Reversible neurotoxicity

Lee SH, Yang YY. Reversible neurotoxicity induced by a combination of clozapine and lithium a case report. Zhonghua Yi Xue Za Zhi (Taipei) 1999 62(3) 184-7. 

The combination of clozapine and lithium has been studied in a randomized controlled trial in 10 patients with schizophrenia and 10 with a schizoaffective disorder taking clozapine with either lithium or placebo for 4 weeks (299). The combination was well tolerated, except for reversible neurotoxic reactions in two patients with schizophrenia, and safety measures showed no significant variations. The authors concluded that the lithium added to clozapine appears to afford potential benefit in schizoaffective disorders without harmful effects for schizophrenia, however, it did not afford improvement but posed a risk of lithium toxicity. 

Meyers CA, Valentine AD, Wong FC, Leeds NE. Reversible neurotoxicity of interleukin-2 and tumor necrosis factor correlation of SPECT with neuropsychological testing. J Neuropsychiatry Clin Neurosci 1994 6(3) 285-8. 

Cases of severe reversible neurotoxicity and parkinsonism are on record (SED-11,143) (SEDA-18, 82) (5,6). Severe nervous system syndromes may also result from interactions (see the monograph on Opioid analgesics). 

Keitner GI, Rahman S. Reversible neurotoxicity widi combined lithium-haloperidol administration. J Clin Psychopharmacol (1984) 4,104-5. 

A study in 14 treatment-resistant depressed patients aged between 61 and 82 found that 7 showed eomplete improvement and 3 showed partial improvement, 3 to 21 days after lithium was added to treatment with the tricyclic or related antidepressants. Lithium adverse effects occurred in 6 patients 4 of whom stopped lithium as a result. One of them was successfully restarted at a lower dose. Tremor was the most frequent adverse effect, and reversible neurotoxicity with a stroke-like syndrome was the most severe. The antidepressants used were amitriptyline, doxepin, maprotiline and trazodone. A meta-analysis of 9 studies on the acute treatment of unipolar or bipolar depression indicated that the combined use of a mood stabiliser (lithium in 6 studies) and a tricyclic antidepressant was associated with an increased risk of switches into (hypo)mania, when compared with a mood stabiliser alone. It was suggested that monotherapy with a mood stabiliser should be tried to see if it is effective, before adding an antidepressant. Tricyclics were considered to be second-line antidepressants, with SSRIs the preferred choice. ... 

A retrospective study of patient records revealed 5 patients with bipolar affective disorder, treated with lithium carbonate 900 mg to 2.4 g daily, who had developed a reversible neurotoxic syndrome with ataxia, dysarthria. 

Nervous System Reversible Neurotoxicity. Reversible neurotoxicity can occur with lithium. A review of 52 cases in the literature in which patients presented with neurotoxic manifestations, but recovered with time was published [82review] Patients ranged from 10 to 80 years old, and women were over-represented. Patients frequently presented with delirium, along with dyscoordination, tremor, and hyperreflexia. Most patients had serum levels below 1.5 mM. Only eight cases had levels greater than 1.5 mM [82 ]. 

A multicenter, observational study investigated the effectiveness and toxicity of colistin in a paediatric intensive care setting. Seventy-nine patients were followed with a median age of 30 months. Four serious adverse events were recorded, including two of each of renal failure and seizures [134 ]. A survey study of 229 paediatric infectious disease specialists gathered data on 92 cases of colistin use in children. Twenty-two percent of children developed nephrotoxicity and four children developed reversible neurotoxicity. Concemingly development of resistance to colistin was noted in 20.5% [135 j. 

A eomparison of the acute and long-term effects of MDMA with those of its homologs MDA and N-ethyl-methylenedioxyamphetamine (MDE) also eontrasts the acute and neurotoxic effects of these compounds. It has previously been demonstrated that all three drugs produce the acute depletion of 5-HT measured at 3 hours (Schmidt 1987b). However, as shown in figure 10, if the animals are allowed to survive for 1 week after drug administration, only MDA- and MDMA-treated rats show the reduction in 5-HT concentrations and [ H]5-HT uptake indicative of neurotoxicity. Therefore, the depletion of 5-HT produced at 3 hours by MDE was completely reversible. These results are similar to our observations with the... 

The data deseribed above demonstrate that destruction of serotonin axons by MDMA involves the serotonin aetive uptake carrier and that administration of citalopram, a selective serotonin uptake blocker, prior to administration of MDMA, ean prevent the decreases in serotonin markers elicited by MDMA alone. These data are eonsistent with previous reports for other potent serotonin neurotoxins, demonstrating that pretreatment with serotonin uptake blockers can prevent the neurotoxic effects of parachloroamphetamine (Ross 1976 Sanders-Bush and Steranka 1978). Furthermore, it has been shown that MDMA-induced neurotoxicity can be prevented or reversed if a serotonin uptake blocker such as fluoxetine is administered no later than 12 hours after MDMA treatment (Schmidt 1986). 

Blanchard BJ, Chen A, Rozeboom LM, Stafford KA, Weigele P, Ingram VM (2004) Efficient reversal of Alzheimer s disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A 101(40) 14326... 

Neurotoxicity. Clinical signs indicative of disturbances of the nervous system in exposed humans have been well documented in short-term studies at high doses and appear to be reversible. These effects are characteristic of cyanide toxicity. Animal studies confirm findings in humans. In longer-term studies, effects on the nervous system have also been reported, but it is not certain if these effects are permanent or reversible following termination of acrylonitrile exposure. 

III. The answer is d, (Hardman, pp 1247, L135.) Leucovorin prevents methotrexate from inhibiting dihydrofolate reductase and reverses all of its adverse effects except neurotoxicity... 

Ladefoged O, Roswall K, Larsen J-J. 1994. Acetone potentiation and influence on the reversibility of 2,5-hexanedione-induced neurotoxicity studied with behavioral and morphometric methods in rats. Pharmacol Toxicol 74 294-299. 

The front end of this tier approach is a screen, the functional observation battery (FOB) Gad (1982) or Irwin (1968) screen. This is the tool of choice for initial (and for most of the compounds covered by this volume, the only screen tests for) identification of potentially neurotoxic chemicals. The use of such screens, other behavioural test methods, or what are generally called clinical observations does, however, warrant one major caution or consideration. That is that short-term (within 24 hr of dosing or exposure) observations are insufficient on their own to differentiate between pharmacologic (reversible in the short term) and toxicological (irreversible) effects. 

The type, severity, number, and reversibility of the effect should be considered. Generally a pattern of related effects is more persuasive evidence of neurotoxicity than one or a few unrelated effects. 

Caffeine is the most widely consumed stimulant drug in the world. It occurs naturally in coffee, tea, and the cola nut and is added to many soft drinks. Many of us consume coffee and soft drinks because of the desirable stimulatory effects produced by caffeine many of us have consumed too much caffeine and felt the consequences. The undesirable effects of caffeine, the agitation, the inability to concentrate, the mild tremors, and the general unpleasantness, are a form of neurotoxicity. Literally your brain, and more specifically, the adenosine receptors in your brain, has too much caffeine. These effects are a reversible form of neurotoxicity. Fortunately, we metabolize caffeine quickly and the undesirable effects end. By experience we have learned how to moderate our caffeine consumption to avoid the unpleasant side effects. A great deal of money is made from the neuroactive and physiological effects of caffeine. You can learn more about this fascinating drug in the chapter on caffeine. 

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