparkinsonian agents, a peripherally acting COMT inhibitor, and moclobemide, an MAOI-A, may have antidepressant effects in humans.30,31 Combined reuptake inhibitors
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Newer antidepressant medications—venlafaxine, nefazodone, and mirtazapine—have appealing pharmacokinetic profiles and, as combined reuptake inhibitors, may be effective for depression in PD patients. Venlafaxine has no apparent contraindication in PD patients. 32 Its most common side effects are similar to those of the SSRIs: nervousness, sweating, nausea, sedation, anorexia, dry mouth, and dizziness.22 Nefazodone, a chemical analogue of trazodone, has relatively more serotonergic than noradrenergic activity, acting both presynaptically and postsynaptically.22 Its short half-life and weak noradrenergic activity reduce the risk of sedation or orthostatic hypotension and may be better tolerated by elderly patients.22 Mirtazapine directly increases noradrenergic neurotransmission by direct alpha2receptor blockade and indirectly enhances serotonergic neurotransmission.33 Depressed patients tolerated mirtazapine much better than amitriptyline and doxepin, evidencing no anticholinergic, adrenergic or SSRI side effects, but complained of sedation.34 Other medications such as atypical antidepressants or agents that act on dopamine, opiate, or neuropeptide receptors may have applications based on the neurobiology of PD and depression. The use of these agents has not yet been comprehensively studied in this setting. 22,35,36
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Electroconvulsive therapy Electroconvulsive therapy (ECT) has proved antidepressant efficacy and merits special consideration in PD patients. ECT is useful if patients are suicidal or are resistant to treatment with antidepressant medications. Despite its adverse effects (amnesia, disorientation, slurred speech, tremors, increased intraocular pressure, urinary retention, paralytic ileus),37 ECT has greater efficacy and tolerability than TCAs.37 In addition, it has
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antiparkinsonian effects.38,39 PD patients are more susceptible to prolonged delirium after unilateral and bilateral ECT treatments,40 and the motor response to ECT is transient.
Comments Once adequate antidepressant therapy has been identified, antidepressant medications should be continued for at least six months before tapering of the drug is attempted. Chronic treatment may be necessary.
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Depression in PD causes significant morbidity and mortality, and it is difficult to treat. Treatment of the elderly PD patient with SSRIs, TCAs, or ECT must be carried out judiciously, with respect for potentially increased pharmacodynamic sensitivity, slower clearance of drug metabolites, and higher plasma concentrations. Anticholinergic effects are less well tolerated by elderly patients; they develop urinary retention, blurred vision, constipation, paralytic ileus, impaction, and dry mouth that prevents them from wearing dentures comfortably. A “serotonin syndrome” occurs infrequently with coadministration of selegiline and SSRIs or TCAs, but the United States Food and Drug Administration recommends against giving any antidepressant (TCA or SSRI) and selegiline simultaneously. Serotonin syndrome consists of hyperpyrexia, tremors, agitation, restlessness, and decreased mental status; it has proved fatal rarely.41
Conclusion
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PD is a common neurological illness. Depression may be difficult to diagnose in a PD patient, because the signs of the disorders overlap. Treatment of depression in PD patients is crucial, because it may significantly slow cognitive decline, reduce deterioration in activities of daily living, and retard progression to more advanced Hoehn and Yahr stages. Figure 1 illustrates a practical approach to the treatment of depression in PD. The pharmacological interventions listed address deficiencies of dopamine, serotonin, and norepinephrine in depressed PD patients.
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Surprisingly few placebo-controlled studies of antidepressant therapy for PD patients exist. Of these, TCAs show efficacy, and selegiline, a selective MAOI has antidepressant and antiparkinsonian efficacy. Nevertheless, the neurobiology of PD and depression indicates that newer medications, including serotonergic agents that act both pre- and postsynaptically and COMT inhibitors, offer potential antidepressant treatment. Adverse effects of polypharmacy in the elderly complicate treatment of depression in most PD patients. A “serotonin syndrome” has occurred frequently enough to preclude coadministration of selegiline with SSRIs or TCAs. Multiple drug-drug interactions between antiparkinsonism and antidepressant medications complicate treatment strategies in these patients. ECT represents a treatment option for depression in PD patients.
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Acknowledgments This work has been funded by an Alzheimer's Disease Center (AG10123) grant from the National Institute on Aging, the Sidell-Kagan Research Fund, and the Department of Veteran Affairs Geriatric Neurology Fellowship.
References
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1. Adams, RD., Victor, M. Principles of Neurology. 4th ed.. McGraw-Hill; New York: 1989. p. 1286 2. Mindham RHS. Psychiatric symptoms in parkinsonism. J Neurol Neurosurg Psychiatry. 1970; 33:188–191. [PubMed: 5443478] 3. Rodin G, Voshart K. Depression in the medically ill: An overview. Am J Psychiatry. 1986; 143:695– 705. 4. Cole SA, et al. Depression and disability in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 1996; 8:20–25. [PubMed: 8845697] 5. Kostic VS, et al. Effect of age at onset on frequency of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1994; 57:1265–1267. [PubMed: 7931395] 6. Starkstein SE, et al. Depression in patients with early versus late onset of Parkinson's disease. Neurology. 1989; 39:1441–1445. [PubMed: 2812320] 7. Wagner ML, Fedak MN, Sage JI, Mark MH. Complications of disease and therapy: A comparison of younger and older patients with Parkinson's disease. Ann Clin Lab Sci. 1996; 26:389–395. [PubMed: 8879356] 8. Barber J, Tomer R, Sroka H, Myslobodsky MS. Does unilateral dopamine deficit contribute to depression? Psychiatry Res. 1985; 15:17–24. [PubMed: 3859881] 9. Brown R, Jahanshahi M. Depression in Parkinson's disease: A psychosocial viewpoint. Adv Neurol. 1995; 65:61–84. [PubMed: 7872153] 10. Goodwin FK. Behavioral effects of L-dopa in man. Sem Psychiatry. 1971; 3:477–492. 11. Shaw AM, Lees AJ, Stern GM. The impact of treatment with levodopa on Parkinson's disease. Q J Med. 1980; 49:283–293. [PubMed: 7465763] 12. Richard IH, Schiffer RB, Kurlan R. Anxiety and Parkinson's disease. J Neuropsychiatr Clin Neurosci. 1996; 8:383–392. 13. Schiffer RB, Kurlan R, Rubin A, Boer S. Evidence for atypical depression in Parkinson's disease. Am J Psychiatry. 1988; 145:1020–1022. [PubMed: 3394854] 14. Tandberg E, Larsen JP, Aarsland D, Laake K, Cummings JL. Risk factors for depression in Parkinson's disease. Arch Neurology. 1997; 54:625–630. 15. Mindham RHS, Marsden CD, Parkes JD. Psychiatric symptoms during L-dopa therapy for Parkinson's disease and their relationship to physical disability. Psychol Med. 1976; 6:23–33. [PubMed: 778880] 16. Jouvent R, et al. Antiparkinsonian and antidepressant effects of high doses of bromocriptine. J Affect Dis. 1983; 5:141–145. [PubMed: 6222093] 17. Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med. 1989; 321:1364–1371. [PubMed: 2509910] 18. Przuntek H, Kuhn W, Draus P. The effect of P-(−)-deprenyl in de novo parkinsonian patients pretreated with levodopa and decarboxylase inhibitor correlated to depression and MHPG, HIAA, and HVA levels in the cerebrospinal fluid. Acta Neurol Scand. 1989; 126:153–156. 19. Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo parkinsonian patients. The French Selegiline Multicenter Trial. Mov Disord. 1993; 8(Suppl 1):S36–S40. [PubMed: 8302306] 20. Baronti F, Davis TL, Boldry RC, Mouradian MM, Chase TN. Deprenyl effects on levodopa pharmacodynamics, mood, and free radical scavenging. Neurology. 1992; 42:541–544. [PubMed: 1549214] 21. Kuhn W, Muller T. The clinical potential of deprenyl in neurologic and psychiatric disorders. J Neurol Transm Suppl. 1996; 48:85–93.
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22. Stoudemire A. New antidepressant drugs and the treatment of depression in the medically ill patient. Psychiatr Clin North Am. 1996; 19:495–514. [PubMed: 8856814] 23. Brown AS, Gershon S. Dopamine and depression. J Neurol Transm. 1993; 91:75–109. 24. Hoffman WF. Treatment of major depression and Parkinson's disease with combined phenylzine and amantadine (letter). Am J Psychiatry. 1985; 142:273. [PubMed: 3970261] 25. Hargrave R, Ashford JW. Phenelzine treatment of depression in Parkinson's disease. Am J Psychiatry. 1992; 149:1751–1752. 26. Moryl E, Danysz W, Quack G. Potential antidepressive properties of amantadine, memantine and bifemelane. Pharmacol Toxicol. 1993; 72:394–397. [PubMed: 8361950] 27. Lavian G, Finberg JPM, Youdim MBH. The advent of a new generation of monoamine oxidase inhibitor antidepressants: Pharmacologic studies with moclobemide and brofaromine. Clin Neuropharmacol. 1993; 16:S1–S7. 28. Haefely W, et al. Pharmacology of moclobemide. Clin Neuropharmacol. 1993; 16:S8–S18. [PubMed: 8313402] 29. Waldmeier PC, Glatt A, Jaekel J, Bittinger H. Brofaromine: A monoamine oxidase-A and serotonin uptake inhibitor. Clin Neuropharmacol. 1993; 16:S19–S24. 30. Mannisto PT, Lang A, Rauhala P, Vasar E. Beneficial effects of co-administration of catechol-Omethyltransferase inhibitors and L-dihydroxyphenylalanine in rat models of depression. Eur J Pharmacol. 1995; 274:229–233. [PubMed: 7768276] 31. Illi A, Sundberg S, Ojala-Karlsson P, Scheinin M, Gordin A. Simultaneous inhibition of catecholO-methyltransferase and monoamine oxidase A: Effects on hemodynamics and catecholamine metabolism in healthy volunteers. Clin Pharmacol Ther. 1996; 59:450–457. [PubMed: 8612391] 32. Cunningham LA. Depression in the medically ill: Choosing an antidepressant. J Clin Psychiatry. 1994; 55(Suppl A):90–97. 98-100. [PubMed: 7961548] 33. Montgomery SA. Efficacy in long-term treatment of depression. J Clin Psychiatry. 1996; 57(Suppl 2):24–30. 34. Marttila M, et al. A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharmacol. 1995; 5:441–446. [PubMed: 8998395] 35. Goetz CG, Tanner CM, Klawans HL. Bupropion in Parkinson's disease. Neurology. 1984; 34:1092–1094. [PubMed: 6431314] 36. Khawaja AM, Rogers DF. Tachykinins: Receptor to effector. Int J Biochem Cell Biol. 1996; 28:721–738. [PubMed: 8925404] 37. Rasmussen, KG., Abrams, R. The role of electroconvulsive therapy in Parkinson's disease. In: Huber, SJ., Cummings, JL., editors. Parkinson's Disease. Neurobehavioral Aspects. Oxford University Press; New York: 1992. p. 255-270. 38. Burke WJ, Peterson J, Rubin EH. Electroconvulsive therapy in the treatment of combined depression and Parkinson's disease. Psychosomatics. 1988; 29:341–346. [PubMed: 3406352] 39. Faber R, Trimble MR. Electroconvulsive therapy in Parkinson's disease and other movement disorders. Movement Disorders. 1991; 6:293–303. [PubMed: 1758447] 40. Figiel GS, et al. ECT-induced delirium in depressed patients with Parkinson's disease. J Neuropsychiatr Clin Neurosci. 1991; 3:405–411. 41. Richard IH, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Neurology. 1997; 48:1070–1077. [PubMed: 9109902]
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Figure 1.
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Algorithmic approach to pharmacological treatment of depression in Parkinson's disease: If depressed and suicidal, treat with ECT; if depressed but not suicidal, reevaluate antiparkinsonism medications. Add selegiline if not already part of antiparkinsonian regimen; if inadequately treated for depression at this point, stop selegiline and begin SSRIs. More studies have focused on proving efficacy of TCAs than SSRIs, but the side-effect profile for SSRIs is more favorable for PD patients. Each antidepressant medication should have a six-week trial at the maximum tolerated therapeutic dosage or at the appropriate plasma level; if inadequately treated for depression with SSRIs, initiate treatment with TCAs; if inadequately treated for depression, consult a specialist in mood disorders, who may use ECT; once adequate antidepressant therapy has been identified, antidepressant medications should be continued for at least six months before tapering of the drug is attempted.
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TABLE I
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Drug-Drug Interactions Drug 1
Drug 2
Effect
Amantadine
Anticholinergics
Increased anticholinergic effect
Fluvoxamine
TCAs
Inhibited TCA metabolism
L-dopa
Lithium
Increased extrapyramidal signs
L-dopa
MAOIs
Hypertensive reaction from increased dopamine and norepinephrine
MAOIs
Methylphenidate
Hypertensive reaction from increased dopamine and norepinephrine
MAOIs
SSRIs or TCAs
Serotonin syndrome
Methylphenidate
SSRIs
Inhibited SSRI metabolism
Nefazodone
SSRIs
Inhibited metabolism of nefazodone
Selegiline
SSRIs or TCAs
Rare serotonin syndrome
SSRIs
TCAs
Serotonin syndrome due to inhibited TCA metabolism
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MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants
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TABLE II
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Antidepressant and Antiparkinsonian Effects of Commonly Used Medications
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Antidepressant Effect
Antiparkinsonian Effect
Amantadine
+
++ dopaminergic
Benztropine
+
++ anticholinergic
Biperiden
+
++ anticholinergic
Bromocriptine
+
++ anticholinergic
Entacapone (COMT inhibitor)
?
+ dopaminergic
L-dopa
0
+++ dopaminergic
Selegiline
+
++
Trihexyphenidyl
+
++
Tyrosine
?
+ dopaminergic
Buspirone
−
— despite dopaminergic agonism
Fluoxetine
−
— EPS
Fluvoxamine
+
?
Paroxetine
?
—
Ritanserin
?
+ dopaminergic
Sertraline
?
—
Trazodone
?
0
Bifemaline
?
?
Brofaromine
?
?
Moclobemide
?
?
Nomifensine
+
+ dopaminergic
Phenelzine
+
— EPS
Mirtazapine
+
?
Nefazodone
+
?
Venlafaxine
?
?
+
— cholinergic
Amoxapine
?
— dopamine blockade
Clomipramine
−
?
Desipramine
+
— tremor
Imipramine
+
+++ dopaminergic
Nortriptyline
+
— cholinergic
Protriptyline
?
— cholinergic
Trazodone
?
0
++
++ dopaminergic
Antiparkinsonian Agents
SSRIs
MAOIs
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Combined Reuptake Inhibitors
TCAs Amitriptyline
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Other Treatments Bupropion
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Antidepressant Effect
Antiparkinsonian Effect
Captopril
?
0
Cholecystokinin
?
0
Lithium
+
— EPS
Tachykinin antagonists
?
0
ECT
+
+++ dopaminergic
Transcranial magnetic stimulation
+
+
+ antidepressant effect = reported to relieve depression; ++ antidepressant effect = positive outcome after placebo-controlled trial; COMT = catechol-O-methyl-transferase; ECT = electroconvulsive therapy; EPS = extrapyramidal signs (akathisia, rigidity, bradykinesia); MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants
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TABLE III
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Antidepressant Medications Used in Parkinson's Disease and Their Doses Generic Name
Initial, Daily Maximum Doses (mg)
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Fluoxetine
20, 60
Fluvoxamine
50, 300
Paroxetine
10, 50
Sertraline
50, 200
Imipramine
75, 150
Amitriptyline
75, 150
Doxepin
75, 300
Trimipramine
75, 200
Amoxapine
50, 300
Desipramine
25, 200
Nortriptyline
75, 100
Protriptyline
15, 60
Maprotiline
25, 225
Trazodone
50, 600
Phenelzine
45, 15
Nefazodone
200, 600
Venlafaxine
150, 375
Mirtazapine
20, 60
Selegiline
10, 30
Bupropion
100, 450
Entacapone
200, 200
Author Manuscript Author Manuscript Clin Geriatr. Author manuscript; available in PMC 2017 May 18.
Clin Geriatr. Author manuscript; available in PMC 2017 May 18. Published in final edited form as: Clin Geriatr. 1998 October ; 6(11): 34–46.
Treatment of Depression in the Patient with Parkinson's Disease Tiffany W. Chow, M.D. and Jeffrey L. Cummings, M.D. From the Departments of Neurology and Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, and the Neuropsychiatry and Neurobehavior Unit, Psychiatry Service, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.
Author Manuscript
Parkinson's disease (PD) is a common neurological illness, with a prevalence of approximately 100/100,000. Among neurological conditions, PD is the most commonly encountered extrapyramidal movement disorder. The cardinal manifestations of PD result from loss of dopaminergic neurons in the substantia nigra and include resting tremor resembling “pill-rolling,” slowing of movement (bradykinesia), poor balance due to impairment of postural reflexes, and rigidity. The natural history of the illness is long, but two-thirds of PD patients are at least partially disabled five years after onset.1
Neuropsychiatric Evaluation for Depression in Parkinson's Disease
Author Manuscript
Depression of varying severity commonly co-occurs with PD, accounting for the majority (up to 90%) of psychiatric referrals of PD patients.2 The estimated rate of clinically important depression in PD patients (37%) is more than twice that seen in medically ill patients (18%).3 Possible risk factors for developing depression with PD include a past history of depression, younger age at onset of parkinsonism, female gender, parkinsonian symptoms predominating on the right side of the body, rigidity, increased severity of disability, anxiety, and psychosis.4-14 Depression may be difficult to recognize in the patient with PD, because the signs of the two disorders overlap. Parkinsonism limits facial expression, slows movements, and quiets the voice, giving the patient a depressed-like affect. Disability or social embarrassment causes patients to withdraw from their usual activities. Thus, parkinsonism may mask underlying depression or, alternatively, clinicians may overdiagnose depression in parkinsonian patients.
Systematic Approach Author Manuscript
Identification and management of depression in PD requires a systematic approach. Once depression has been recognized, the first step is to reevaluate the current antiparkinsonian treatment regimen; following this, sequential steps are taken to optimize antidepressant therapy. Treatment guidelines for depression in PD lack the benefit of placebo-controlled, double-blind assessment of antidepressant efficacy in this setting.
Reevaluating the Antiparkinsonian Regimen Antiparkinsonian agents comprise either dopaminergic therapy or anticholinergic therapy. Ldopa combined with carbidopa enhances dopamine synthesis by providing more substrate. L-dopa/carbidopa is available in both regular and sustained-release forms. Amantadine
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stimulates increased dopamine release and inhibits its reuptake presynaptically. Pergolide and bromocriptine are postsynaptic dopaminergic agents. Monoamine oxidase inhibitors (MAOIs) decrease catabolism of dopamine and other catecholamines. Selegiline inhibits MAO, type B (MAO-B). Entacapone inhibits catechol-O-methyltransferase (COMT), another enzyme that breaks down dopamine. Dopaminergic agents are most beneficial for rigidity and bradykinesia; anticholinergic medications (benztropine, trihexiphenidyl) decrease the resting tremor of PD.
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Mood responses to antiparkinsonian treatment have been limited with respect to dopaminergic therapies, but MAOIs show promise as antidepressants, possibly because they have a combined effect on several catecholamines. Initially, depression was believed to be related to use of L-dopa to treat parkinsonism. Precipitation or exacerbation of depression by L-dopa cannot be excluded, but in most cases, the mood changes have alternate explanations. If depression occurs as a consequence of therapy, it responds to lowering the dosage of L-dopa.11 When tested as an antidepressant, L-dopa was not effective.10,15 In one study, bromocriptine at a dose of 85 to 220 mg daily produced significant improvement in both parkinsonian and depressive symptoms, but it has at best an adjunctive role as an antidepressant.16 Amantadine and anticholinergic medications are reported to relieve depression in some PD patients but have not been proved to be effective in double-blind, placebo-controlled trials. The side effects of anticholinergic medications make them difficult to use in many elderly PD patients. Selegiline
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The catecholaminergic activity of MAOIs has shown promising antidepressant effects.17-20 Of the two types of MAOIs, MAOI-A blocks the catabolism of norepinephrine and 5-HT; MAOI-B blocks catabolism of dopamine. Selegiline is an MAOI-B. Selegiline is metabolized to amphetamine and methamphetamine, which have sympathomimetic activity with doses greater than 30 mg per day,21 but the antidepressant activity of selegiline is mainly attributed to its MAOI properties.20 Selective serotonergic reuptake inhibitors (SSRIs)
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More studies have focused on proving efficacy of tricyclic antidepressants (TCAs) than SSRIs, but SSRIs are reported to have lower side effects, supporting their use in PD patients: they do not affect cardiac conduction, decrease seizure threshold, exert significant quinidinelike effects, or alter blood pressure.22 The main contraindication is the potential competition for metabolism by the cytochrome P450 system; sertraline has relatively fewer inhibitory effects than fluoxetine and paroxetine on this system of enzymes.22 Each antidepressant medication should have a six-week trial at the maximum tolerated therapeutic dosage or at the appropriate plasma level. Table I summarizes interactions between antiparkinsonism and antidepressant medications. As seen in Table II, fluoxetine may worsen parkinsonism; all SSRIs may cause akathisia. Both side effects respond to reduction of the SSRI.22
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Tricyclic antidepressants
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TCAs have dopaminergic, noradrenergic, and serotonergic effects. TCAs are less easily used than SSRIs for PD patients because of orthostatic hypotension and anticholinergic effects. See Table III for recommended dosages. Patients unresponsive to SSRIs may improve with TCA therapy; an agent with lower anticholinergic side effects (e.g., desipramine, nortriptyline) should be chosen. Monoamine oxidase and catechol-O-methyl-transferase inhibitors Late-life depression may be modulated by age-related dopamine depletion due to increases in MAO-B activity.23 Under this assumption, MAOIs other than selegiline, such as phenelzine, bifemaline, moclobemide, and brofaromine, may prove beneficial in treatment of depression in PD.24-29
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A COMT inhibitor combined with an MAOI-A would synergistically maximize catecholamines in the central nervous system. This combination has been effective in rat models for depression but has not been tested in depressed PD patients. Coadministration of COMT inhibitors with antiparkinsonian agents, a peripherally acting COMT inhibitor, and moclobemide, an MAOI-A, may have antidepressant effects in humans.30,31 Combined reuptake inhibitors
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Newer antidepressant medications—venlafaxine, nefazodone, and mirtazapine—have appealing pharmacokinetic profiles and, as combined reuptake inhibitors, may be effective for depression in PD patients. Venlafaxine has no apparent contraindication in PD patients. 32 Its most common side effects are similar to those of the SSRIs: nervousness, sweating, nausea, sedation, anorexia, dry mouth, and dizziness.22 Nefazodone, a chemical analogue of trazodone, has relatively more serotonergic than noradrenergic activity, acting both presynaptically and postsynaptically.22 Its short half-life and weak noradrenergic activity reduce the risk of sedation or orthostatic hypotension and may be better tolerated by elderly patients.22 Mirtazapine directly increases noradrenergic neurotransmission by direct alpha2receptor blockade and indirectly enhances serotonergic neurotransmission.33 Depressed patients tolerated mirtazapine much better than amitriptyline and doxepin, evidencing no anticholinergic, adrenergic or SSRI side effects, but complained of sedation.34 Other medications such as atypical antidepressants or agents that act on dopamine, opiate, or neuropeptide receptors may have applications based on the neurobiology of PD and depression. The use of these agents has not yet been comprehensively studied in this setting. 22,35,36
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Electroconvulsive therapy Electroconvulsive therapy (ECT) has proved antidepressant efficacy and merits special consideration in PD patients. ECT is useful if patients are suicidal or are resistant to treatment with antidepressant medications. Despite its adverse effects (amnesia, disorientation, slurred speech, tremors, increased intraocular pressure, urinary retention, paralytic ileus),37 ECT has greater efficacy and tolerability than TCAs.37 In addition, it has
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antiparkinsonian effects.38,39 PD patients are more susceptible to prolonged delirium after unilateral and bilateral ECT treatments,40 and the motor response to ECT is transient.
Comments Once adequate antidepressant therapy has been identified, antidepressant medications should be continued for at least six months before tapering of the drug is attempted. Chronic treatment may be necessary.
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Depression in PD causes significant morbidity and mortality, and it is difficult to treat. Treatment of the elderly PD patient with SSRIs, TCAs, or ECT must be carried out judiciously, with respect for potentially increased pharmacodynamic sensitivity, slower clearance of drug metabolites, and higher plasma concentrations. Anticholinergic effects are less well tolerated by elderly patients; they develop urinary retention, blurred vision, constipation, paralytic ileus, impaction, and dry mouth that prevents them from wearing dentures comfortably. A “serotonin syndrome” occurs infrequently with coadministration of selegiline and SSRIs or TCAs, but the United States Food and Drug Administration recommends against giving any antidepressant (TCA or SSRI) and selegiline simultaneously. Serotonin syndrome consists of hyperpyrexia, tremors, agitation, restlessness, and decreased mental status; it has proved fatal rarely.41
Conclusion
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PD is a common neurological illness. Depression may be difficult to diagnose in a PD patient, because the signs of the disorders overlap. Treatment of depression in PD patients is crucial, because it may significantly slow cognitive decline, reduce deterioration in activities of daily living, and retard progression to more advanced Hoehn and Yahr stages. Figure 1 illustrates a practical approach to the treatment of depression in PD. The pharmacological interventions listed address deficiencies of dopamine, serotonin, and norepinephrine in depressed PD patients.
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Surprisingly few placebo-controlled studies of antidepressant therapy for PD patients exist. Of these, TCAs show efficacy, and selegiline, a selective MAOI has antidepressant and antiparkinsonian efficacy. Nevertheless, the neurobiology of PD and depression indicates that newer medications, including serotonergic agents that act both pre- and postsynaptically and COMT inhibitors, offer potential antidepressant treatment. Adverse effects of polypharmacy in the elderly complicate treatment of depression in most PD patients. A “serotonin syndrome” has occurred frequently enough to preclude coadministration of selegiline with SSRIs or TCAs. Multiple drug-drug interactions between antiparkinsonism and antidepressant medications complicate treatment strategies in these patients. ECT represents a treatment option for depression in PD patients.
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Acknowledgments This work has been funded by an Alzheimer's Disease Center (AG10123) grant from the National Institute on Aging, the Sidell-Kagan Research Fund, and the Department of Veteran Affairs Geriatric Neurology Fellowship.
References
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Figure 1.
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Algorithmic approach to pharmacological treatment of depression in Parkinson's disease: If depressed and suicidal, treat with ECT; if depressed but not suicidal, reevaluate antiparkinsonism medications. Add selegiline if not already part of antiparkinsonian regimen; if inadequately treated for depression at this point, stop selegiline and begin SSRIs. More studies have focused on proving efficacy of TCAs than SSRIs, but the side-effect profile for SSRIs is more favorable for PD patients. Each antidepressant medication should have a six-week trial at the maximum tolerated therapeutic dosage or at the appropriate plasma level; if inadequately treated for depression with SSRIs, initiate treatment with TCAs; if inadequately treated for depression, consult a specialist in mood disorders, who may use ECT; once adequate antidepressant therapy has been identified, antidepressant medications should be continued for at least six months before tapering of the drug is attempted.
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TABLE I
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Drug-Drug Interactions Drug 1
Drug 2
Effect
Amantadine
Anticholinergics
Increased anticholinergic effect
Fluvoxamine
TCAs
Inhibited TCA metabolism
L-dopa
Lithium
Increased extrapyramidal signs
L-dopa
MAOIs
Hypertensive reaction from increased dopamine and norepinephrine
MAOIs
Methylphenidate
Hypertensive reaction from increased dopamine and norepinephrine
MAOIs
SSRIs or TCAs
Serotonin syndrome
Methylphenidate
SSRIs
Inhibited SSRI metabolism
Nefazodone
SSRIs
Inhibited metabolism of nefazodone
Selegiline
SSRIs or TCAs
Rare serotonin syndrome
SSRIs
TCAs
Serotonin syndrome due to inhibited TCA metabolism
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MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants
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TABLE II
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Antidepressant and Antiparkinsonian Effects of Commonly Used Medications
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Antidepressant Effect
Antiparkinsonian Effect
Amantadine
+
++ dopaminergic
Benztropine
+
++ anticholinergic
Biperiden
+
++ anticholinergic
Bromocriptine
+
++ anticholinergic
Entacapone (COMT inhibitor)
?
+ dopaminergic
L-dopa
0
+++ dopaminergic
Selegiline
+
++
Trihexyphenidyl
+
++
Tyrosine
?
+ dopaminergic
Buspirone
−
— despite dopaminergic agonism
Fluoxetine
−
— EPS
Fluvoxamine
+
?
Paroxetine
?
—
Ritanserin
?
+ dopaminergic
Sertraline
?
—
Trazodone
?
0
Bifemaline
?
?
Brofaromine
?
?
Moclobemide
?
?
Nomifensine
+
+ dopaminergic
Phenelzine
+
— EPS
Mirtazapine
+
?
Nefazodone
+
?
Venlafaxine
?
?
+
— cholinergic
Amoxapine
?
— dopamine blockade
Clomipramine
−
?
Desipramine
+
— tremor
Imipramine
+
+++ dopaminergic
Nortriptyline
+
— cholinergic
Protriptyline
?
— cholinergic
Trazodone
?
0
++
++ dopaminergic
Antiparkinsonian Agents
SSRIs
MAOIs
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Combined Reuptake Inhibitors
TCAs Amitriptyline
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Other Treatments Bupropion
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Antidepressant Effect
Antiparkinsonian Effect
Captopril
?
0
Cholecystokinin
?
0
Lithium
+
— EPS
Tachykinin antagonists
?
0
ECT
+
+++ dopaminergic
Transcranial magnetic stimulation
+
+
+ antidepressant effect = reported to relieve depression; ++ antidepressant effect = positive outcome after placebo-controlled trial; COMT = catechol-O-methyl-transferase; ECT = electroconvulsive therapy; EPS = extrapyramidal signs (akathisia, rigidity, bradykinesia); MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants
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TABLE III
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Antidepressant Medications Used in Parkinson's Disease and Their Doses Generic Name
Initial, Daily Maximum Doses (mg)
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Fluoxetine
20, 60
Fluvoxamine
50, 300
Paroxetine
10, 50
Sertraline
50, 200
Imipramine
75, 150
Amitriptyline
75, 150
Doxepin
75, 300
Trimipramine
75, 200
Amoxapine
50, 300
Desipramine
25, 200
Nortriptyline
75, 100
Protriptyline
15, 60
Maprotiline
25, 225
Trazodone
50, 600
Phenelzine
45, 15
Nefazodone
200, 600
Venlafaxine
150, 375
Mirtazapine
20, 60
Selegiline
10, 30
Bupropion
100, 450
Entacapone
200, 200
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