Mechanisms

The Parkinson's-Reversing Breakthrough

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The underlying mechanism for depression in PD remains poorly understood, but the phenotypic expression of depressive disorders has been attributed to a combination of medical, neurochemical, and psychosocial phenomena. Depression may be a "reactive" response or demoralization phenomenon associated with the diagnosis of PD and its relative disability. However, when compared with patients with other chronic disabling conditions matched for functional disability, patients with PD exhibit greater depressive symptomatology (76). Additionally, in patients with PD, depression often precedes the onset of motor symptoms (25,77,78), and the natural history of depression in PD does not parallel the progression of physical symptoms, suggesting that it is an independent process (79,80). In comparison with control subjects, patients with PD are approximately twice as likely to experience a mood disorder (anxiety, depression, nervousness, overstrain) in the 10 years preceding onset of motor symptoms (77). These findings suggest that, in a subset of patients, depression may be an early nonmotor phenotype of PD and that disability, although it may contribute to depressive symptoms in PD, is not the sole etiologic determinant. As with anxiety, mood fluctuations are sometimes associated with medication "on" and "off" states (28).

Affective and behavioral changes (e.g., aggression, depression, mania) have also been reported as complications of deep brain stimulation (DBS), especially subthalamic nucleus (STN) DBS (81). Interestingly, depression has been infrequently reported to develop, as a result of thalamic and pallidal DBS (82). In a review of 23 articles reporting on the effect of STN DBS on mood state in PD, nine studies reported a mood elevating or antidepressant effect in 16.7% to 76% of patients, 13 studies reported a depressant effect in 2% to 33.3% of patients, and eight studies reported a mania-inducing effect in 4.2% to 8.1% of patients (83). In one series of 24 consecutive patients undergoing STN DBS, six patients (25%) experienced significant worsening of mood and three were transiently suicidal despite motor improvement (84). In a series of 137 patients who underwent STN DBS, 16 (12%) developed depression (85). Mood disturbances induced by STN DBS could be the result of stimulation spreading to adjacent nonmotor circuits, aberrant electrode placement, or activation of inappropriate contacts, resulting in stimulation of adjacent cells or fiber tracts. In some cases, alteration of the contact selection reverses the depression (86,87) Additionally, anxiety or depressive symptoms may be due to exacerbation or unmasking of previously existing disorders (88). It is also possible that depressive or anxiety symptoms may be a reactive response if the procedure was less successful than anticipated and, in some cases, depressive symptoms may be part of a "dopaminergic withdrawal syndrome" that occurs secondary to postprocedure dose-reduction of dopamimetic agents (81).

Pathologic degeneration of mesolimbic dopamine, norepinephrine, and 5-HT pathways in conjunction with degeneration of orbital-frontal circuits and subcortical structures, such as the locus coeruleus, dorsal raphe nuclei, and ventral tege-mental area, are also postulated to be associated with the expression of depressive symptoms (33,35,89,90). Imaging utilizing PET with 18fluorodeoxyglucose demonstrates increased hypometabolism in the caudate and orbital inferior frontal lobe of depressed PD patients as compared with nondepressed PD patients and with non-PD controls (91). Additionally, a significant inverse correlation between orbital inferior frontal lobe metabolic activity and severity of depressive symptoms was observed (91). Serotonergic fibers originating in the dorsal raphe project heavily toward frontal dorsal areas and serotonergic abnormalities may further disrupt activity in the dorsal frontal areas. An in vivo single photon emission computed tomography study with [123I] P-carboxymethoxy-iodophenyl tropane (P-CIT) demonstrated that in patients with PD, disruption of the brainstem raphe 5-HT system is highly correlated with mood and mentation (90).

Abnormalities in dopaminergic and noradrenergic innervation to subcortical structures have also been demonstrated. Depressed PD patients have lower [11C]RTI-32 binding (i.e., loss of dopaminergic and noradrenergic innervation) than nonde-pressed PD patients in the locus coeruleus and in several regions of the limbic system, including the amygdala, anterior cingulate cortex, the thalamus, and the left ventral striatum (35). Remy et al. (35) reported that binding of [11C]RTI-32 in the left ventral striatum was inversely correlated with the degree of apathy and the intensity of depression in the patients. This finding of laterality is consistent with other studies, reporting a link between depression and right-sided symptoms (72,92). A significant reduction in dopamine transporter availability in the left anterior putamen has also been found to be correlated with increasing severity of anxiety and depression symptoms in patients with PD (93). Abnormalities of dopamine innervation may produce mood fluctuations via effects on the posterior cingulate cortex (PCC), an area strongly linked to mood and anxiety and with known regional cerebral blood flow (rCBF) responsiveness to dopamimetic drugs. Abnormal activity in the medial frontal gyrus and PCC was demonstrated in a study of eight patients with PD, and clinically significant levodopa-related mood fluctuations (mania, depression, or anxiety) were compared to 13 patients with similarly severe PD and fluctuations of motor state but not of mood (94). The rCBF response to levodopa in the medial frontal gyrus and PCC was significantly different between mood fluctuators and control patients, with controls exhibiting a normal response after levodopa administration, whereas the mood fluctuators did not exhibit a response. The implication is that mood fluctuations may arise in PD patients who have abnormal dopaminer-gic modulation within the caudate nucleus, anterior cingulate cortex, or orbital frontal cortex, all of which innervate the PCC. Overall, the studies on the functional anatomy of depression in PD demonstrate that deficits in serotoninergic and cate-cholaminergic innervations to cortical and subcortical components are involved.

Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid, a 5-HT metabolite, have been reported to be lower in PD patients with major depression as compared with nondepressed PD patients and PD patients with minor depression (95). However, some studies have detected no differences in CSF bio-genic amine concentrations between depressed and nondepressed PD patients (96). The effect of elevated homocysteine levels on mood and cognition has also been investigated. Levodopa-induced elevations in plasma homocysteine levels in patients with PD were associated with greater depressive symptomatology, as well as impaired performance on a battery of cognitive tests (97). The association between elevated homocysteine levels and psychiatric symptomatology requires further investigation.

A search for specific susceptibility genes for depression in PD has focused on genes associated with the actions of 5-HT. Some studies have been linked to allelic variation in the 5-HT transporter gene to anxiety and depression in PD (98,99), whereas others have found no association (100). Preliminary data also demonstrate that in patients with PD, the presence of two long alleles in the CNR1 gene, which codes for CB1 cannabinoid receptors, is associated with a reduced prevalence of depression. This suggests that pharmacological manipulation of cannabinoid neurotransmission could be a novel therapeutic approach for treatment of depression in PD (101).

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Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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