Children at Risk for Bipolar Disorder May Have Adverse Reactions to Antidepressants

February 11, 2016 · Posted in Current Treatments · Comment 

adverse reaction to antidepressantsAt the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Jeffrey R. Strawn reported that among children at high risk for bipolar disorder (because of a family history of the disorder) who are prescribed antidepressants for depression and anxiety, adverse reactions are common. These reactions include irritability, aggression, impulsivity, and hyperactivity, and often lead to discontinuation of the antidepressant treatment.

Younger patients at risk for bipolar disorder were more likely to have an adverse reaction to antidepressants. Risk of an adverse reaction decreased 27% with each year of age.

Lithium Has Minimal Effects On Renal Function: Results Of Two New Large Controlled Studies

December 10, 2015 · Posted in Current Treatments · Comment 

kidney function on lithiumEarlier this year we described a 2015 study by Harald Aiff and colleagues that suggested that long-term lithium use was associated with a risk of kidney failure. That study, published in the Journal of Psychopharmacology, included 630 patients who had taken lithium for at least 10 years. One-third of these patients had evidence of kidney dysfunction, and in 5%, the impairment was severe. Two new studies provide some data that suggest these risks may not be lithium-specific and are comparable to risks that come with taking other medications.

The first, by Stefan Clos et al. in The Lancet Psychiatry, included 1,120 patients followed for up to 12 years. On average, these patients had been exposed to lithium for a little over 4.5 years. Clos and colleagues determined patients’ estimated glomerular filtration rate (eGFR), a measure of how well the blood is filtered by the kidneys. The researchers concluded that there was “no effect of stable lithium maintenance therapy on the rate of change of eGFR over time” compared to other drugs such as quetiapine, olanzapine, or valproate.

The second new study, by Lars Vedel Kessing and colleagues in the journal JAMA Psychiatry, included 26,731 patients exposed to lithium and 420,959 exposed to anticonvulsants. Kessing and colleagues concluded that both exposure to lithium and exposure to an anticonvulsant were associated with an increased rate of chronic kidney disease, but lithium was not associated with end-stage kidney disease (the kind that requires dialysis or renal transplantation).

The three studies taken together suggest the following: Taking lithium for an average of 4–5 years does not affect kidney functioning, and longer exposure may not harm kidney function any more than other medications (such as anticonvulsants) would. However, kidney functioning (in terms of eGFR) does decline with age, and is also lower among those with higher baseline eGRF, those with other illnesses, those taking other drugs that affect the kidneys, and those who experience an episode of lithium toxicity. Read more

Atypical Antipsychotics May Slow Loss of Gray Matter in Schizophrenia

September 28, 2015 · Posted in Current Treatments · Comment 

gray matter loss in schizophrenia

Progressive losses in gray matter have been observed in the cortex of people with schizophrenia, and those at high risk for the illness. In the past, studies have shown that the amount of antipsychotics a patient is exposed to is correlated with the extent of their deficits in gray matter, suggesting that antipsychotic treatment could exacerbate gray matter loss.

A new meta-analysis by Antotonio Vita and colleagues in the journal Biological Psychiatry shows that first-generation antipsychotics were associated with greater losses in gray matter compared with atypical antipsychotics, which seemed to slow the loss of gray matter.

The meta-analysis analyzed data from 18 longitudinal studies comparing a total of 1155 patients with schizophrenia to 911 healthy control participants. Magnetic resonance imaging (MRI) scans showed that over time, patients with schizophrenia lost more cortical gray matter volume. The patients’ cumulative intake of any kind of antipsychotic between MRI scans was associated with gray matter losses. But when Vita and colleagues drilled down to find differences between patients taking first-generation antipsychotics and those taking second-generation atypical antipsychotics, they found that patients with higher average daily intake of first-generation antipsychotics had greater losses in gray matter, while patients with higher average daily intake of atypical antipsychotics had less progressive losses in gray matter.

This study is the first to compare the effects of first-generation antipsychotics, which were developed in the 1960s, with those of atypical antipsychotics, which came into frequent use in the late 1980s, on cortical gray matter loss in schizophrenia. While first-generation antipsychotics are associated with the side effect of tardive dyskinesia, involuntary movements of the face and jaw, atypical antipsychotics are most commonly associated with weight gain.

Three studies have randomly assigned patients with schizophrenia to receive either first-generation or atypical antipsychotics. In these studies as well, second-generation antipsychotics were associated with smaller losses in gray matter.

The authors speculate that either second-generation antipsychotics may have neuroprotective effects, or first-generation antipsychotics may have neurotoxic effects. They also suggest that first-generation antipsychotics may not have the capacity to interfere with the natural progression of schizophrenia in terms of gray matter losses.

Future studies may investigate differences between specific antipsychotic medications’ effects on gray matter volume. Vita and colleagues reported that in the analysis, the atypical antipsychotic clozapine was associated with the least loss of gray matter of any medication in the included studies.

Editor’s Note: This study is important because it adds to findings questioning the conclusions of a large National Institute of Mental Health–sponsored study known as CATIE and a meta-analysis by John Geddes published in the journal BMJ in 2000, in which he wrote that “There is no clear evidence that atypical antipsychotics are more effective or better tolerated than conventional (first generation) antipsychotics.” Read more

Clozapine-Induced Myocarditis More Common Than Thought

June 29, 2015 · Posted in Current Treatments · Comment 

heartNew research indicates that myocarditis, inflammation of the middle layer of the heart wall, occurs in about 3% of patients who begin taking clozapine (Clozaril). Researcher Kathlyn J. Ronaldson and colleagues recently published research to this effect in the journal Acta Psychiatrica Scandinavica. Many cases of myocarditis, which can be fatal, begin with fever. Other symptoms include rapid or abnormal heart rhythms, shortness of breath, fluid retention, and fatigue. Because the illness resembles a viral infection, it may be misdiagnosed.

In 2010 Ronaldson and colleagues reported in the Journal of Clinical Psychiatry that tachycardia (rapid resting heart rate) and elevated levels of a group of proteins knows as troponin in the blood are almost always present during the first 45 days of treatment in patients who develop myocarditis. The researchers found that the time to onset of myocarditis was 14 to 22 days in almost all cases. Eosinophilia (high levels of a certain type of white blood cell) may occur in the week after peak troponin levels, and high levels of the inflammatory protein CRP (above 100mg/L) occurred in 79% of cases.

Ronaldson and colleagues suggest that patients who are prescribed clozapine be monitored for myocarditis during the first four weeks of treatment, particularly during the third week.

Long-Term Lithium Treatment Has Risks for Kidney Function, Even with Precautions

June 3, 2015 · Posted in Current Treatments · Comment 

renal functionLong-term lithium use has long been associated with decreased renal function. But some Swedish researchers noticed that most long-term studies of patients with renal failure had begun in the 1960s and 1970s. In the 1980s, when it became clear that lithium could reduce renal function, doctors began to institute new safety measures for lithium users, including monitoring of blood levels of the drug and of creatinine, a substance that is excreted by the kidneys as part of normal muscle metabolism. So the researchers undertook a new study to examine whether the protocols instituted in the 1980s had reduced the renal risks of long-term lithium use. Unfortunately, they found that some reduced renal function is still common among people who use lithium for longer than 10 years, and this risk does not necessarily decrease when patients stop taking lithium.

The researchers, led by Harald Aiff, published the study in the Journal of Psychopharmacology in 2015. They identified 4,879 patients who had been prescribed lithium, and narrowed this list down to 630 adult patients who had taken lithium for at least 10 cumulative years, who had normal levels of creatinine when they began taking lithium, and on whom good data existed. About one-third of these patients had evidence of chronic renal impairment, and in 5% of these the impairment was severe or very severe.

Aiff and colleagues’ findings show that lithium treatment requires careful monitoring, especially over the long term. Patients must consider the risk/benefit ratio of lithium treatment. Since prevention of mood episodes can preserve an average ten years of life expectancy, and lithium has the best data for efficacy in preventing manic and depressive episodes, patients must weigh the risks of insufficiently treated bipolar illness against the possibility for long-term decreases in kidney function.

Cariprazine for Mania Appears Safe and Well-Tolerated

September 30, 2014 · Posted in Potential Treatments · Comment 

white pills

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Lakshmi Latham presented a poster on three studies of the atypical atypical antipsychotic caripazine, a treatment that has not yet been approved by the Federal Drug Administration. We call it an atypical atypical because it is a partial agonist at dopamine D2 and D3 receptors, meaning it stimulates the receptors a little, but in the presence of high levels of dopamine it blocks excess activity by sitting on the receptor and preventing the actions of the excess dopamine. Aripiprazole is also a partial agonist at dopamine and serotonin 5HT1a receptors, but caripazine differs in that it has a particular affinity for the D3 receptor.

Previous analyses had revealed that cariprazine has good acute antimanic efficacy. All three studies described by Latham were randomized, double-blind, placebo-controlled three-week studies in patients with bipolar mania. In total the studies included 1065 patients, 442 of whom received placebo and 623 of whom received cariprazine.

Cariprazine doses from three studies were pooled, and ranged from 3-12 mg/day. Additional analyses evaluated the 3-6 and 9-12 mg/day groups specifically.

Approximately 70% of patients completed the study. The most common side effects included akathisia or restless legs (placebo, 5%; cariprazine, 20%), extrapyramidal disorder characterized by abnormal motor symptoms (5%, 13%), restlessness (2%, 6%) and vomiting (4%, 9%). The incidence of serious side effects was similar across the placebo and the treatment groups. Side effects that led to discontinuation of participation in the study occurred in 7% of placebo patients and 12% of cariprazine patients. Suicidal ideation was an infrequent side effect (placebo, 4; cariprazine, 2), and there were no suicide attempts.

Mean changes in weight were small (averaging 0.17kg in patients taking placebo and 0.54kg in those taking cariprazine), and the proportion of patients with 7% or higher increase in weight were similar across the two groups (both 2%). Mean changes in blood pressure and pulse were slightly greater with cariprazine and were related to dosage. Cariprazine was not associated with mean increases in electrocardiogram (EKG) parameters except for a slight increase in ventricular heart rate versus placebo (5.0 and 0.9 bpm, respectively). Mean changes in lipids and glucose were generally small and similar between groups. Levels of the hormone prolactin decreased in both groups.

Latham concluded that cariprazine treatment for three weeks was safe and well-tolerated.

Possible Heart Failure Risk with Pramipexole

February 27, 2014 · Posted in Current Treatments · Comment 

heart failure

We’ve written before about the drug pramipexole, which is typically used to treat Parkinson’s disease and restless legs, but can also improve depressed mood and cognition in those with bipolar disorder. The Federal Drug Administration (FDA) published a warning in 2012 that the drug may increase risk of heart failure, though more research is needed to confirm this link. In a review of existing studies, the FDA found that heart failure occurred more often in participants taking pramipexole than those taking placebo, but the finding did not reach statistical significance.

Genetic Test Predicts Risk of Severe Rash While Taking Carbamazepine

February 24, 2014 · Posted in Current Treatments, Risk Factors · Comment 
The types of rash that can occur with carbamazepine

The types of rash that can occur with carbamazepine

Carbamazepine (also known by its trade name Tegretol or, for extended release, Equetro) is one of the most widely used drugs for the treatment of epilepsy, and is relatively underutilized in the treatment of bipolar disorder. One of the reasons is fear of a rare serious rash or other side effects.

The risk of the serious rash ranges from about one in 5,000 to one in 10,000.  Loss of white blood cells that fight infection (a condition called agranulocytosis) occurs in about one in 20,000 people taking carbamazepine, while a decrease in white blood cells, red blood cells, and platelets (aplastic anemia) occurs in about one in 100,000 patients.

There is no way of predicting who will develop the blood disorders in reaction to carbamazepine use. A patient should contact their doctor and get a white blood cell count if they develop some warning signs of these conditions, such as a fever or sore throat without other explanation or signs of bleeding or red spots under the skin (called petechiae) that could indicate low platelets.

Genetic Test for Risk of Rash

A genetic test is available that can help estimate the likelihood of the serious rash among certain populations. In those of Asian descent, particularly Han Chinese, Thai, Malaysian, and Indian populations, having a version of the gene HLA-B known as HLA-B*1502 is highly associated with developing the rash. (The odds ratio was 79.84 in a 2013 meta-analysis by Tangamornsuksan et al. in the journal JAMA Dermatology).

In those of northern European or Japanese descent, having a version of the gene HLA-A known as HLA-A*3101 is associated with the severe rash. (Odds ratio for developing the most severe rash was 25.93 in a study of Europeans published by McCormack et al. in the New England Journal of Medicine in 2011 and 10.8 in a study of Japanese published by Ozeki et al. in the journal Human Molecular Genetics in 2011). This HLA-A*3101 gene is present in about 2 to 5% of Europeans and 9% of Japanese.

A mild, non-serious rash with redness and itchiness occurs in about 5 to 10% of patients taking carbamazepine, and almost always goes away quickly upon stopping the drug. For patients taking carbamazepine who develop any rash, stopping the drug is the safest and most conservative thing to do. However, those who have taken the HLA test who know they do not have the risk genes and have only the benign rash might want to consider continuing to take the drug.

Benefits of Carbamazepine

There are a number of reasons why carbamazepine may be worthy of a   treatment trial in patients with bipolar disorder who are not doing well on other agents. Carbamazepine works well in many patients with bipolar illness who have some of the common clinical predictors of a poor response to lithium. These include: having dysphoric (anxious, irritable) rather than euphoric mania, having an anxiety or substance disorder comorbidity, having had many prior episodes or rapid cycling (four or more episodes/year), not having distinct episodes with a period of wellness in between, having a sequential pattern of depression followed by mania followed by a well interval (D-M-I rather than M-D-I), having a schizoaffective disorder with delusions or hallucinations that persist after a manic or depressive episode has ended, and having no family history of mood disorders (especially bipolar disorder).

Some patients who do not respond to another anticonvulsant such as valproate do respond to carbamazepine. Patients with bipolar depression who have had a prior history of alcoholism may also do particularly well on carbamazepine. A benefit of the long-acting version of carbamazepine called Equetro is that it can be taken at bedtime and thus help with sleep and minimize daytime side effects.

Editor’s Note: Carbamazepine induces liver enzymes called CYP3A4 that increase the metabolism (breakdown) of carbamazepine and other drugs. Several drugs that inhibit 3A4 (such verapamil and erythromycin) prevent the breakdown of carbamazepine, causing blood levels of the drug to increase and produce side effects. If you are taking carbamazepine, tell your pharmacist so he or she can monitor any other drugs you are taking for potential interactions with carbamazepine.

Knowing about the rare skin and blood side effects of carbamazepine and some of the clinical predictors of a good response to the drug may be helpful in determining whether the potential benefits of carbamazepine outweigh the risks.

Lithium Increases Parathormone and Reduces Vitamin D Levels

February 7, 2014 · Posted in Risk Factors · Comment 

elderly woman with pills

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.

Metformin Effective for Treating Antipsychotic-Induced Amenorrhea, Weight Gain, and Insulin Resistance in Women

May 24, 2013 · Posted in Potential Treatments · Comment 

scaleTreatment with antipsychotics often has side effects such as amenorrhea (loss of the menstrual period) and weight gain that make sticking to a treatment regimen difficult for some patients. A 2012 study by Wu et al. in the American Journal of Psychiatry suggests that the drug metformin, often used to treat diabetes, can reverse these changes. The 84 female patients recruited for the study were being treated for a first episode schizophrenia, were on one antipsychotic, and had experienced amenorrhea for several months. They received either placebo or 1000mg/day of metformin in addition to their antipsychotic treatment for six months. Seventy-six women completed the trial.

Metformin was able to reverse the side effects in many of the women. Menstruation returned in 28 of the patients taking metformin compared to only two patients taking placebo. Among those on metformin, body mass index (BMI) decreased by a mean of 0.93, compared to a mean increase in those on placebo (0.85). Insulin resistance improved in the women on metformin as well.

Editor’s Note: Metformin can also delay the onset of type II diabetes in those in the borderline diabetic range. The weight loss on metformin was not spectacular and other options include the combination of the antidepressant bupropion (Wellbutrin) and the opiate antagonist naltrexone (Revia, 50mg/day), monotherapy with topiramate (Topamax), the fixed combination of topiramate and phentermine (Qsymia), or monotherapy with zonisamide (Zonegran).

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