lithium-chloride and Tremor

Tremor is a relatively frequent side effect of lithium and of antidepressants with serotonergic properties. It can be expected that combinations of lithium (which is itself serotonergic) with such antidepressants will enhance not only efficacy, but also the incidence of side effects, including tremor. To quantitatively monitor the effect of antidepressant augmentation of ongoing lithium therapy on tremor, lithium-maintained patients with a breakthrough episode of major depression were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (N = 14) or amitriptyline 75 mg/day (N = 17). The initial dosages could be increased after 2 weeks to 40 mg/day and 150 mg/day, respectively, and the patients were treated for 6 weeks. Tremor activity was assessed weekly, quantitatively by accelerometry and qualitatively with the Dosage Record and Treatment Emergent Symptom Scale. Statistical analysis detected no significant difference between the treatment groups with respect to changes in mean tremor activity relative to baseline. However, analysis of the pooled data showed that tremor increased significantly during the course of combined lithium and antidepressant therapy, with the greatest increments occurring independent of dosage approximately 3 weeks after initiation of combination treatment. Although the mean tremor activity subsided toward the end of treatment, tremor activity on the whole was still significantly greater after 6 weeks of combined lithium and antidepressant treatment than at the start of combination therapy. Increased tremor was not associated with decreased medication compliance, and no patient discontinued treatment because of increased tremor. Tremor frequency was not affected by the study treatments.

Topics: Adult; Aged; Amitriptyline; Antidepressive Agents; Antimanic Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Paroxetine; Statistics, Nonparametric; Tremor

The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium (10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3-II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithium chronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).

Topics: Animals; Apoptosis Regulatory Proteins; Ataxin-3; Autophagy; Autophagy-Related Protein 7; Beclin-1; Brain; Disease Models, Animal; Disease Progression; Exploratory Behavior; Humans; Lithium Chloride; Machado-Joseph Disease; Male; Mice, Transgenic; Microtubule-Associated Proteins; Motor Activity; Nerve Tissue Proteins; Neuromuscular Agents; Nuclear Proteins; Postural Balance; Repressor Proteins; Treatment Outcome; Tremor; Weight Loss

Harmaline-induced tremor in rodents is a model of essential tremor. We utilized a novel assay to quantify tremor activity in mice and found that tremor activity was dependent on harmaline dose. The first-line clinical essential tremor treatments propranolol, primidone and gabapentin and gamma-hydroxybutyrate (GHB) significantly attenuated harmaline-induced tremor. The anticonvulsants valproate and carbamazepine and the mood stabilizer lithium suppressed harmaline-induced tremor. The gamma-amino-butyric acid (GABA) receptor subtype A receptor agonist muscimol attenuated harmaline-induced tremor. By contrast, the GABA(B) receptor agonist R-baclofen increased tremor at the lowest dose tested, but had no effects at higher doses. Administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine or 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801) attenuated harmaline-induced tremor. The competitive NMDA antagonist D-4-[(2E)-3-phosphono-2-propenyl]-2-piperazinecarboxylic acid (d-CPPene) dose-dependently blocked harmaline-induced tremor, as did the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX). The metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) was inactive against tremor. The dopamine reuptake inhibitor GBR12909 and the dopamine D(1)/D(2) receptor agonist apomorphine attenuated harmaline-induced tremor. Follow-up studies indicated that dopamine D(2)/D(3) but not dopamine D(1) receptor activation likely mediates the effects of apomorphine and GBR12909. Administration of compounds with sedative side-effects had no effect on tremor activity. In summary, the present data confirm the pharmacological validity of harmaline-induced tremor in mice, quantified via a novel assay, as an animal model of essential tremor. Further, these data provide additional evidence for the roles of ionotropic glutamate, GABA(A) and dopamine D(2)/D(3) receptors in the neurobiology of harmaline-induced tremor.

Topics: Affect; Animals; Anticonvulsants; Baclofen; Behavior, Animal; Benzazepines; Carbolines; Chlordiazepoxide; Dopamine; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Glutamates; Harmaline; Lithium Chloride; Male; Mice; Mice, Inbred ICR; Muscimol; Neurotransmitter Agents; Piperazines; Propranolol; Raclopride; Receptors, Glutamate; Sodium Oxybate; Tremor

Topics: Aged; Anticonvulsants; gamma-Aminobutyric Acid; Humans; Lithium Chloride; Male; Pregabalin; Tremor