Depression in Parkinson's Disease
Depression associated with Parkinson's disease affects around 40% of patients but unfortunately, it is frequently unrecognised and untreated. However, recognition and appropriate treatment of depression in patients with Parkinson's disease is essential for clinical practice. A review of the literature concerning the epidemiology and pathophysiology of depression associated with Parkinson's disease is undertaken with specific attention given to treatment possibilities.
Parkinson's disease (PD) is among the most frequent and serious neurological disorders of later life with an estimated prevalence of one percent. The typical neurological manifestations of PD (pill-rolling tremor, muscular rigidity and hypokinesia) as well as other associated symptoms (bradykinesis/akinesis, slowness in initiating movement, postural changes, festinant gait, marked fatigue etc.) lead to a serious disability particularly in the late stage of the illness.
PD is clearly a neuropsychiatric disorder since psychiatric symptoms as well as defined psychiatric disorders (depressive disorders, dementias and psychotic disorders) can be seen in a substantial proportion of patients.
Epidemiology of depression in Parkinson's disease
It is well documented that the most common psychiatric illness associated with PD is depression (Starkstein et al., 1990; Cummings, 1992; Robertson, 1997; Schuurman et al., 2002).
Comorbid depression results in a worse outcome and makes the treatment more difficult. Unfortunately, depression in PD patients is frequently unrecognised and not treated.
However, depression associated with PD is highly treatable and the successful treatment enhances the patients' compliance with the therapy and the adaptive coping with the medical illness.
Frequency and clinical characteristics of depression in Parkinson's disease
Reviewing 26 studies published between 1922 and 1990, Cummings (1992) reported that a mean rate of depression in PD was 40% (range: 4 - 70%). He also noted that the lowest reported figures were found in studies that were done before standardised methodology or operationalised diagnostic criteria were in general use.
Considering only the 9 studies published between 1987 and 1990, the rate of depression ranged from 25 to 70% and the mean figure was 43%.
A recent review of Okun and Watts (2002) also shows that depression associated with PD is quite frequent and affects 25-40% of the patients.
There are two main types of depression encountered in PD:
- about half of depressed patients with PD met the criteria for major depressive episode (almost in all cases unipolar major depression)
- another half had minor depressive disorder or its chronic form called dysthymic disorder (Starkstein et al 1990; Cummings, 1992; Robertson, 1997)
Depression associated with PD shows some clinical differences from primary major depressive episode: in the comorbid cases there are high levels of dysphoria, anxiety, pessimism, irritability and suicidal ideation. However, on the other hand, guilt, self-blaming and psychotic features as well as completed suicide is rare (Cummings, 1992; Robertson, 1997).
Risk factors for depression in Parkinson's disease
Risk factors for depression in patients with PD are female gender, previous history of depressive illness, hypo- or bradykinesis, gait instability, greater functional disability, greater degree of left brain involvement and an earlier age of onset of PD.
On the other hand, family history of depressive and other psychiatric disorders and current age of the patient do not correlate with the presence of depression (Cummings, 1992; Robertson, 1997). It is important to note that in about 25% of cases patients had already been depressed before the onset of PD (Mayeux, 1981).
A recent retrospective study from general practice showed that depression itself might also be a risk factor for PD: 19 out of the 1358 depressed patients (1.39%) later developed PD, while the same figure among the 67,570 non-depressed subjects was 259 (0.38%). In other words, the development of PD in depressed patients was about three times more frequent than in the case of non-depressed primary care patients (Schuurman et al., 2002).
Aetiology and pathophysiology of depression in Parkinson's disease
Earlier aetiological models have suggested that the development of depression in PD was mainly a simple psychological reaction to the severe physical disability caused by the movement disorder.
However, Robins (1976) reported much higher rates of depression among the patients with PD than in a group of age and sex-matched patients with the same level of physical disability of peripheric causes (hemiplegia, paraplegia, arthritis etc.).
This finding refutes the above mentioned ("psychological reaction") hypothesis and strongly suggests that depression is a more integrant part of PD indicating that the mood disturbance might be more closely related to the brain (neurotransmitter) pathology, i.e. that depression is the direct result of underlying biochemical changes caused by the disease process (Cummings, 1992; Robertson, 1997).
The exact cause of depression in PD is still unknown, but it is very likely that the aetiology is multifactorial and the role of psychosocial factors cannot also be ruled out.
The well known morphological changes of PD involve a variety of subcortical nuclei (substantia nigra, ventral tegmental area, nucleus basalis, hypothalamus, dorsal raphe nucleus, locus ceruleus, caudate nucleus etc.) that are the major sources of neurotransmitters.
The pathological process of these subcortical structures leads to neurochemical depletion remote from these nuclei. A moderate to marked depletion (i.e. 40-90% reduction) of dopamine, norepinephrine and serotonin in these nuclei has been reported in PD (Cummings, 1992).
On the other hand, like in the cases of primary major depression, several studies have found lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) in patients with PD and major depression than in those without mood disturbance (Goodwin and Jamison, 1990; Mayeux, 1990).
Therefore, according to our present knowledge, the pathophysiology of depression in PD might be primarily related to these neurotransmitter abnormalities (and to the accompanying receptor changes), since disturbance of central serotonin, norepinephrine and dopamine metabolism is consistently demonstrated in primary depressive disorders without any medical comorbidity (Goodwin and Jamison, 1990).
Recent neurobiological studies also show that mood disturbance in PD may be mediated by dysfunction in mesocortical and prefrontal reward, motivational and stressresponse systems (Cummings, 1992).
Treatment of depression in Parkinson's disease
Antiparkinsonian drugs, when administered in the recommended dose-range for the treatment of PD, exert limited (dopamine-receptor agonists, selegiline) or no clinically significant (anticholinergic drugs, L-Dopa, amantidine, carbidopa) antidepressant efficacy in patients with PD (Cummings, 1992; Robertson, 1997).
Moreover, some of them (amantidine, carbidopa, levodopa) may also precipitate depression (Cummings, 1992;Wise and Taylor, 1990).
Therefore, manipulation of these drugs is recommended as the first step, and if ineffective, specific antidepressive pharmacotherapy is indicated.
Selegiline, a selective MAO-B inhibitor, is employed as a part of the treatment of PD, but it does not appear to have a marked effect on depression in doses at which this selectivity is present (less than 15 mg/day). However, in higher doses (25 mg/day or above), selegiline loses its MAO-B selectivity and starts to act as a non-selective MAO-I, inhibiting the degradation not only of dopamine, but also of serotonin and noradrenaline and works as an effective antidepressant (Mann et al., 1989).
Traditional antidepressants (tricyclics and others), such as impramine, desipramine, nortrityline and bupropion have all been shown to be effective in the treatment of depression in patients with PD (Cummings, 1992; Robertson, 1997; Kennedy and Frazier, 1999).
However, because of their safer nature and lower interaction- potential, selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants (venlafaxine, mirtazapine, nefazodone) as well as moclobemide (a reversible MAO-A inhibitor) become recently the first-choice agents (Caley and Friedman, 1992; Cunningham, 1994; Robertson, 1997; Greenblatt et al., 1998; Kennedy and Frazier, 1999; Rihmer et al., 2000).
Since a significant association has been reported between low CSF 5-HIAA and depression in Parkinson's patients (Mayeux, 1990), SSRIs seem to be potentially excellent drugs for treating depression in patients with PD.
In contrast to the suggestions of some previous case histories, Caley and Friedman (1992) found that fluoxetine, in doses up to 40 mg/day, did not exacerbate parkinsonian symptoms in 23 depressive out-patients with PD.
A recent openlabel prospective study including more than 50 depressed patients with PD also showed that SSRIs (citalopram, fluoxetine, fluvoxamine and sertraline) were effective in treating depression and they did not worsen PD (Dell'Agnello et al., 2001). Parkinson's patients are often on selegiline therapy (5-15 mg/day) because of their movement disorder. Despite manufacturer warnings, the incidence of serotonin syndrome while combining low dose of selegiline with antidepressant, seems to be very low (Kennedy and Frazier, 1999).
Citalopram, the most selective SSRI with a very favourable side effect and interaction profile, is a potentially promising drug in this respect. A recent 8-week-long open clinical study evaluated the effectiveness and safety of a selegiline-citalopram combination for major depression in 8 out-patients whose mild or moderate PD had previously been treated with low dose of selegiline (5-10 mg/day) and who were still on selegiline during the citalopram treatment.
The majority of the patients (6/8) responded well to citalopram (20 mg/day) and no adverse events occurred.
The findings suggest that combination of low dose of selegiline and citalopram is an effective and safe method in the treatment of major depression of patients with PD (Rihmer et al., 2000).
Investigating 18 depressed and 28 nondepressed patients with PD, Rampello et al. (2002) found that, when combined with levodopa, citalopram was effective in the treatment of depression and induced an improvement of motor performance both in depressed and non-depressed patients.
ECT might also be an effective treatment in depression with PD, particularly in drug intolerant or drug resistant cases (Cummings, 1992).
Other antidepressant treatments, such as sleep deprivation, light therapy as well as transcranial magnetic stimulation, are not well studied in PD and warrant further investigation.
1. Caley CF, Friedman JH. Does fluoxetine exacerbate Parkinson's disease? J Clin Psychiatry 1992; 53: 278-282.
2. Cummings JL. Depression and Parkinson's disease. A review. Am J Psychiatry 1992; 149: 443-454.
3. Cunningham LA. Depression in the medically ill: Choosing an antidepressant. J Clin Psychiatry 1994; 55 (Suppl. A): 90-97.
4. Dell'Agnello G, Ceravolo R, Nuti A, Bellini G, Piccinni A, D'Avino C, Dell'Osso L, Bonuccelli U. SSRIs do not worsen Parkinson's disease: Evidence from an open-label, prospective study. Clin Neuropharmacol 2001; 24: 221-227.
5. Goodwin FK, Jamison KR. Manic-depressive illness. Oxford University Press, New York 1990.
6. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998; 59 (Suppl. 15): 19-27.
7. Kennedy GJ, Frazier A. Medical comorbidity and mental disorders in older adults. Curr Opin Psychiatry 1999; 12: 451-455.
8. Mann JJ, Aarons SF, Wilner PJ, Keilp JG, Sweeney JA, Pearlstein T, Frances AJ, Kocsis JH, Brown RP. A controlled study of the antidepressant efficacy and side effects of deprenyl, a selective monoamine oxidase inhibitor. Arch Gen Psychiatry 1989; 46: 45-50.
9. Mayeux RM, Stern Y, Rosen J. Depression, intellectual impairment, and Parkinson disease. Neurology 1981; 31: 645-650.
10. Mayeux R. Depression in the patient with Parkinson's disease. J Clin Psychiatry 1990; 51 (Suppl.): 20-23.
11. Okun MS, Watts RL. Depression associated with Parkinson's disease: Clinical features and treatment. Neurology 2002; 58 (4 Suppl. 1): S63-S70.
12. Rampello L, Chiechio S, Raffaele R, Vecchio I, Nicoletti F. The SSRI, citalopram improves bradykinesia in patients with Parkinson's disease treated with L-dopa. Clin Neuropharmacol 2002; 25: 21—24.
13. Rihmer Z, Sátori M, Pestality P. Selegiline-citalopram combination in patients with Parkinson's disease and major depression. Int J Psych Clin Pract 2000; 4: 123-125.
14. Robertson MM. Depression in neurological disorders. Depression and physical illness, ed. by Robertson MM, Katona CLE. John Wiley and Sons, Chichester 1997: 305-340.
15. Robins AH: Depression in patients with parkinsonism. Brit J Psychiatry 1976; 128: 141-145.
16. Schuurman AG, van den Akker M, Ensinck KT, Metsemakers JF, Knottnerus JA, Leentjens AF, Buntinx F. Increased risk of Parkinson's disease after depression: A retrospective cohort study. Neurology 2002; 58: 1501-1504.
17. Starkstein SE, Preziosi TJ, Bolduc PL, Robinson RG. Depression in Parkinson's disease. J Nerv Ment Dis 1990; 178: 27-30.
18. Wise MG, Taylor SE. Anxiety and mood disorders in medically ill patients. J Clin Psychiatry 1990; 51 (Suppl 1): 27-32.
Published on CNSforum 13 Sep 2005