Lithium Plus An Atypical Antipsychotic Was More Effective Than Valproate Plus An Atypical Antipsychotic In One Study, But Not Another
Evaristo Nieto et al. of Spain presented a poster about the naturalistic study of the efficacy of acute treatment of manic inpatients with lithium and valproate at the 2014 meeting of the International College of Neuropsychopharmacology. In the lithium group, all patients were treated with lithium and oral antipsychotics (N=85). In the valproate group, all were treated with valproate and oral antipsychotics (N=92). Outcome was measured using scores on scales for mania and for general functioning (the YMRS and the CGI-S). The atypical antipsychotic was typically olanzepine or risperidone.
Nieto et al. found that the mean change in CGI scores from baseline to the day of discharge was significantly higher in the lithium group (-2.84 versus -2.6), and concluded that, “Although it is used in more severe cases, treatment of manic inpatients with lithium associated with antipsychotics is more effective than treatment with valproate associated with antipsychotics.”
However, W.M. Bank et al. came to the opposite conclusion in a Korean study. Bank et al. “compared the 1-year rehospitalization rates of first-episode bipolar manic patients?who were discharged while being treated with lithium or valproate in combination with an?atypical antipsychotic….The rehospitalization rate was 17.3% during the 1-year follow-up period.”
Bank et al. found significantly higher rates of rehospitalization in the lithium (23.1%) compared to the?valproate (13.3%) group using the Kaplan-Meier formula for estimations.
In a recent study comparing the efficacy of lithium and the second-generation antipsychotic quetiapine, the drugs had remarkably similar results. Researcher Andrew Nierenberg et al. presented the results at the 2014 meeting of the American Society of Clinical Psychopharmacology. In the 6-month study called CHOICE (Clinical Health Outcome Initiative Comparative Effectiveness), 482 patients received either lithium or quetiapine in addition to other medications in a manner consistent with clinical practice. For the purposes of the study, those receiving lithium could not receive quetiapine or another antipsychotic, and those receiving quetiapine could not receive lithium or another antipsychotic, but both groups could receive other types of adjunctive medications.
By the end of the 6-month study period, most patients had improved substantially, but only about a quarter of each group became truly well. The researchers suggest that patients may need a longer period of treatment or other interventions such as psychotherapy or combination treatment. Clinicians were told to use the maximum dose of lithium or quetiapine that each patient could tolerate. Mean maximum doses were 1007.5mg of lithium and 344.9mg of quetiapine.
One surprise for the researchers was that 24% of lithium patients and 27% of quetiapine patients required no other medications and improved on monotherapy.
While results were very similar for two drugs, lithium produced slightly greater side effects and produced slightly better results in patients with anxiety. This may have been due to those patients also receiving benzodiazepines, and the researchers are analyzing data to see whether the patients with anxiety did indeed receive this kind of adjunctive treatment. Quetiapine was slightly better in patients who had more manic symptoms.
In another surprise finding, patients with bipolar II disorder fared better overall than patients with bipolar I disorder. Patients with higher suicide risk did worse than those with lower suicide risk.
In a special symposium on bipolar disorder at the 2014 meeting of the American Psychiatric Association, researcher Mike Bauer reviewed a new meta-analysis that showed lithium not only has significant effects in preventing manias, but also depressions. Researcher Geddes et al. had, in a previous study called BALANCE, found that lithium was superior to valproate (Depakote). Together these findings led Bauer to the conclusion that lithium is under-used in the treatment of bipolar disorder, especially in the US, where lithium is prescribed less often than valproate.
An article by researcher Kessing in the British Journal of Psychiatry in 2012 relied on naturalistic follow up data and also showed that lithium was superior to valproate in preventing hospitalizations.
A study by researcher Willem Nolen indicated that in mono-therapy, levels of lithium in the blood needed to be 0.6 meq/L or higher in order for lithium to work better than placebo. Lithium augmentation that produced lower blood levels of 0.3 meq/L was not significant on its main outcome measure of preventing new episodes. However, compared to treatment as usual, those randomized to lithium used lower doses of atypical antipsychotics, and other data indicated that these patients had fewer suicide attempts and increased hippocampal volume.
Bauer noted that lithium-related goiter and low thyroid are easily treated, and that kidney damage while taking lithium can be prevented by avoiding episodes of lithium intoxication. It is easy to conclude that lithium should be used more often, especially given its positive effects against suicide and brain gray matter and hippocampal volume loss.
Lithium is known for protecting neurons by inducing neurotrophic factors and inhibiting cell death factors. In a new study, other mood-stabilizing drugs had similar neuroprotective and neurotrophic effects on cultured neurons from the hippocampus.
At the 2014 meeting of the International Society for Bipolar Disorders, CH Lee et al. presented evidence that lithium, carbamazepine, valproic acid, and lamotrigine all increase the outgrowth of dendrites from these cultured neurons. Therapeutic levels of these drugs increased the production of proteins like brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neurolignin 1 (NLG 1), beta-neurexin, and synaptophysin. However, so far only lithium has been shown to increase the volume of the human hippocampus as measured with MRI.
A 2004 meta-analysis of previous research showed that lithium was better than placebo at preventing affective episodes and preventing manic episodes. The evidence for the drug’s efficacy in preventing depression was less clear. A new meta-analysis by E. Severus et al. (not yet published) confirms the previous findings and provides new evidence that lithium is also better than placebo at preventing depressions.
The study also suggested that lithium is better than anticonvulsant mood stabilizers at preventing relapse and recurrence, but this finding only reached statistical significance in the prevention of new manic and hypomanic episodes.
Editor’s Note: These findings highlight the desirability of greater lithium use. The drug is currently prescribed less often in the US than it is in Europe. In addition to lithium’s efficacy in the long-term preventative treatment of bipolar disorder, there is evidence that lithium is also the best agent for suicide prevention and for neuroprotective effects.
Suicide is a serious risk for people with mood disorders. We have noted before that various studies of lithium show that the drug lowers suicide risk in people with mood disorders. A 2013 meta-analysis by Andrea Cipriani et al. in the journal BMJ confirms this finding. The review of 48 randomized controlled trials comparing lithium with placebo or other active drugs in the long-term treatment of mood disorders showed that lithium reduces the risk of suicide and death from any cause.
Lithium was more effective than placebo at reducing number of suicides and deaths from any cause, and more effective than carbamazepine and anticonvulsants in general at reducing deliberate self-harm. The authors wrote that lithium seems to reduce risk of suicide and death by more than 60% compared to placebo.
Lithium may reduce suicide risk by preventing relapse of mood disorders, but it may also have other mechanisms of action, such as decreasing aggression or impulsivity.
One thing to note about these findings is that the reduction in suicide risk also applies to those with unipolar depression, not just those with bipolar disorder. There is a case to be made that lithium treatment could be targeted specifically to reduce suicide risk.
Lithium treatment is associated with a moderate incidence of hyperparathyroidism, usually observed as an elevated concentration of calcium in the blood in addition to elevated parathormone levels, and often associated with the development of a tumor (adenoma) of the parathyroid gland.
In a recent study by Van Melick et al. published in the International Journal of Geriatric Psychiatry, among 111 patients with an average age of 75 years, 24-hour calcium excretion was elevated in only 3% of the patients, but levels of parathormone were elevated in 48%. Duration of lithium treatment was associated with lower vitamin 25OH D. Vitamin D is important for healthy bones and good cognitive functioning.
Editor’s Note: Lithium-induced hyperparathyroid should be investigated in those with elevated calcium levels, and if found, surgical removal of the parathyroid gland may be indicated. Low vitamin D is common in the US population. It is also particularly low in patients with mania and elderly patients on who have been on lithium for more than ten years. (Levels are below normal in 77% of these elderly individuals.) Assessment of vitamin D levels in those on long-term lithium is advisable, in addition to monitoring the thyroid, kidney function, and calcium metabolism.
There is some evidence that lithium can affect brain structure, particularly the size of various parts of the brain. A study by Hajek et al. presented at the 2013 meeting of the International Society of Bipolar Disorders examined patients with bipolar disorder who had either received lithium for at least two years (37 patients) or had received under three months of treatment with lithium (19 patients), and compared the size of the hippocampus in these two groups and one control group (50 people). The patients with bipolar disorder all had the disorder for at least 10 years (25 years on average) and had had a minimum of five episodes.
Those treated with lithium long-term had greater hippocampal volume than the non-lithium patients (despite having spent more time in episodes of illness), and equal volume to healthy controls. Measurements were collected via magnetic resonance imaging (MRI), and analyses were done two different ways to avoid being confounded by the changes lithium may have on water balance in the brain, a phenomenon that was recently found to affect MRI images.
Editor’s Note: These data add to the large number of studies in animals and humans indicating that lithium, in addition to preventing episodes and suicides, may have neurotrophic and neuroprotective effects.
Oxidative stress has been implicated in a wide range of illnesses, but what is it exactly? Our bodies use the oxygen we breathe to burn the fuel we get from food, and while this is a natural process, it produces byproducts known as free radicals, which are unstable molecules that can strip electrons from other molecules in a process called oxidation. Antioxidants (such as vitamin C) act as a source of electrons, helping keep other cells stable and healthy. Oxidative stress refers to the stress on our bodies from the normal effects of free radicals combined with environmental stressors like tobacco smoke or radiation.
In work presented at the 2013 meeting of the Society of Biological Psychiatry, Anna Andreason showed that over-activity of neurons increases oxidative stress through the production of reactive oxygen species (ROS). These are a type of free radicals that can damage cells in two ways: nitrosylation of proteins (adding nitric oxide to a thiol molecule), and oxidation, which results in more lasting effects on synaptic structures. The chemical compound rotenone damages mitochondria by producing ROS, and Andreason found that lithium was able to reverse this production and reverse the adverse effects of oxidative stress.
Lithium Has an Amazing Array of Positive Effects
Editor’s Note: The ability of lithium to protect mitochondria (the energy storehouse of a cell) adds to an increasingly long list of lithium’s neurotropic and neuroprotective benefits. Lithium increases cell survival factors BDNF and Bcl-2, increases markers of neuronal integrity such as N-Acetylaspartic acid (NAA), increases the volume of the hippocampus and cortex, and now helps protect mitochondria from oxidative stress. Lithium also increases the length of telomeres, which cap the ends of chromosome and protect them from damage during the DNA replication that occurs each time a cell divides. Short telomeres are associated with many kinds of medical and psychiatric diseases, as well as shorter life spans. No wonder that in addition to preventing mania and depression it has other clinical benefits, such as preventing memory deterioration, medical mortality, and suicide.
Willem Nolen, a researcher who has spent 40 years studying unipolar and bipolar disorder, recently retired from his position at Groningen Hospital in the Netherlands. In February, his retirement was celebrated with a symposium where he and other researchers discussed some of their important findings from the last several decades.
Nolen recently published a double-blind randomized study showing that in patients who were initially responsive to monotherapy with quetiapine (Seroquel), continuing the drug (at doses of 300-800mg/night) or switching to lithium were both more effective than switching to placebo over 72 weeks of long-term follow-up.
This study shows that quetiapine, which is only FDA-approved for long-term preventative treatment when used in combination with lithium or valproate (Depakote), also has efficacy when used as monotherapy.
Lithium is Highly Effective in Long-term Prevention
Nolen’s work also adds to an impressive amount of literature showing that lithium is highly effective in long-term prevention. This case is especially noteworthy because lithium was effective even in patients who had initially been selected for their response to quetiapine. (Studies that use this kind of “enriched sample” can only claim that quetiapine has long-term efficacy in those patients who initially respond well to the drug.) The data on lithium are even more impressive since the patients in this study were not enriched for lithium response.
Nolen has also conducted multiple studies of lithium, but optimal doses and target blood levels of the drug remain controversial. The therapeutic range of lithium is usually considered to be 0.6 to 1.2 meq/L, but some have argued that lower levels may still be effective. In a new analysis of those patients in the quetiapine study who were switched to lithium treatment, Nolen found that only lithium levels above 0.6 meq/L produced better results than placebo in long-term prophylaxis. Read more