Depression tetrabenazine

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

In Huntington s chorea, tetrabenazine is used to control movement disorders. It probably causes a depletion of nerve endings of dopamine. However, it has a useful action in only a proportion of patients and its use may be limited by the development of depression, a symptom that may already be present due to the underlying disease itself. 

Reserpine depletes cerebral dopamine by preventing intraneuronal storage (see Chapter 6) it is introduced in low doses (eg, 0.25 mg daily), and the daily dose is then built up gradually (eg, by 0.25 mg every week) until benefit occurs or adverse effects become troublesome. A daily dose of 2-5 mg is often effective in suppressing abnormal movements, but adverse effects may include hypotension, depression, sedation, diarrhea, and nasal congestion. Tetrabenazine (12.5-50 mg orally three times daily) resembles reserpine in depleting cerebral dopamine and has less troublesome adverse effects it is now available in the USA. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and... 

Tetrabenazine, reserpine Deplete amine transmitters, especially dopamine, from nerve endings Reduce chorea severity Huntington s disease other applications, see Chapter 11 Oral Toxicity Hypotension, sedation, depression, diarrhea tetrabenazine somewhat less toxic... 

A 55-year-old man with a 15-year history of schizophrenia treated with various neuroleptic drugs developed a tremor and was given tetrabenazine 75 mg/day, with complete regression of the tremor. Three months later he developed depression, a known adverse effect of tetrabenazine, which was discontinued, with subsequent partial improvement of his depressive symptoms but reappearance of the tardive tremor. Clozapine 25 mg/day was started and increased to 75 mg/day his tardive tremor again disappeared. 

MAOIs TETRABENAZINE Risk of confusion and agitation Uncertain although tetrabenazine depletes norepinephrine, if it is started on a patient who is already taking MAOIs it may stimulate the release of accumulated neurotransmitter. This would not be expected if a patient started MAOI while already taking tetrabenazine Tetrabenazine may cause depression so should be used with caution in patients with depression. If necessary, consider using an alternative antidepressant or start an MAOI after tetrabenazine has been established... 

Lilly 51641 (30) was a selective and long-lasting inhibitor of MAO-A in rat brain and other tissues. Compound 31 was the most active of a series of phenethylamines which had selective inhibitory effects on rat brain MAO-A and antidepressant activity in animals,95 Anti-tetrabenazine activity was correlated with inhibition of mouse brain MAO for a series of imidazoles, and potential antidepressant activity was greatest with 3. 96 The oxa-zolidone toloxatone (33) acted as a specific and reversible MAO-A inhibitor in rats, was clinically effective in depression, and may act per se and through its hydroxylated metabolites.97... 

Another option is to administer dopaminergic depletors such as tetrabenazine and reserpine, which have been found to reduce the severity of TD. However, depression is well recognized during treatment with tetrabenazine and especially with reserpine. Another possible step is to increase the APD dose, although this has the consequence of an unpleasant feeling of entering a vicious cycle. 

Central excitation and possibly hypertension can occur if rauwolfia alkaloids are given to patients already taking an MAOI, but is less likely if the rauwolfia alkaloid is given first. Theoretically additive blood-pressure lowering effects are also a possibility. The use of drugs that have the potential to cause depression, such as the rauwolfia alkaloids or tetrabenazine, is generally contraindicated in patients needing treatment for depression. 

A -Phenyldihydroindoles, in which there is also a structural relation to type (80-88), are the antidepressants amedalin (104) and daledalin (105). Clinical effectiveness was ascribed to both [271-273], but (104) gave scrotal and urination discomfort [272]. Compound (105) was as effective in depression as amitriptyline (5) but caused headache in 6 of 38 patients studied [273]. The pharmacological profile of (104) showed potent antagonism of reserpine induced hypothermia and tetrabenazine-induced sedation in rats. In dogs, a potentiation of NA pressor response was obtained by 1 mg kg p.o., which can be attributed to a neuronal uptake inhibiting effect of (104) [271,274]. In their series, (104) and (105) were the most potent in potentiation of adrenergic mechanisms [274]. 

Stimulant effect was reported [302]. In pharmacological tests, (119) potentiated many adrenaline like compounds and antagonized reserpine, tetrabenazine and phenothiazine. It has no anticholinergic, depressive, analgesic or local anaesthetic properties [303]. Notwithstanding structural analogy with harmaline (120), data on MAO inhibition were not presented. 

A bridged benzazocine, the analgesic cyclazocine (142), with scarcely any structural relation with this group, showed reserpine and tetrabenazine antagonism [345,346]. There was clinical improvement in patients with depression in an open trial, but a narrow therapeutic range has been mentioned [347]. 

Compounds which proved very active in the well known reserpine and/or tetrabenazine antagonizing tests are sometimes found to be of low activity or inactive in clinical practice however e.g. (31), (52). This illustrates the well known fact of the poor correlation between existing animal experiments and clinical efficacy in human depression research for developing more reliable animal tests is continuing, e.g. [7]. 

Observational stndies In an open extension study of tetrabenazine in 75 patients with Huntington s chorea for up to 80 weeks, three participants withdrew because of adverse events, including depression, delusions with associated previous suicidal behavior, and vocal tics [74 ]. When mild and unrelated adverse events were excluded, the most common adverse events were sedation/somno-lence ( = 18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared with baseline. 

Tetrabenazine was synthesized in the 1950s as part of research into compounds with reserpine-Uke activity and was initially used in the treatment of schizophrenia. Its common reversible adverse effects include drowsiness/sedation, weakness, parkinsonism, depression, and acute akathisia. 

In a prospective evaluation of 19 patients (12 women), meanage56 (range37—76)years, with Huntington s disease [65"] 18 patients completed the study and were rated after an average of 5.9 (range 2-11) months at a final mean tetrabenazine dose of 63 (range 25-150) mg/day. Adverse events included akathisia, insomnia, constipation, depression, drooling, and subjective weakness. 

In a retrospective chart review of 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years 42% men) for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19), treatment lasted for a mean of 2.3 years and efficacy was sustained in most cases [66"]. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). 

Psychiatric In a retrospective review of the charts of 518 patients treated with tetrabenazine, 246 had no history of depression, of whom 28 (11%) developed depression [7(f]. Of272 patients with a documented history of depression had a significantly higher rate of worsening in 50 cases (18%). 

Kenney C, Hunter C, Mejia N, Jankovic J. Is history of depression a contraindication to treatment with tetrabenazine Clin Neuropharmacol 2006 29(5) 259-64. 

In several antidepressant tests, (46) is very active the oral EDso in reserpine and tetrabenazine tests is 03-1 mg kg" [133,134]. Compound (46), and also its meta-MeO analogue, with 5biogenic amine uptake mechanisms in mouse and rat heart were half as potent as, and of shorter duration than, those of imipramine (I). Uptake of NA in rat medulla or hypothalamus was not inhibited by (46), but alteration of the NA-metabolite pattern was similar to that associated with (I) [136]. Ginically a rapid onset of action of (46) in depressed patients was claimed [ 137], but in subsequent trials only a minority adhered to this view in general no difference from imipramine was demonstrated in various double-blind trials [132]. It appeared to have less peripheral anticholinergic and possibly a lower intrinsic activity in blocking the monoamine uptake process than (1). In depressed patients with clear anxiety components, (46) showed also favourable results [138]. 

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