Lithium   is   one   of  the   oldest   and   most  widely   used   drugs   for  the   treatment   of neuropsychiatric  diseases  such  as  bipolar  disorder.  It  has  a  serious  defect  -  toxicity. Researchers  at the University of South  Florida  (USF) have been trying to find  a safer lithium,  and  they  found  that  lithium  salicylate,  an  alternative  salt  form,  may  be  the answer.

Researchers found that oral lithium salicylate can produce stable lithium levels in rats for up  to  48  hours  without  the  toxic  peak  associated  with  the  rapid  absorption  of  FDA approved Li2CO3. They concluded that lithium salicylate may be more effective than  lithium  carbonate,  but  it  will  not  be  accompanied  by  toxicity  risk,  which  is  a potentially important development of the next generation of lithium therapy.

Their results were published in the latest issue of RSC progress, a journal of the Royal Society of chemistry.

Although Li2CO3 is very effective in treating mania in bipolar disorder and is thought to reduce suicide in the depression stage of the disease, patients taking Li2CO3 often do not comply because of side effects, including hand tremor, diarrhea, vomiting, weight gain  and hypothyroidism. New drugs that  are  as effective  as Li2CO3 but have no toxicity have not yet come out.

Dr. Adam J. Smith, the lead author of the study, said: "although the therapeutic window of lithium is very narrow and there are patent substitutes, the lithium therapy approved by FDA in the United States is still regarded as the 'gold standard' for the treatment of manic depression." He is a neuroscientist at the USF health center's center of excellence in neurosurgical aging and brain repair.

"Our   previous   research   shows   that   redesigning   lithium   therapy   through   crystal engineering may produce better performance and reduce toxicity."

Smith said that crystal engineering is the use of intermolecular interactions to design and synthesize molecular solid crystal structures with desired characteristics.

In  their  latest  study,  published  in  RSC  progress,  researchers  tested  two  previously

untested lithium  salts  -  salicylate  and lactate, both  of which  are  structurally  different from Li2CO3. In laboratory rats, they found that lithium salicylate and lithium lactate   showed   "completely   different   pharmacokinetics"   compared   with   the   FDA approved  and  widely  used lithium  carbonate.  Pharmacokinetics  refers  to  the way the human body absorbs, distributes and expels drugs.

"To  our  knowledge,  this  is  the  first  pharmacokinetic  study  of lithium  salicylate  and lithium lactate in laboratory animals," Smith said.

The researchers report that these findings support the earlier suggestion that the ideal lithium preparation should be a compound that can both "flatten" the peak of high blood levels and slow down the decline of blood concentration.

"In  our  study,  this  is  exactly  the  pharmacokinetic  characteristic  of lithium  salicylate production,"  said  senior  author  Dr.  Doug  Shyle, who  is  also  a  researcher  at  the  USF center of excellence for healthy aging and brain repair. "It is worth noting that after 48 hours, lithium salicylate produced higher lithium levels in the blood and brain, but there was no sharp peak, leading to the toxicity of lithium currently used."

The  researchers  said  that  the  48  hour  window  period  represented  a  key  difference between lithium salicylate and the current FDA approved lithium therapeutic drugs. If these preclinical results are also established in humans, this will allow less frequent dose regimens  and  may reduce the troublesome  side  effects that plague traditional lithium therapy.

"Psychiatry has long struggled with the fact that although lithium is very effective in the treatment of bipolar disorder, the narrow therapeutic window and side effects often make lithium difficult and sometimes dangerous in clinical work," said Todd Gould, M.D. of the Department of Theology at the University of Maryland, a neurobiology expert on lithium mechanisms and bipolar disorder.

The pharmacokinetic data of Dr. Smith and his colleagues show that in addition to the commonly used Li2CO3, lithium salt may have a wider therapeutic window and fewer potential side effects. Studies in humans are also needed to confirm its safety and to prove that the pharmacokinetic characteristics observed in rats are similar to those observed in humans. "

Researchers  at  the  University  of San  Francisco  continue  to  pursue  a  safer  and  more effective  lithium  therapy  and  expect  to  carry  out  the  required  experiments  soon  to support early clinical trials.