Lithium Neurotoxicity at Normal Therapeutic Levels

Bell, A. J.; Cole, Adam R.; Eccleston, D.; Ferrier, I. Nicol

doi:10.1192/bjp.162.5.689

Cited by 54 publications

(31 citation statements)

References 6 publications

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“…81,82,83 In addition, lithium use was found to be associated with an increased incidence of anti-parkinson drug use or a PD diagnosis. 16 The mechanisms underlying these motor abnormalities are not known, but could be because of persistent or transient extrapyramidal syndromes caused by damage to the basal ganglia and SN.…”

Section: Discussionmentioning

confidence: 99%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T 2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tauand amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

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Section: Discussionmentioning

confidence: 99%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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“…EEG changes have also been reported in patients (378,385,386) and in normal volunteers (387). A recent article included preexisting EEG abnormalities as a risk factor for the development of neurotoxicity at therapeutic lithium levels (388).…”

Section: Lithiummentioning

confidence: 99%

Depression in Epilepsy: Etiology, Phenomenology, and Treatment

1999

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Summary: A history of depression or depressive symptomatology has been reported in up to two-thirds of patients with medically intractable epilepsy, whereas community studies have demonstrated affective disorder only in a quarter of these patients. Depression has been reported peri-and interictally. However, differentiation may be difficult in patients with frequent seizures. Most authors have found no correlation between depression and epilepsy variables. However, complex partial seizures, especially of temporal lobe origin, appear to be etiologic factors, particularly in men with left-sided foci. Depression is also more common in patients treated with polytherapy especially with barbiturates, phenytoin, and vigabatrin. Depression has also been described de novo after temporal lobectomy. Psychosocial factors also play a part, but underlying risk factors (e.g., genetic, endocrine and metabolic) may explain the increased rates of depression in people with epilepsy compared to those with other neurologic and chronic medical conditions. The depression appears to be endogenous. Patients tend to exhibit fewer neurotic traits and more psychotic symptoms such as paranoia, delusions, and persecutory auditory hallucinations. Treatment approaches include psychotherapy, rationalization of antiepileptic drug medication, antidepressant treatment, and ECT. The tricyclic and related antidepressants appear to be epileptogenic, especially in people at high risk (personal or family history of seizures, abnormal pretreatment EEG, brain damage, alcohol or substance abuse/withdrawal and concurrent use of CNS-active medication). Seizures tend to occur early in treatment or after dose increments, especially if rapidly titrated. There is little evidence that the newer antidepressants, e.g., selective serotonin reuptake inhibitors, moclobemide, venlafaxine, or nefazodone are more epileptogenic than placebo.

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“…One case report of a 17-year-old bipolar female had 2.6 mM Lithium has different neuroprotective mechanisms 960 YOUNG serum levels several hours before birth of her infant. The ity (53,54), even at normal therapeutic levels (21,303). Increased sensitivity to lithium may also occur in painfant blood levels were 2.1 mM at birth and 1.4 mM 3 days later, suggesting a lithium half-life of greater than tients with stroke (206) but apparently not in head injury where lithium is sometimes used to treat aggressive be-24 h. During the 4 days, the infant was lethargic and exhibited poor suck-swallow coordination and required havior (103).…”

Section: Lithium-induced Granulocytosismentioning

confidence: 99%

Review of Lithium Effects on Brain and Blood

2009

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Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3β (GSK3β). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/β-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

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Lithium Neurotoxicity at Normal Therapeutic Levels

Cited by 54 publications

References 6 publications

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Depression in Epilepsy: Etiology, Phenomenology, and Treatment

Review of Lithium Effects on Brain and Blood

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