The link between depression and coronary heart disease risk may be via autonomic dysfunction that manifests as reduced heart rate variability.27 Participants in 6 of the 13 studies that looked at depression as it relates to heart rate variability had coronary heart disease. Findings from those studies indicate that depression was associated with reduced heart rate variability. However, the effect sizes were too small to draw firm conclusions and there was much variation between the studies.
Inflammatory markers include C-reactive protein, interleukin-6, tumor necrosis factor, and fibrinogen. In a 2-year follow-up study, Frasure-Smith and colleagues28 investigated the relationship between depression and inflammatory markers. Elevated depressive symptoms and raised C-reactive protein levels 2 months after an acute event were overlapping risk factors for later cardiac events in men. Carney and colleagues29 demonstrated that fibrinogen was most highly associated with altered heart rate variability in depressed patients with coronary heart disease and proposed that this could be attributable to deficits in parasympathetic modulation of immunity and coagulation. In contrast, findings from the Heart and Soul Study suggest that major depression is associated with lower levels of C-reactive protein, fibrinogen, and interleukin-6.30 Differences in assessment scales and sample heterogeneity may have contributed to these disparate findings. Whatever the precise mechanism, untreated depression in cardiac patients is hazardous.
Treatment for depression
In the Sertraline(Drug information on sertraline) Antidepressant Heart Attack Trial (SADHART), a study of 369 patients with a heart attack or unstable angina (mean age, 57), the SSRI sertraline was superior to placebo. Safety data were excellent.31 In the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study, patients with a recent history of heart attack (mean age, 61) benefited from cognitive therapy designed to modify negative thinking that may have contributed to their depression.32 Neither study showed improvement in cardiac outcomes, but there was a suggestion that larger trials might show that sertraline contributes to reduced mortality via its mechanism (shared by other SSRIs) of decreasing platelet activity.
Tricyclic antidepressants (TCAs) are type 1A antiarrhythmics that reduce heart rate variability, 2 factors linked to increased mortality. There is limited evidence on which to judge other antidepressants.33 Venlafaxine is known to raise blood pressure, although in older patients it can also lead to postural hypotension. It should not be used in patients with a high risk of ventricular arrhythmia. Therefore, the current recommended treatment for depression following an acute cardiac event or with stable heart disease is an SSRI.
As with heart disease, there is a 2-way interaction between depression and diabetes, although depression is only a modest risk factor for diabetes once lifestyle factors are accounted for.34 Other possible factors include activation of neuroendocrine pathways (leading, for example, to hypercortisolemia) and inflammatory responses that result in increased insulin resistance and the metabolic syndrome. In a large follow-up epidemiological study of middle-aged and elderly patients, those with incident type 2 diabetes were most likely to be depressed. This finding suggests that the impact of a new diagnosis is a significant factor for depression.35 It also suggests that early support might mitigate depression.
In patients aged 70 to 79 years there was a 30% increased risk of incident depression (odds ratio [OR], 1.31; 95% CI, 1.07 - 1.61), which was attenuated after adjustment for diabetes-related comorbidities (OR, 1.20; CI, 0.97 - 1.48); this still represents a significantly increased risk.36 Some studies suggest a link between depression and diabetic complications and poorer glycemic control.35,36 Painful neuropathy may be another causal factor. Diabetes can cause small-vessel pathology in the brain that leads to subcortical encephalopathy, not unlike that seen in vascular depression. This may lead to both cognitive impairment and depressed mood.
TCAs are more likely to impair diabetic control than SSRIs. Fluoxetine(Drug information on fluoxetine) should be used with caution, however, because as it can cause hypoglycemia.1 TCAs can be effective for painful neuropathy. Mirtazapine(Drug information on mirtazapine) may cause weight gain (a risk factor for diabetes), lithium(Drug information on lithium) toxicity is increased if there is nephropathy, and valproate(Drug information on valproate) may give a false-positive result on urine testing for glucose.
There is increasing interest in alternative and complementary medicine to improve glycemic control and mood in diabetic patients, including Ayurvedic medicine, exercise, yoga, and acupuncture.37 There are also reports of the benefits of CBT.38 However, as with the treatment of depression in heart disease, it has yet to be demonstrated that such interventions actually are disease modifying (as measured by glycated hemoglobin levels).37
Parkinson disease is characterized by slowness of movement, rigidity, resting tremor, shuffling gait, and postural instability.39 The reported prevalence of depressive symptoms varies widely from 7% to 76%, with an average of 40%.39,40 The cause of depression in Parkinson disease is multifactorial, but there is evidence linking it to neurodegeneration with an associated reduction in the neurotransmitter level not only of dopamine(Drug information on dopamine) but other catecholamines important in mood regulation. However, 3,4-dihydroxy- l-phenylalanine (l-dopa) does not seem to improve mood in Parkinson disease patients. Serotonin and noradrenaline are probably more important.41,42
In Parkinson disease with comorbid depression, there is more involvement of dopaminergic and noradrenergic pathways and reduced frontal metabolism than in Parkinson disease without depression.43 Other causal factors include social isolation, cognitive impairment, severity of disease, and duration of illness, although there is no consistent relationship between the last 239 Untreated depression in patients with Parkinson disease is associated with increased physical disability, impaired quality of life, and decreased social interaction. Ravina and colleagues44 found that more than 40% of their Parkinson disease patients had clinically significant depression that might benefit from intervention.
Treatment options for Parkinson disease with comorbid depression include antidepressants, electroconvulsive therapy, exercise, and CBT. Support groups and self-help programs are also encouraged.
Well-controlled clinical trials in the treatment of depression in Parkinson disease are scarce40 SSRIs are most frequently prescribed. Although there are concerns that SSRIs can cause emergent extrapyramidal effects, this is controversial.45 The combination of an SSRI and selegiline(Drug information on selegiline) can lead to the potentially fatal serotonin syndrome (altered level of consciousness, myoclonus, sweating, hyperreflexia, tremor, diarrhea, shivering, uncoordination, and fever). TCAs are not recommended because of anticholinergic effects. Tianeptine(Drug information on tianeptine) (which increases the presynaptic recapture of 5-hydroxyindole acetic acid) and moclobemide(Drug information on moclobemide) (a reversible and selective inhibitor of monoamine oxidase) have also been tried.40,41
Evidence from a small study suggests that the use of the dopamine receptor agonist mirapex combined with l-dopa may improve not only motor activity, daily activities, quality of life, and dyskinesias but also anxiety and depression in patients with Parkinson disease.46 Modafinil(Drug information on modafinil), used to counteract sleepiness, has been used in Parkinson disease; in at least 1 antidepressant drug trial (not of Parkinson disease patients) it modestly diminished fatigue and sleepiness in patients with partially responsive SSRI-treated depression.47 Lastly, deep brain stimulation is a treatment for both Parkinson disease and severe depression. To what extent this treatment may exert a specific antidepressant effect in patients with Parkinson disease is unknown, however.48