Theta-burst stimulation is a type of repeated transcranial magnetic stimulation (rTMS) currently being investigated for the treatment of severe depression. In rTMS a magnetic pulse applied to the scalp causes neurons to fire. A recent study of 60 patients by Cheng-Ta Li et al. published in the journal Brain compared continuous, intermittent, and combined theta-burst treatment with a sham treatment. While all four groups of patients with treatment-resistant depression improved, indicating some placebo effect, patients in the group who received intermittent stimulation over the left prefrontal cortex and those who received a combination of intermittent left prefrontal cortex stimulation and continuous right prefrontal stimulation showed the greatest improvement in their depression. Those patients with greater prior treatment resistance responded less well across all of the treatments.
Editor’s Note: Studies continue to explore the optimum parameters for rTMS, but large studies and meta-analyses continue to show that the treatment has positive effects in depression.
Transcranial direct current stimulation (tDCS) shows promise for a range of problems. In new research presented at the 2014 meeting of the Society of Biological Psychiatry, it was reported to be effective for improving cognition in bipolar disorder, alleviating depression, and reducing hallucinations.
How TDCS Works
At the meeting, researcher Marom Bikson discussed tDCS technology. The treatment can be delivered with a 12-volt battery. The anode directs current inward and is excitatory, while the cathode directs current outward and is inhibitory. The dendrites at the top of neurons under the anode are hyperpolarized by the tDCS, leading to relative depolarization of the cell soma, thus increasing excitation. TDCS, unlike repetitive transcranial magnetic stimulation (rTMS), which causes cells to fire, is only neuromodulatory, inducing minor changes in membrane polarization.
TDCS Improved Cognition in Bipolar Disorder
At the 2014 meeting of the American Psychiatric Association, Roberto Delle Chiaie et al. reported that two mA tDCS for 20 minutes for 15 days (anode over the left prefrontal cortex and cathode over the right cerebellum) improved immediate and delayed recall, trail making with a pointer, and motor coordination in 17 euthymic bipolar patients. This very promising result deserves further study and replication.
Antidepressant Effects of TDCS
At the 2014 meeting of the Society of Biological Psychiatry, Collen Loo reported that tDCS had positive effects in depressed patients compared to sham treatment. This complements a 2013 article by Brunoni et al. in JAMA Psychiatry that tDCS plus the selective serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft) was more effective than either treatment alone.
TDCS for Treatment-Resistant Hallucinations
Jerome Brunelin et al. reported at the meeting that tDCS had positive effects in patients with schizophrenia who had hallucinations that resisted treatment. The positive electrode (anode) was placed over the left prefrontal cortex and the negative electrode (cathode) over the left temperoparietal area, where hallucinations are thought to originate. Stimulation was at two mA for 20 minutes, five days per week for two weeks. Effects lasted as long as 30 days and were associated with reduced functional connectivity of these brain regions.
Low frequency (1Hz) rTMS, which decreases neural activity, also improves refractory hallucinations when applied over the temperoparietal area, which is important for language. Placing the cathode over this area in tDCS is also inhibitory, so comparisons of rTMS with tDCS for suppressing hallucinations would be of great interest and importance.
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.
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.
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.
Not 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.
While past research on mood disorders has targeted structural and functional abnormalities in the brain, newer research has considered targets such as inflammation, metabolism, and cell resilience. Exercise can have positive effects on systems that regulate metabolism, immune function, and cellular respiration, and therefore improve affective and cognitive difficulties.
At the 2014 meeting of the International Society for Bipolar Disorders, Mohammad Alsuwaidan presented a meta-analysis of the effects of exercise in mood disorders gleaned from English-language studies between 1966 and July 2008. Exercise increased brain norepinephrine, serotonin, and phenylethanolamine (PEA).
Alsuwaidan believes runner’s high, the feelings of euphoria people often experience after strenuous exercise, may not be linked to opiate (or endorphin) release, as most people believe, but instead to release of PEA or the cannabinoid anandamide, which activates CB 1 cannabinoid receptors, decreases GABA, and increases dopamine in the nucleus accumbens, the reward center of the brain.
Exercise also increases neurogenesis and the production of brain-derived neurotrophic factor (BDNF), which supports the growth of neurons and synapses. Marathon runners also have a post-race elevation in the anti-inflammatory cytokines IL-10 and IL-1Ra.
In people who are out of shape, exercise increases oxidative stress and other toxicities that do not occur with in those who exercise more regularly. Alsuwaidan extolls the benefits of high impact exercise five to seven times per week, and engaging a trainer to encourage exercise. Four minutes of intense exercise (such that you sweat and are not able to talk) is about equal to 45 minutes of mild exercise.
Researchers are exploring the therapeutic potential of nutraceuticals, or nutritional treatments. Folate, also known as folic acid or vitamin B9, is one of the most important nutritional elements for mental health.
The folate found in foods such as dark leafy greens must be broken down further in order to be used in the body. Folate first breaks down into dihydrofolate (DHF), which is turned into tetrahydrofolate (THF). At the 2014 meeting of the International Society for Bipolar Disorders, researcher J.H. Baek described a pathway by which THF is turned into a form called 5,10 MTHF, which is turned into a form called 5 MTHF. 5 MTHF is important for the function of the enzyme tryptophan hydroxylase and for clearing homocysteine, an amino acid that is cardio- and neuro-toxic.
L-methylfolate, the active ingredient in the medication Deplin, is an already-broken-down form of folate that the brain can use more readily than the folate from food. L-methylfolate is converted directly to 5 MTHF, so it is effective in 15% to 35% of the normal population who have a deficiency in the enzyme MTHF reductase, which converts THF to 5 MTHF. One genetic variant (a C to T allele variation 677) that results in one type of deficiency in MTHF reductase has a 42% incidence among Asians, 34% among Caucasians, and 8% among Africans, and these individuals would benefit from l-methylfolate.
Folate and Medications for Bipolar Disorder
Certain medications lead to deficits in folate, so patients should consider taking a nutritional supplement.
The anticonvulsant drug lamotrigine inhibits the conversion of folate to DHF and DHF to THF, so folate supplementation is a good idea for those patients taking lamotrigine.
The mood stabilizer valproate inhibits the conversion of toxic homocysteine to methionine and then to s-adenosyl methionine (SAMe), which acts like an internally-produced antidepressant. Thus valproate increases homocysteine, and patients on valproate should be routinely treated with folate and vitamin B12 to help lower homocysteine levels in the blood.
Folate supplements are recommended for depressed patients who are having an inadequate response to antidepressants, since the nutrient helps antidepressants work better even when patients do not have a folate deficiency. Researcher Andrew Stoll recommends folate (1mg for women and 2mg for men). However, those patients who have one of the genetic conditions that leads to a deficiency in MTHF reductase should take l-methylfolate instead of regular folate. Researcher Mauricio Fava and colleagues showed that l-methylfolate at doses of 15mg (but not 7.5mg) was more effective than placebo in patients with unipolar depression.
Vitamin D plays an important role in many brain functions, including synapse creation, calcium signaling, reduction of free radicals, neurotransmitter production, immune regulation, and brain development. Deficiencies in vitamin D have been linked to depression and schizophrenia. Some research has suggested that vitamin D supplementation can improve depressive symptoms, but there is still debate about a possible role for vitamin D in treating bipolar disorder.
At the 2014 meeting of the International Society for Bipolar Disorders, researcher Baseok Cha discussed the importance of vitamin D supplementation in bipolar patients, who often have deficient or insufficient levels. People receive 50 to 90% of their vitamin D from sunlight, and the rest from diet and supplements. Too much sunscreen can be a problem if it prevents a person from receiving enough vitamin D from sunlight.
The type of vitamin in supplements, D3, is converted to 25 hydroxy vitamin D in the liver, and then to 1,25 hydroxy vitamin D in the kidney. Levels of 25 hydroxy vitamin D below 20 indicate deficiency while levels between 20 and 29 indicate insufficiency. Low levels of 25 hydroxy vitamin D3 in newborns is a risk factor for schizophrenia, and vitamin D supplementation reduces this risk. Fish oils increase vitamin D, and it is possible that some of the therapeutic effects of omega-3 fatty acids in depression relate to vitamin D.
Two out of four recent studies of vitamin D supplementation have been positive, the last by Khoraminya et al. in the Australia and New Zealand Journal of Psychiatry in 2013, in which daily doses of 1,500 IU were used. Cha et al. found significantly lower levels of 25 hydroxy vitamin D in a Korean study of 21 patients with schizophrenia, 86 patients with bipolar disorder, and 42 patients with depression (mean levels about 15 µg/ml) compared to 31 controls (mean levels about 20 µg/ml).
Vitamin D plays an important role in the nervous system, regulating the production of neurotrophins, calcium channels, and calcium binding proteins, and it may have antidepressant effects. Researchers are learning more about how the vitamin’s effects take place.
At the 2014 meeting of the International Society for Bipolar Disorders, Yilmazer et al. reported that vitamin D treatment increased the production of glia-derived neurotrophic factor (GDNF). Neurotrophins like GDNF enhance the survival and growth of neurons. Since other neurotrophins (i.e. brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEG-F)) are low in depression, vitamin D’s effect on GDNF could be important to its antidepressant effects.