Neuroprotective effects of psychotropic drugs in Huntington's disease

• Published in: International journal of molecular sciences Vol. 14; no. 11; pp. 22558 - 22603
• Main Author: Lauterbach, Edward C
• Format: Journal Article Book Review
• Language: English
• Published: Switzerland MDPI AG 15-11-2013; Molecular Diversity Preservation International (MDPI)
• Subjects: animal model; Animals; antidepressant; antipsychotic; anxiolytic; apoptosis; Disease Models, Animal; epigenetics; gene expression; Humans; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - pathology; Huntington’s disease; hypnotic; Mice; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; mood stabilizer; neurodegenerative disease; Neuroprotective Agents - administration & dosage; Psychotropic Drugs - administration & dosage; Review
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms141122558

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington's disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin). In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine.