Psilocybin May Improve Treatment-Resistant Depression

November 10, 2016 · Posted in Potential Treatments · Comment 
ingredient in magic mushrooms may treat depression

Psilocybin mushrooms

A small, uncontrolled study in the journal Lancet Psychiatry suggests that psilocybin, an ingredient in hallucinogenic mushrooms, relieved depression symptoms for up to three months in seven of 12 participants with unipolar depression that had not responded to at least two antidepressant medications.

Psilocybin has a different mechanism of action than typical treatments for depression. It activates 5HT2A serotonin receptors.

The participants, who had moderate to severe depression, were given two oral doses of psilocybin, a low dose (10mg) to establish the safety of the intervention, and a higher dose (25mg) seven days later. Psychedelic effects (anxiety, confusion, nausea, and headache) peaked within two to three hours and had dissipated by six hours after the intervention.

Depression began to improve within 24 hours after the 25mg dose. Depression symptoms were significantly improved by one week after the intervention. Eight of the 12 participants had a complete remission of their depression after one week, and this lasted the full three months in five participants. By the end of the three months, a total of seven of the 12 participants met the criteria for response to psilocybin.

The study’s authors, led by Robin L. Carhart-Harris, suggest that their preliminary results warrant more systematic investigation of psilocybin, but because there was no comparison group in this study, a large placebo effect cannot be ruled out.

Efficacy of Direct Current Stimulation in Major Depression

November 16, 2015 · Posted in Potential Treatments · Comment 

tDCSA new meta-analysis presented at the 2015 meeting of the Society of Biological Psychiatry has clarified the efficacy of transcranial direct current stimulation (tDCS) in major depression. TDCS is a treatment in which electrodes deliver a steady low level of electrical stimulation to the brain. The meta-analysis presented by Andre Brunoni and colleagues used individual patient data from six recent studies comparing tDCS treatment to a sham treatment, totaling 289 patients. TDCS treatment was superior to the sham control in terms of antidepressant response (34% to 19%), remission rates (23.1% to 12.7%), and improvement in depression.

After adjusting for confounding factors, the researchers found that patients who had failed to respond to previous treatments were less likely to respond well to tDCS than other patients. They also found that higher doses of tDCS (in terms of current density, duration, and number of sessions) predicted a better response than lower doses.

Over 5 Years, Vagal Nerve Stimulation Better than Treatment as Usual for Severe Depression

July 10, 2015 · Posted in Potential Treatments · Comment 

vagal nerve stimulationVagal nerve stimulation (VNS) is an FDA-approved treatment for both seizures and depression that has resisted other treatments. It requires an operation for the insertion of a stimulator in the chest wall and electrodes on the left vagus nerve in the neck. A new study by Scott T. Aaronson and colleagues presented at the 2015 meeting of the Society of Biological Psychiatry observed severely depressed patients, 494 who received VNS and 301 who received treatment as usual in the community, over a period of five years. The patients who received VNS had greater response rates, they were more likely to have experienced remission, and their remissions lasted longer than those who received treatment as usual. Overall the patients who received VNS had lower mortality rates and suicide rates as well. VNS might be a good option for patients with depression that has not responded to most other treatments.

Meta-Analysis Shows Effectiveness of Ketamine for Bipolar and Unipolar Depression

April 22, 2015 · Posted in Potential Treatments · Comment 

ketamine infusion

Ketamine, an anesthetic sometimes used intravenously in the treatment of depression, can bring about rapid onset of antidepressant effects. A new meta-analysis by researcher Michael Bloch and colleagues presented at a recent conference showed that ketamine’s maximum antidepressant effects occur within one day of administration, and its effects remain significant (compared to control conditions) one week following infusion. Ketamine’s effects were diminished in patients taking other medications. There was a trend for better response in patients with bipolar disorder than with unipolar disorder.

Bloch and colleagues analyzed eight earlier studies including a total of 180 participants. In each study, ketamine had been compared to a control condition, either an infusion of saline solution or of midazolam, which mimics ketamine’s sensory effects but does not have antidepressant effects. The researchers are calling for more meta-analyses of ketamine studies to determine which patients respond best to ketamine and how to sustain ketamine’s effects.

Editor’s Note: In another poster presented at the same conference, James Murrough reported that patients with slower processing speed responded best to ketamine. Other findings have shown that those with a history of alcohol abuse and a common genetic variant of brain-derived neurotrophic factor (BDNF), the val-66-val allele of proBDNF, are more likely to respond to ketamine.

ECT versus Drug Therapy for Bipolar Depression

March 3, 2015 · Posted in Current Treatments · Comment 

ECTElectroconvulsive therapy is often considered a primary treatment option for patients with severe bipolar disorder that has resisted pharmacological treatment. Researcher Helle K. Schoeyen and colleagues recently published the first randomized controlled trial comparing ECT (in this case right unilateral brief pulse ECT) with algorithm-based pharmacological treatment in 76 patients with treatment-resistant bipolar depression.

The response rate was significantly higher in the ECT group than in the patients who received drug treatment (73.9% versus 35.0%). However, the two treatment groups had similarly low remission rates (34.8% for ECT and 30.0% for pharmacological treatment).

The algorithm-based pharmacological treatment used in the study was based on a sequence of treatments endorsed by researchers Frederick K. Goodwin and Kay Redfield Jamison in their 2007 book Manic-Depressive Illness. A selected treatment was chosen for each participant based on his or her medical history. If the first treatment was ineffective or intolerable, the patient would be switched to the next treatment option. Antipsychotics, antidepressants, anxiety-reducing drugs, and hypnotics were some of the other treatments included in the algorithms.

Patients in the study had previously showed a lack of response to at least two different antidepressants and/or mood stabilizers with documented efficacy in bipolar disorder (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses for a period of 6 weeks (or until they quit because of side effects).

Editor’s Note: Even when ECT is effective, there is the issue of how to maintain that good response. We previously reported that in a 2013 study by Axel Nordenskjöld et al. in the Journal of ECT, intensive followup treatment with right unilateral brief pulse ECT combined with pharmacotherapy was more effective than pharmacology alone at preventing relapses. Patients who improved after an acute series of ECT (three times/week) then received weekly ECT for six weeks and every two weeks thereafter, totaling 29 ECT treatments in one year.

Other studies of more intermittent continuation ECT have not proved more effective than medication. Thus high intensity right unilateral brief pulse ECT is one option for extending the effects of successful ECT.

More Data on Memantine for Treatment-Resistant Depression

February 3, 2015 · Posted in Potential Treatments · Comment 

depressed man

In 2012 we reported on an open study by Athanasios Koukopoulos and colleagues that explored whether the NMDA glutamate receptor antagonist memantine (Namenda), which is used to treat dementia, could be helpful to people with treatment-resistant bipolar disorder. In an update of that study, the researchers, led by Giulia Serra, compared patients’ symptoms during three years of treatment as usual, followed by three years with memantine added to their stable medication regime (at doses of 20–30 mg/day). Patients improved progressively over the three years of taking memantine.

Improvements in symptoms included decreased time ill, decreased severity of symptoms, decreased duration of new episodes, and fewer episodes per year. Memantine was particularly helpful for those patients who had had rapid or continuous cycling. Side effects were minimal.

Given the success of this open study, randomized controlled trials are needed to explore this much-needed option for people with treatment-resistant bipolar disorder.

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.

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.

The Nucleus Accumbens in Depression

January 13, 2014 · Posted in Neurobiology · Comment 
The Nucleus Accumbens

The Nucleus Accumbens

Brain-derived neurotrophic factor (BDNF) keeps neurons healthy and is critical for long-term memory and synapse formation. BDNF levels increase in the nucleus accumbens (the brain’s reward center) and decrease in the hippocampus during clinical depression and chronic cocaine use. In rodents, the same changes in BDNF levels occur during defeat stress (which resembles human depression).

Rodents who are repeatedly defeated by a larger rodent exhibit behaviors such as social withdrawal, lethargy, and decreased interest in sucrose. The increases in BDNF in the nucleus accumbens of these rodents could reflect the learning that takes place during the repeated defeat stress and the depression-like behaviors that follow it. Blocking the BDNF increases in the nucleus accumbens prevents these behaviors from developing.

Chadi Abdallah and other researchers at Yale University recently found that the left nucleus accumbens of patients with treatment-resistant depression is enlarged compared to normal controls, and the drug ketamine, which produces rapid-onset antidepressant effects, rapidly decreases the volume of the nucleus accumbens in the depressed patients. The mechanism by which it does so is unknown, but could reflect some suppression of the depressive learning.

Any relationship between the volume of the nucleus accumbens and its levels of BDNF is unknown, but ketamine’s effect on the size of this brain region could be linked to a decrease in the defeat-stress memories.

Rationale for Using Ketamine in Youth with Treatment-Resistant Depression

December 3, 2013 · Posted in Potential Treatments · Comment 

Teen receives injection

At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Vilma Gabbay of the Mount Sinai School of Medicine reiterated the findings from the TORDIA (Treatment of SSRI-Resistant Depression in Adolescents) study that 20% of young people with depression remained resistant to treatment, childhood-onset depression was more likely to be recurrent and more difficult than adult-onset depression in the long run, and suicide was the second leading cause of death in 12- to 17-year-olds in 2010 according to a Centers for Disease Control report in May 2013. Anhedonia (a loss of pleasure in activities once enjoyed) was the most difficult symptom to treat in adolescents.

Gabbay carefully explained some of the rationales for using ketamine in young people with depression. The presence of inflammation is a poor prognosis factor, and ketamine has anti-inflammatory effects, decreasing levels of inflammatory markers CRP, TNF-alpha, and Il-6.Given that ketamine has been widely used as an anesthetic for surgical procedures, its safety in children has already been demonstrated. Ketamine did not appear to cause behavioral sensitization (that is, increased effect upon repetition) in a report by Cho et al. in 2005 that included 295 patients.

As noted previously, Papolos et al. reported in a 2012 article in the Journal of Affective Disorders that intranasal ketamine at doses of 50 to 120 mg was well-tolerated and had positive clinical effects in 6- to 19-year-olds with the fear of harm subtype of bipolar disorder that had been highly resistant to treatment with more conventional drugs.

Gabbay reluctantly endorsed further cautious controlled trials in children and adolescents, in light of ketamine’s suggested efficacy and good safety profile, which stands in contrast to its popular reputation as a party drug or “Special K.”

Editor’s Note: The discussant of the symposium, Neal Ryan of Western Psychiatric Institute and Clinic, added an exquisitely brief discussion suggesting that ketamine should ultimately be studied in combination with behavioral and psychotherapeutic procedures to see if its therapeutic effects could be enhanced. He made this suggestion based on the data that ketamine has important synaptic effects, increasing brain-derived neurotrophic factor (BDNF), which is important for healthy cells and long-term memory, and reverting thin dendritic spines caused by stress back to their normal mushroom shape. This editor (Robert Post) could not be more in agreement.

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