Lithium Superior to Valproate at Preventing Manias and Depressions

June 25, 2014 · Posted in Current Treatments · Comment 

smiling womanIn 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.

N-acetylcysteine Decreases Smoking

June 23, 2014 · Posted in Potential Treatments · Comment 

woman breaks a cigarette in half

It appears that the nutritional supplement n-acetylcysteine (NAC) may be useful for people who want to quit smoking. Researcher Eduardo S. T. Prado et al. reported that compared to placebo, NAC decreased the number of cigarettes a patient smoked per day and the amount of carbon monoxide they exhaled. Participants in the study took 1,500mg of NAC twice a day.

Editor’s Note: It looks as though NAC is effective in most addictions, including gambling, cocaine, heroin, marijuana, alcohol, and now smoking. Since it also helps depressed mood and anxiety in patients with bipolar illness (a finding first reported by researcher Michael Berk et al. in 2008), and can improve trichotillomania and obsessive compulsive disorder (OCD), it could be an important adjunctive treatment for many patients with bipolar illness who also suffer from many of these comorbidities. The usual dose in most of these studies was 500mg twice a day for one week, then 1,000mg twice a day thereafter, as opposed to the doses of 1,500mg twice a day that were used in the smoking study.

Antidepressant Vilazodone Superior to Placebo, Plus No Sexual Side Effects

June 20, 2014 · Posted in Current Treatments · Comment 

young couple kissing

Vilazodone (Viibryd) was approved by the Federal Drug Administration (FDA) as an antidepressant in 2011. The drug is a serotonin 5-HT reuptake inhibitor and a partial agonist of the serotonin 5-HT1A receptor like the anti-anxiety drug buspirone (Buspar). Neither buspirone nor vilazodone is associated with significant sexual dysfunction, unlike most of the antidepressants that only inhibit the serotonin transporter (selective serotonin reuptake inhibitors or SSRIs). Researcher Leslie Citrome et al. reported at the 2014 meeting of the American Psychiatric Association that at 40mg/day, the rate of remission was 32% on vilazodone versus 20% on placebo.

At the same meeting, researcher Carl Gommoll et al. reported on vilazodone’s side effects. The drug was generally well-tolerated. Side effects that occurred in 5% or more of the patients taking vilazodone and half as many taking placebo included diarrhea, nausea, vomiting, and insomnia.

New Antidepressant Vortioxetine May Improve Cognition and Treatment-Resistant Depression

June 18, 2014 · Posted in Potential Treatments · Comment 

vortioxetine

Vortioxetine (Brintellix) is a new antidepressant that has a range of effects on serotonin receptors, making it different from selective serotonin reuptake inhibitors (SSRIs), the most common type of antidepressants, which work only on the serotonin transporter. Researcher Johan Areberg et al. reported at the 2014 meeting of the American Psychiatric Association that the drug is an antagonist at receptors 5-HT3, 5-HT7, and 5-HT1D; a partial agonist at 5-HT1B; a full agonist at 5-HT1A; and an inhibitor of the 5-HT transporter. The researchers suggested that at doses of 5mg/day, vortioxetine occupies the 5-HT3 receptors and 50% of the serotonin transporter. As dosage increases to 20mg/day, vortioxetine is believed to occupy all of the serotonin targets at clinically relevant levels. Doses of 20mg/day were found to be effective in nine studies. Researcher Gennady Smagin et al. also reported that vortioxetine activates central histamine receptors.

Vortioxetine appears to be useful in patients who have previously failed to respond to antidepressants. Researcher George I. Papakostas et al. reported that in a cohort of about 500 patients who responded inadequately to previous prescriptions of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), the 252 taking vortioxetine improved more than the 241 taking the antidepressant agomelatine.

Editor’s Note: Vortioxetine’s superior effects are impressive, as agomelatine, which is approved for use in at least 41 countries including the UK, Canada, and Australia, but is not available in the US, has previously been shown to be more effective than a number of SSRIs in head-to-head comparisons. Agomelatine improves sleep and circadian rhythms via its dual effects as an agonist at melatonin M1 and M2 receptors and an inhibitor of 5HT2C receptors, which results in the release of norepinephrine and dopamine in the frontal cortex.

Vortioxetine may be unique among antidepressants in that it appears to improve cognition. Researcher John E. Harrison et al. reported that patients saw increases in executive function, attention, speed of processing, and memory while taking vortioxetine. This is consistent with studies in aged mice, whose cognition improves more on vortioxetine than on the SSRI fluoxetine, according to researcher Yan Li and colleagues.

New Drug Cariprazine Has Anti-Manic Effects

June 16, 2014 · Posted in Potential Treatments · Comment 

cariprazine

Cariprazine is a new antipsychotic drug from Hungarian company Gedeon Richter. It functions as a dopamine D3 and D2 partial agonist. The drug has shown significant antimanic effects in three placebo-controlled studies. At the 2014 meeting of the American Psychiatric Association, researcher Robert E. Litman presented findings that 32% of patients with moderate to severe mania improved to a point of minimal or no illness while taking cariprazine, versus 22% who improved similarly while taking placebo. Doses in the studies Litman presented ranged from 3mg/day to 12mg/day.

At the same meeting, researcher Lakshmi N. Yatham discussed cariprazine tolerability. At a mean dose of 7.44mg/day, side effects of cariprazine compared to placebo included akathisia (restless legs) in 20% of patients compared to 5%, extrapyramidal side effects (irregularities in movement) in 13% of patients compared to 5%, vomiting in 9% of patients compared to 4%, and restlessness in 6% of patients compared to 2%. Twelve percent of patients discontinued treatment due to side effects while taking cariprazine, compared to 7% taking placebo. Weight increased by an average of 0.54kg among patients taking cariprazine compared to an average of 0.17kg among those taking placebo. Yatham and colleagues concluded that cariprazine treatment is generally safe and well-tolerated.

It is expected that data on the positive effects of cariprazine in bipolar depression in two placebo-controlled studies will soon be published.

Also at the meeting, researcher Nika Adham et al. reported that in animal studies, cariprazine had greater affinity for the dopamine D3 receptor than aripiprazole (Abilify), another partial agonist at D2 and D3 receptors. D3 receptors are important for the regulation of cognition and mood. It is expected that cariprazine might eventually be useful in the treatment of schizophrenia.

 

Acetly-l-carnitine May Be Effective in Treatment-Resistant Depression

June 12, 2014 · Posted in Potential Treatments · Comment 

acetyl-l-carnitine pillsNot all patients with unipolar depression respond to the currently available antidepressants. Acetyl-l-carnitine is a compound that enhances mitochondrial function and neuroplasticity and is effective in the treatment of peripheral neuropathy (damage to the peripheral nerves, which sometimes occurs in chemotherapy or diabetes). It is now being investigated as an antidepressant for patients who have not responded to typical antidepressants.

According to a review of the treatment by S.M. Wang et al. published in the Journal of Psychiatric Research in 2014, acetyl-l-carnitine treated depression better than placebo did in four randomized clinical studies. It was better than placebo and equally as effective as the antidepressant fluoxetine and the atypical antipsychotic amisulpride in various studies of dysthymic disorder. It also improved depressive symptoms in people with fibromyalgia and minimal hepatic encephalopathy (liver damage). The usual dose of acetyl-l-carnitine is 1 to 2 grams/day.

Editor’s Note: The role acetyl-l-carnitine will play in treating people with treatment-resistant unipolar or bipolar depression remains to be better clarified.

Inflammation Predicts Depression Persistence

June 9, 2014 · Posted in Risk Factors · Comment 
IL-6

IL-6

Links between inflammation and depression continue to be identified in new research. Researcher N. Vogelzangs et al. reported in a 2014 article in Neuropharmacology that inflammatory and metabolic dysregulation in antidepressant users predicted an outcome of depression two years later. Elevated levels of the marker of inflammation Il-6, low HDL (or “good”) cholesterol, high triglycerides, and high blood sugar were associated with poor response to medication and chronicity of depression. Of 315 people treated with antidepressants (average age 43), 138 were in remission at 2 years, while 177 (56.2%) were still depressed. People with four or more types of inflammatory or metabolic dysregulations had a 90% chance of still being depressed at 2 years.

Among inflammatory markers including CRP and TNF-alpha, IL-6 alone was associated with chronic depression. Il-6 can cross the blood-brain barrier. We have previously reported that researcher Scott Russo found that in rats in a depression-like state known as defeat stress (brought about by repeated defeat by a larger rodent), blocking Il-6 can prevent depressive behaviors such as social avoidance or loss of preference for sucrose.

Like inflammation, metabolic abnormalities also complicate depression. Lipid dysregulation and hyperglycemia are associated not only with depression persistence, but also with the new onset of depression in humans.

Vogelzangs et al. conclude that these data “ suggest that inflammatory and metabolic dysregulation worsens depression course owing to reduced [antidepressant] response and that alternative intervention treatments may be needed for depressed persons with inflammatory and metabolic dysregulation.”

It is noteworthy that a 2014 meta-analysis of the anti-inflammatory drug celecoxib (Celebrex) published by Farhad Faridhosseini et al. in Human Psychopharmacology, showed that the drug, often prescribed for arthritis, is effective for unipolar depression when added to patients’ regular treatment.

It remains to be ascertained whether celecoxib’s effects are seen in depression in general, or if they pertain only to the 30% of depressed patients who show inflammation at baseline. Typical markers of inflammation include Il-6, CRP, TNFa, and Il-1.

Statins, prescribed to lower cholesterol, also have anti-inflammatory effects, and are also effective in preventing depression.

Determining treatment approaches for those patients showing signs of inflammation or metabolic irregularities remains a high priority for study. The preliminary data noted here suggest that treating these dysregulations in those with depression may be useful.

Psychotherapy More Effective Than Collaborative Care in Bipolar Depression with Anxiety Disorder Comorbidity

June 6, 2014 · Posted in Current Treatments · Comment 

anxious man

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a long-term study of treatments for bipolar disorder, recently found that psychotherapy was more effective than their normal collaborative care model (consisting of regular illness evaluation and treatment) for patients with bipolar disorder and a current or lifetime presence of an anxiety disorder.

An anxiety disorder comorbidity is consistently associated with a poor outcome in patients with bipolar disorder. In a 2014 article by Deckersbach et al. in the American Journal of Psychiatry, the STEP-BD research group reported that the effect of psychotherapy was particularly strong in those with comorbid post-traumatic stress disorder (PTSD) or generalized anxiety disorder.

While antidepressants are typically used to treat anxiety disorders in unipolar depression, this has not been proven effective in bipolar disorder. Not only do patients with bipolar disorder tend to respond poorly to antidepressants, but in research collected by this editor Robert Post and colleagues in the Bipolar Collaborative Network, patients with bipolar disorder who had an anxiety disorder fared even more poorly on antidepressants as adjuncts to mood stabilizers than those with bipolar disorder without an accompanying anxiety disorder.

The poor response to antidepressants in bipolar depression in general, and particularly in those with a comorbid anxiety disorder, together with the finding that psychotherapy is highly effective, suggest that adjunctive psychotherapy is a more appropriate choice for patients with bipolar depression and a comorbid anxiety disorder.

The choice of the best pharmacological treatment of this comorbid anxiety disorder deserves specific comparative study. Candidates would include the mood stabilizing anticonvulsants valproate, lamotrigine, and carbamazepine; the atypical antipsychotics with efficacy in bipolar depression (quetiapine, lurasidone, and olanzapine combined with fluoxetine); and those used as an adjunct in unipolar depression (quetiapine again and aripiprazole).

Cynicism Linked to Dementia

June 4, 2014 · Posted in Risk Factors · Comment 

distrust

A decades-long study called Cardiovascular Risk Factors, Aging and Dementia (CAIDE) observed older participants for signs of dementia, and collected data on participants’ levels of cynical distrust, for example, the belief that others will lie or cheat for personal gain and that it’s safer not to trust anyone.

A 2014 study by Elisa Neuvonen et al. in the journal Neurology reported that after adjusting for demographic and other factors, those participants with the highest levels of cynical distrust of others were at higher risk for dementia as they aged. This relationship was not explained by depressive symptoms. The authors suggest that a positive attitude may protect the brain.

The researchers acknowledge that it is possible the distrust may be a result of brain changes leading to dementia, rather than the cause of it.

Those with the highest levels of cynical distrust were also at higher risk for death, but this association disappeared when the researchers controlled for socioeconomic factors and health behaviors such as smoking.

The researchers hope to investigate whether having a cynical attitude early in life is more robustly linked to mortality. It would be exciting to determine whether a shift to a more positive attitude earlier in life could prevent dementia.

Editor’s Note: A high level of chronic anger is associated with shorter telomeres. Telomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are linked to multiple medical and psychiatric disorders. It may be that cynical distrust shortens telomeres, and is thus associated with dementia.

Twin Study Helps Clarify Epigenetic Component to Bipolar Disorder

May 21, 2014 · Posted in Risk Factors · Comment 

twins

An epigenetic finding from a study of twins may shed light on why some people develop bipolar disorder and others don’t.

Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound. In this way twins’ DNA can differ—not in its sequence but in its physical structure and the ease with which it produces proteins.

At the 2014 meeting of the International Society for Bipolar Disorders, researcher J. Ayers Ringlera et al. presented their study of pairs of twins in which one twin had bipolar disorder and the other didn’t. The ill twins showed more methylation of SLC1A2, the gene for the excitatory amino acid transporter 2 (EAAT2), which clears the excitatory neurotransmitter glutamate from the synapse of neurons. Methylation of the gene suppresses the amount of transporter expressed, so less glutamate gets cleared.

Editor’s Note: Glutamate abnormalities play a role in bipolar disorder. This finding by Ringlera et al. may explain why the drug N-acetylcysteine (NAC) works in bipolar disorder—NAC increases the number of glial glutamate transporters and helps clear excess glutamate from the synapse.

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