Despite repeated studies, including meta-analyses, showing that antidepressants that work in unipolar depression do not work in bipolar depression as adjuncts to mood stabilizers, antidepressants remain widely used for the treatment of bipolar depression. A recent study of the antidepressant agomelatine has shown that it is not effective in bipolar depression. In patients taking lithium or valproate but still depressed, agomelatine was no better than placebo at reducing depression.
Agomelatine has an unusual mechanism of action (blockade of 5HT-2C receptors and activation of melatonin M1 and M2 receptors) that helps normalize sleep and circadian rhythms, but only in unipolar depression. Until this study by Lakshmi Yatham and colleagues in the British Journal of Psychiatry, it was thought that these properties would make the drug ideal for bipolar depression.
Three atypical antipsychotics are have been approved by the Federal Drug Administration for bipolar depression: quetiapine (Seroquel), lurasidone (Latuda), and the olanzepine-fluoxetine combination Symbyax. These, used alongside mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) are more effective treatments for bipolar depression. There are other adjunctive treatments that may be helpful, such as the antioxidant N-acetylcysteine, vitamin D3, and folate.
In a six-month study of Caucasian patients, normal variations in the gene that is responsible for brain-derived neurotrophic factor (BDNF) predicted whether patients would respond better to a selective serotonin reuptake inhibitor (SSRI) antidepressant versus a serotonin and norepinephrine reuptake inhibitor (SNRI) or a tricycle antidepressant. There are several common variants of the BDNF gene, depending on which types of amino acids appear in its coding—valine or methionine. Patients with the most common version, two valines (or Val66Val), responded better to SSRIs. About two-thirds of the population has this version of the gene, which functions most efficiently. The remaining third have at least one methionine in the BDNF gene. Patients with a Met variation responded better to SNRIs and tricyclic antidepressants.
The study by R. Colle and colleagues was published in the Journal of Affective Disorders in 2015. Of the patients who were prescribed SSRIs, 68.1% of patients with the Val/Val version responded to the medication after three months, compared to 44% of the patients with a Met version. Of patients prescribed SNRIs or tricyclics, 60.9% of the Met patients reached remission by six months, compared to only 33.3% of the Val/Val patients.
Editor’s Note: In an earlier BNN we reported that according to research published by Gonzalo Laje and colleagues in the journal Biological Psychiatry in 2012, depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, while those with the intermediate functioning Val66Met allele respond less well.
Repeated transcranial magnetic stimulation is a non-invasive procedure that has been approved for the treatment of severe depression since 2008. In rTMS treatment, a figure-8–shaped electromagnetic coil is placed against the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain up to 1.5 cm deep. More recently, in 2013, the Federal Drug Administration approved a device with an H-shaped coil that delivers deep transcranial magnetic stimulation (dTMS). It can stimulate a wider area, and up to 8 cm deep.
Y. Levkovitz and colleagues have published the first double-blind randomized controlled multicenter trial of dTMS, reporting in the journal World Psychiatry that the intervention was effective and safe in patients who had not responded to antidepressant medication.
The study included 212 patients aged 22–68 years. All participants had failed to respond to one to four antidepressants or had not been able to tolerate the side effects of at least two antidepressants during their current episode of depression. The patients were randomized to receive either a sham treatment or 18 Hz dTMS over the prefrontal cortex acutely for four weeks and biweekly for 12 weeks for a total of 20 sessions.
The patients who received dTMS showed significantly greater improvement in symptoms than those who received the sham treatment, with a moderately large effect size of 0.76. Response and remission rates were also better in those who received dTMS. Response rates were 38.4% for the dTMS group versus 21.4% in the sham group. Remission rates were 32.6% for the dTMS group and 14.6% for the sham group. These difference in response remained stable during the three months of the study.
Side effects were minor except for a seizure that occurred when the protocol for the treatment was breached.
At the International College of Neuropsychopharmacology (CINP) World Congress of Neuropsychopharmacology in 2014, several presentations and posters discussed treatments that bring about rapid-onset antidepressant effects, including ketamine, isoflurane, sleep deprivation, and scopolamine.
Multiple studies, now including more than 23 according to researcher William “Biff” Bunney, continue to show the rapid-onset antidepressant efficacy of intravenous ketamine, usually at doses of 0.5 mg/kg over 40 minutes. Response rates are usually in the range of 50–70%, and effects are seen within two hours and last several days to one week. Even more remarkable are the six studies (two double-blind) reporting rapid onset of antisuicidal effects, often within 40 minutes and lasting a week or more. These have used the same doses or lower doses of 0.1 to 0.2mg/kg over a shorter time period.
Attempts to sustain the initial antidepressant effects include repeated ketamine infusions every other day up to a total of six infusions, a regimen in which typically there is no loss of effectiveness. Researcher Ronald Duman is running a trial of co-treatment with ketamine and lithium, since both drugs block the effects of GSK-3, a kinase enzyme that regulates an array of cellular functions, and in animals the two drugs show additive antidepressant effects. In addition, lithium has been shown to extend the acute antidepressant effects of one night of sleep deprivation, which are otherwise reversed by a night of recovery sleep.
Ketamine’s effects are related to the neurotransmitter glutamate, for which there are several types of receptors, including NMDA and AMPA. Ketamine causes a large burst of glutamate presumably because it blocks NMDA glutamate receptors on inhibitory interneurons that use the neurotransmitter GABA, causing glutamatergic cells to lose their inhibitory input and fire faster. While ketamine blocks the effects of this glutamate release at NMDA receptors, actions at AMPA receptors are not blocked, and AMPA activity actually increases. This increases brain-derived neurotrophic factor (BDNF), which is also required for the antidepressant effects of ketamine. Ketamine also increases the effects of mTOR, a kinase enzyme that regulates cell growth and survival, and if these are blocked with the antibiotic rapamycin, antidepressant effects do not occur.
In animal studies, ketamine increases dendritic spine growth and rapidly reverses the effects of chronic mild unpredictable stressors on the spines (restoring their mature mushroom shape and increasing their numbers), effects that occur within two hours in association with its rapid effects on behaviors that resemble human depression.
About 50–70% of treatment-resistant depressed patients respond to ketamine. However, about one-third of the population has a common genetic variation of BDNF in which one or both valine amino acids that make up the typical val-66-val allele are replaced with methionine (producing val-66-met proBDNF or met-66-met proBDNF). The methionine variations result in the BDNF being transported less easily within the cell. Patients with these poorly functioning alleles of BDNF are less likely to get good antidepressant effects from treatment with ketamine.
Ketamine in Animal Studies
Researcher Pierre Blier reviewed the effects of ketamine on the neurotransmitters serotonin, norepinephrine, and dopamine. In rodents, a swim stress test is used to measure depression-like behavior. Researchers record how quickly the rodents give up trying to get out of water and begin to float instead. Blier found that ketamine’s effects on swim stress were dependent on all three neurotransmitters. For dopamine, ketamine’s effects were dependent on increases in the number of dopamine cells firing, not on the firing rate, and for norepinephrine, ketamine’s effects were dependent on increases in burst firing patterns. Each of these effects was dependent on glutamate activity at AMPA receptors. Given these effects, Blier believes that using ketamine as an adjunct to conventional antidepressants that tend to increase these neurotransmitters may add to its clinical effectiveness.
Important Anecdotal Clinical Notes
Blier reported having given about 300 ketamine infusions to 25 patients, finding that two-thirds of these patients responded, including one-third who recovered completely, while one-third did not respond to the treatment. Patients received an average of 12 infusions, not on a set schedule, but according to when they began to lose response to the last ketamine infusion. If a patient had only a partial response, Blier gave the next ketamine treatment at a faster rate of infusion and was able to achieve a better response. These clinical observations are among the first to show that more than six ketamine infusions may be effective and well tolerated. Read more
Saffron, the expensive yellow spice derived from the plant Crocus sativus, was the subject of a recent meta-analysis in the journal Human Psychopharmacology. The meta-analysis included six studies of a total of 230 adult outpatients with major depressive disorder. In two of these studies, 30mg/day of saffron extract was as effective as 20mg/day of the antidepressant fluoxetine and 100mg/day imipramine for the treatment of mild to moderate depression had been in other studies.
Saffron is suggested to have anticancer, anti-inflammatory, antioxidant, and antiplatelet effects, and current clinical trials are exploring whether it could prevent and treat Alzheimer’s disease.
The current study was an effort to systematically analyze clinical trials on saffron to establish treatment parameters such as dosage in addition to safety information.
In the past there has been some concern that selective serotonin reuptake inhibitor (SSRI) antidepressants taken during pregnancy could increase an infant’s risk of cardiac problems. There was particular concern that the SSRI paroxetine could lead to right ventricular outflow tract obstruction, and sertraline could lead to ventricular septal defects. A 2014 study by KF Huybrechts et al. in the New England Journal of Medicine analyzed data from 949,504 women in a Medicaid system from three months before pregnancy until one month after delivery during the years 2000-2007.
Infants born to mothers who had taken antidepressants during their first trimester were compared to infants whose mothers had not taken antidepressants. In total, 6.8% or 64,389 women had used antidepressants in their first trimester.
While the rate of cardiac defects in newborns was greater among those mothers who had taken antidepressants (90.1 infants per 10,000 infants who had been exposed to antidepressants versus 72.3 infants per 10,000 infants who had not been exposed to antidepressants), this relationship diminished as confounding variables were removed. The relative risk of any cardiac defect after taking SSRIs was 1.25, but this decreased to 1.12 when restricted to only those mothers who were diagnosed with depression, and to 1.06 when the researchers controlled for things like depression severity. (All relative risk numbers were calculated with a 95% confidence interval.)
The researchers concluded that there is no substantial risk of increased cardiac defects in children born to mothers who took antidepressants during their first trimester.
In the clinic of researcher Eduard Vieta in Barcelona, a study was recently completed showing that antidepressant use in patients with bipolar disorder (where antidepressants are not effective) had dropped from around 50-60% in 2007 (in Baldessarini’s study) to about 30% in 2013 and 2014, and conversely lithium, anticonvulsants, and atypical antipsychotics, which have much more evidence of efficacy, were all used much more often, or about 60% of the time.
Editor’s Note: Hopefully these data from Spain will soon be matched by similar data in the US showing that evidenced-based treatments for bipolar depression are in fact being used instead of antidepressants, which can have adverse effects, such as switching into mania or cycle acceleration.
A decade ago the Federal Drug Administration (FDA) released several warnings that children, adolescents (ages 10–17), and young adults (ages 18-29) taking antidepressants were at increased risk for suicidal ideation and behavior. A recent study found that following these warnings, antidepressant use among adolescents, young adults, and adults dropped, and psychotropic drug poisonings (a validated measure of suicide attempts) increased among adolescents and young adults. Numbers of completed suicides did not change for any age group.
The decision to place the warnings on antidepressant packaging was somewhat controversial because it was based on studies that were not necessarily designed to measure suicide risk. The relationship between depression, medication, and suicide is complicated. Medication can improve mood, but patients may seek out medication because of pre-existing suicidal thoughts, and the medication may not reduce these in young people.
The reduction in antidepressant use that occurred after the warnings was accompanied by a drop in depression diagnoses in children and adults. Studies have suggested that the decreases in antidepressant were not accompanied by increases in other treatments, such as psychotherapy or atypical antipsychotics, among young people. Increased monitoring of patients was called for in the FDA’s box warning, but did not take place.
The study of the aftermath of the FDA warnings, published by Christine Y. Lu et al. in a 2014 article in the journal BMJ, used data from 11 insurance networks throughout the US. The researchers used an interrupted time series study design, which is used to show whether a policy causes an abrupt change in the expected slope of study outcomes. Data covered the pre-warning period (first quarter of 2000 to third quarter of 2003), the warning “phase-in” period (last quarter of 2003 to last quarter of 2004) and the post-warning period (first quarter of 2005 to last quarter of 2010). The study cohorts included around 1.1 million adolescents, 1.4 million young adults, and 5 millions adults per quarter.
Among adolescents, the previously upward trend in antidepressant use declined by 31.0% in the second year after the warnings, and psychotropic drug poisonings increased by 21.7% (a figure that was statistically significant for males). Poisonings by any drug increased by 13.9% in the second year after the warnings. After 2008, the downward trend in antidepressant use reversed, indicating that either the initial effects of the warning had worn off or that modifications to the warnings in May 2007, which encouraged patients and doctors to consider the risk of antidepressants alongside the risk of leaving mood disorders untreated, led to increased use.
Among young adults, the upward trend in antidepressant use declined by 24.3% in the second year after the warnings, and psychotropic drug poisonings increased by 33.7%, a statistically significant change for both male and female patients.
Among adults, to whom the warnings were not directed, antidepressant use decreased by 14.5% in the second year after the warnings.
The study by Yu et al. is the first to show that suicide attempts actually increased after the FDA warnings. The authors suggest that the increase in suicide attempts might be a consequence of undertreating mood disorders, since antidepressant use dropped simultaneously. The warnings and related media attention may have led to these unintended consequences, since media reports can sometimes be oversimplified.
C-reactive protein, or CRP, is a protein found in blood plasma, the levels of which rise in response to inflammation. In a recent study, levels of CRP were able to predict which of two antidepressants a patient was more likely to respond to.
The 2014 article by Rudolph Uher et al. in the American Journal of Psychiatry reported that low levels of CRP (<1 mg/L) predicted a good response to the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) while higher levels of CRP predicted a good response to the tricyclic antidepressant nortriptyline, a blocker of norepinephrine reuptake.
The research was part of the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured in the blood of 241 adult men and women with major depressive disorder. In the article the researchers say that CRP and its interaction with medication explained more than 10% of the individual variance in response to the two antidepressants.
If these findings can be replicated with these and similarly acting drugs, it would be a very large step in the direction of personalized medicine and the ability to predict individual response to medications.
Bipolar illness affects 4.5% of the US population. According to researcher Kathleen Merikangas, 1.0% have bipolar I disorder, 1.1% have bipolar II disorder, and the remainder have subthreshold symptoms. Mark Frye, Chairman of the Department of Psychiatry at the Mayo Clinic, gave a lecture on antidepressants in bipolar illness at the 2014 meeting of the American Psychiatric Association.
The newest data from meta-analyses indicate that traditional antidepressants that are effective in unipolar depression are not effective in bipolar depression. Some patient groups, especially those with very early onset depression and mixed depression, are at increased risk of switching into mania and making a suicide attempt while taking antidepressants.
Unipolar depressed patients with a genetic variation that produces a short form of the serotonin transporter (5HT-LPRs/s) are at increased risk for depression in adulthood following a history of childhood adversity, and tend to respond less well to antidepressants. Frye found that 5HT-LPRs/s is weakly associated with switching into mania when antidepressants are given to patients with bipolar depression.
At the same symposium, researcher Mike Gitlin reviewed data on combination therapy, which is rapidly becoming the norm, indicating that in most circumstances, it is superior to monotherapy.
Researcher David Miklowitz reviewed the impressive data on the superiority of most forms of targeted psychotherapy or psychoeducation compared to treatment as usual for bipolar depression. He noted his own finding that Family Focused Therapy (FFT) not only is effective in adolescents and adults with bipolar disorder, but also in reducing illness and dysfunction in those with prodromal disorders (such as depression, cyclothymia, and bipolar not otherwise specified) in situations where there is a family history of bipolar disorder.
Eight components of FFT are:
- Recognition of prodromal symptoms and development of treatment strategies for them.
- Recognition and management of stress and triggers using cognitive restructuring.
- Development of a relapse prevention plan and rehearsal of what to do.
- Regularization of sleep.
- Encouragement of treatment adherence with an eye to a good future.
- Enhancement of emotional self-regulation skills, including cognitive restructuring.
- Improvement of family relationships and communication.
- Education about substance abuse avoidance and treatment for that and other comorbidities.
Many of these are also key components of group psychoeducation, cognitive-behavioral therapy, and interpersonal and social rhythms therapy, and all of these are effective in treating and preventing bipolar depression compared to treatment as usual. It is noteworthy that in the research of Francesc Colom, 90% of patients randomized to treatment as usual relapsed within 24 months, while psychoeducation was highly effective in preventing relapses over the next five years.
This editor (Robert M. Post), the discussant for the symposium, emphasized that the main take-away messages of the speakers were: use more lithium, use more caution and fewer antidepressants in treating bipolar depression, use more combination therapy for acute illness and for maintenance, and definitely use more psychotherapy. Read more