You have to wonder if reduced VMAT2 levels as appears to happen in PD would promote increased cytosolic lifetime of individual DA molecules, promoting either autoxidation/cytosolic oxidative stress and/or increased MAO throughput/overload of the soluble mitochondrial electron carriers/mitochondrial oxidative stress.
Imipramine is a selective SERT inhibitor that binds with moderate affinity to both DAT and NET (Table 1). Imipramine displays high affinity for β, 5-HT2A, 5-HT1A, H1, M, and σ 1receptors and exhibits moderate affinity for σ 2 receptors (Kd of 0.31, 0.34, 2.24, 26, 85, 343, and 2,107 nM, resp.) [129, 234–237]. The chemical formula of imipramine is depicted in Figure 1.
In the 6-OHDA-lesioned rat, imipramine (10 mg/kg i.p.) improved the performance at the forced swim test, a model of depression-like behaviour [238].
The binding of [3H]-imipramine in thrombocytes of PD patients was assessed. Binding levels were significantly lower in depressed PD patients than in healthy controls, but no difference was found between depressed and nondepressed PD patients or between nondepressed PD patients and controls [239]. Another study, however, found decreased [3H]-imipramine binding levels in the thrombocytes of PD patients compared to age-matched normal individuals [240], whereas another one did not find any difference between PD patients and normal controls [241]. Another study employing [3H]-imipramine found reduced binding levels in the putamen of PD patients [242]. [3H]-Imipramine binding levels were also reduced in the putamen and prefrontal cortex of PD patients when compared to normal individuals [243].
In a case-report, a 69-year-old PD patient with depression was put on imipramine (125 mg p.o. id) as monotherapy. Imipramine improved tremor and depressive symptoms [244].
In a case-series of 12 patients with postencephalitic, vascular, or idiopathic PD, imipramine (50–150 mg p.o. id) had a favourable effect on parkinsonian features [245]. Imipramine also exerted a favourable effect on Parkinsonism and depressive symptoms in a small case-series of 3 PD patients [246]. In a case-series of 6 depressed PD patients, imipramine as monotherapy improved depression in 5 subjects and had no effect on tremor and bradykinesia [247]. In a case-series of 21 PD patients with depression, imipramine (various doses) alleviated depression in the majority of patients, without deteriorating Parkinsonism [248]. Imipramine also alleviated depression in a case-series 8 PD patients, without worsening parkinsonian disability [249].
In a four-month randomised, cross-over, double-blind, placebo-controlled trial, 70 patients with Parkinsonism (5 with a history of encephalitis, 10 with cerebrovascular disease, and 55 with idiopathic PD) were administered imipramine (up to 200 mg p.o. id). Imipramine led to an improvement of depression in 60% of patients, improved akinesia in 54% of patients, rigidity in 42%, tremor in 28%, and hypersalivation in 57% [250]. In a randomised, double-blind, placebo-controlled study, imipramine (50 mg p.o. bid to tid) was administered as monotherapy to 8 patients with Parkinsonism. Imipramine worsened tremor in one woman with postencephalitic PD and produced no effect in two others. The 5 remaining patients (4 with idiopathic PD and one with postencephalitic PD) were improved. One patient experienced a sialorrhoea reduction, whereas one bedridden patient became able to sit and one wheelchair-bound patient became able to walk [251]. In a case-series of postencephalitic (N = 11) and idiopathic (N = 13) PD patients, imipramine as monotherapy variably improved motor and nonmotor aspects of parkinsonism. The efficacy of the drug for specific symptoms was different from patient to patient [252].
In an open-label, add-on study performed in 66 L-DOPA-untreated PD patients, 43 patients were improved by imipramine. Of these, 14 noted an improvement of depressive symptoms. Eight patients were on imipramine monotherapy and 6 of these experienced an improvement in Parkinsonism [253]. In an open-label, non-randomised, uncontrolled trial, 10 PD patients were administered imipramine (25–50 mg p.o. tid) with and without trihexyphenidyl. The majority of patients reported some improvement of tremor, rigidity, and bradykinesia following the introduction of imipramine [254]. In a nonrandomised, uncontrolled, open-label study, imipramine (100–250 mg p.o. id) was administered to 15 PD patients as monotherapy. Five patients did not respond to treatment, and rigidity and bradykinesia deteriorated in some of these nonresponders. Five patients improved mildly, mainly in bradykinesia and rigidity, but not in tremor. Five patients were markedly improved and regained some autonomy [255]. In a study of 8 patients with Parkinsonism, imipramine as monotherapy or in combination with trihexyphenidyl led to an improvement of depressive symptoms and rigidity [256].
In a case-series, imipramine (50 mg p.o. tid) was administered to 50 patients with Parkinsonism. 37 patients were improved. Bradykinesia was the most improved symptom. Cases of confusion induced by imipramine were reported [257]. In another case-series, imipramine (100–200 mg p.o. id) was administered to 15 PD patients. Parkinsonism improved in 12 patients. Three patients developed confusion [258–260]. In another case-series, imipramine (30–40 mg p.o. id) was administered to 17 PD patients and improved Parkinsonism in the majority of them [261].
In a 2-month double-blind, placebo-controlled, partly cross-over trial, imipramine (total daily dose of 10–75 mg p.o.) was administered to 32 PD patients, 21 of whom were included in the analysis. Nine received imipramine as monotherapy. No formal statistical analysis was performed, but imipramine was deemed to improve bradykinesia and rigidity but had no effect on tremor [262]. In another study, imipramine (75–150 mg p.o. id) also produced an improvement in tremor and bradykinesia in 12 PD patients [263].
In a nonrandomised, uncontrolled study, dimepramine (50–225 mg p.o. id)—a compound chemically related to imipramine, with undisclosed pharmacological properties that is believed to possess anticholinergic and adrenergic/dopaminergic agonist effects—was administered to 9 patients with parkinsonism (3 with postencephalitic PD and 6 with idiopathic PD). Dimepramine deteriorated cognitive performance and impaired arousal. The drug also decreased autonomic arousal responses, as evaluated by electrodermic skin conduction tests [264].
All of the aforementioned studies were performed with imipramine administered either as monotherapy or in combination with anticholinergic agents. To our knowledge, no study was published in which imipramine was administered with L-DOPA. However, it is possible that imipramine might reduce the efficacy of the anti-Parkinsonian action of L-DOPA, since imipramine interferes with the absorption of L-DOPA at the gastrointestinal level in both rat [265] and human [266].
A study is published in Russian [267] and another one in Danish [268] in which imipramine was used included PD patients; the details of this study will not be reviewed here.
Thoughts