Several studies in adults and children suggest that omega-3 fatty acid supplementation may have antidepressant effects. At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry in October, Melissa DelBello, a professor at the University of Cincinnati, reported on a new study of omega-3 fatty acids in depressed children who had a parent with bipolar disorder. The children taking omega-3 fatty acids were more likely to improve than those taking a placebo, but the findings were only of marginal significance.
Cold-water fish are a good source of omega-3 fatty acids, and DelBello said salmon is by far the best in this regard. People who live in countries where fish is consumed in greater quantities are less likely to suffer from depression. Other sources of omega-3 fatty acids include shellfish, plant and nut oils, English walnuts, flaxseed, algae oils, and fortified foods.
The omega-3 fatty acids from fish are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), while the omega-3 fatty acids from plants are alpha-linolenic acid (ALA), which breaks down into EPA and DHA. All of these are anti-inflammatory, though one must consume much greater quantities of ALA to match the benefits of EPA and DHA. In contrast, omega-6 fatty acids, which are much more common in the typical American diet, are pro-inflammatory.
In DelBello’s study of 56 depressed children of a parent with bipolar disorder, the participants were randomized to either 1.8 g of omega-3 fatty acids (1.2 g of EPA and 0.6 g of DHA) or placebo (olive oil). Those who received the omega-3 fatty acids had a 55.6% rate of remission versus 34.5% for those who received placebo, but while the odds ratio of 2.4 favored the omega-3 fatty acids, the difference in remission rates was not statistically significant, likely because of the small size of the study. However, improvement on the Children’s Depression Rating Scale was significantly different across the two groups, with children taking omega-3s improving more. Omega-3 fatty acids are known to have an anticoagulant effect (preventing the clotting of blood), and four children in the study did have prolonged clotting times (but no clinical problems with bleeding).
Editor’s Note: Given the existing literature on omega-3 fatty acids and the trend in this study, omega-3s are worthy of consideration for the treatment and potentially for the prevention of depression in children. This later possibility is further suggested by findings from Australia that, when compared to placebo, omega-3 fatty acids significantly reduced the rate of conversion from prodromal (preliminary) psychotic symptoms to a full-blown diagnosis of schizophrenia.
In a 2013 study of children by Luby et al. in the Journal of the American Medical Association Pediatrics, poverty in early childhood was associated with smaller white and gray matter in the cortex and with smaller volume of the amygdala and hippocampus when the children reached school age. The effects of poverty on hippocampal volume were mediated by whether the children experienced stressful life events and whether a caregiver was supportive or hostile.
The children were recruited from primary care and day care settings between the ages of three and six, and were studied for five to ten years. They were initially assessed annually for three to six years and information on psychosocial, behavioral, and developmental dimensions were collected. Then the children took part in a magnetic resonance imaging (MRI) scan and continued annual assessments that included information such as whether the children experienced stressful life events.
Previous research has shown that poverty affects children’s psychosocial development and economic success in adulthood. This research shows that poverty also affects brain development. The findings suggest important targets for intervention that could help prevent these developmental deficits.
Evidence is growing that stressful events in childhood are associated with an earlier onset of bipolar disorders and a more difficult course of illness than in those who did not experience this type of adversity. Monica Aas and colleagues in Norway have found for the first time that emotional abuse in childhood, especially before age five, also increases risk of bipolar disorder. This study indicates that while bipolar disorder has a genetic component, environmental factors also play a role.
In Norway and France, the research group surveyed patients with bipolar disorder and people in the general population about childhood trauma, including emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect. Among the almost 800 participants, patients with bipolar disorder were twice as likely as control participants to have experienced multiple types of trauma. However, emotional abuse was the only factor specifically linked to bipolar disorder. People who were emotionally abused in childhood were more than twice as likely to develop bipolar disorder in adulthood. Moreover, the more severe the emotional abuse, the more likely it was that a child would go on to develop bipolar disorder.
Among the adults with bipolar disorder, emotional abuse and sexual abuse in childhood predicted younger age of illness onset, more suicide attempts, more rapid cycling, and greater proneness to depression. Emotional or sexual abuse were linked to the most suicide attempts, and sexual abuse was linked to rapid cycling.
More trauma in childhood was also linked to affective instability in adults. Aas’ research was presented at the 14th International Congress on Schizophrenia Research.
The psychiatric community has been preparing for the 2013 release of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by the American Psychiatric Association for years. Each new edition of the manual reflects changing conceptions of illnesses and their diagnosis and treatment.
Tom Insel, the director of the National Institute of Mental Health (NIMH), the largest research organization in the world devoted to the understanding and treatment of mental disorders, caused a stir this past spring when he wrote in a blog post that the DSM-5 lacks validity and that patients deserve better.
The DSM-5 guidelines for diagnosis of mental disorders rely on descriptions of clusters of symptoms, and Insel suggested that new methods of diagnosis that rely on laboratory measure should be developed. The NIMH is launching a project called Research Domain Criteria (RDoC) to incorporate genetics, imaging, and other data in a new classification system for illnesses, and is re-orienting their funding toward projects that “look across current categories,” for example by including all patients in a mood disorder clinic rather than only those who meet DSM-5 criteria for major depressive disorder.
A major concern about this change at the NIMH, which funds much of the research that leads to Federal Drug Administration-approved treatments, is that it will diminish funding for treatment studies in specific diagnostic categories where research is already sparse, such as childhood onset bipolar illness. This may leave many children and adults without a sound evidence base upon which their doctors can base treatment decisions.
Under the NIMH’s new rubric, clinical treatment studies to collect comparative data and evidence-based treatment research would likely lose out to studies focused on the broad collection and identification of biomarkers and the pursuit of new treatment targets. Answering an important clinical question such as whether symptoms of childhood onset bipolar disorder respond to the same medications as oppositional defiant disorder (ODD) or disruptive mood dysregulation disorder (DMDD) might not be a high priority for study.
David Kupfer, chair of the APA’s DSM-5 Task Force, responded to Insel’s statement saying that while it would be great to identify biomarkers and genetic indicators for mental illnesses, “this promise, which we have anticipated since the 1970s, remains disappointingly distant.” Insel acknowledged in his statement that this is only the beginning of development of research domain criteria, and that “for the present” the DSM will continue to be used.
Electroconvulsive therapy (ECT) is an effective treatment for patients with treatment-resistant depression, but still many patients relapse after the treatment. Medications can prolong the period of remission, but even so, relapse rates have increased in recent decades (probably at least partly because ECT was once a standard initial treatment but is now only used with those patients with the most difficult-to-treat illnesses.) A 2013 meta-analysis by Jelovac et al. in Neuropsychopharmacology reviewed existing research on relapse and which medications might be able to best prolong remission after ECT.
The researchers analyzed 32 studies that each included at least 2 years of followup. In studies from the recent era in which patients received continuation treatment with medication following ECT, 51.1% of patients relapsed within a year, and the majority of those (37.7%) relapsed within the first 6 months after ECT. Among patients treated with continuation ECT, a similar proportion (37.2%) also relapsed within 6 months of the initial ECT treatment. In randomized controlled trials, treatment with antidepressants with or without lithium following ECT halved the rate of relapse within 6 months compared to placebo.
Even with continuing intermittent ECT treatment, risk of relapse remains high, especially within the first 6 months. The authors concluded that maintenance of wellbeing following ECT must be improved.
Editor’s Note: One possibility for prolonging remission is the more intensive continuation regimen using right unilateral ultrabrief pulse ECT suggested by Nordenskjöld et al. in the Journal of ECT in 2013. Continuation treatment with a combination of ECT and medication resulted in 6-month relapse rates of 29% (compared to 54% with medication alone) and one-year relapse rates of 32% (compared to 61%).
Finding an Appropriate Control
Comparing ketamine to placebo has challenges because ketamine produces mild dissociative effects (such as a feeling of distance from reality) that are noticeable to patients. At the 2013 meeting of the Society of Biological Psychiatry, James W. Murrough and collaborators at the Mount Sinai School of Medicine reported their findings from the first controlled trial of intravenous ketamine in depression that uses an active control, the short-acting benzodiazepine midazolam, which has sedative effects and decreases anxiety, but is not known as an antidepressant. On virtually all measures intravenous ketamine was a more effective antidepressant following 2 infusions per week.
These data help dispel one of the criticisms of intravenous ketamine, that studies of the drug have not been sufficiently blinded (when patients and medical staff are kept from knowing which patients receive an active treatment and which are in the placebo control group) and that the lack of an appropriate active placebo contributed to the dramatic findings about ketamine’s antidepressant effects. It now appears that these criticisms have been appropriately answered and that intravenous ketamine is highly effective not only in comparison to placebo but also to an active comparator.
This research was presented as a poster at the meeting and published as abstract #442 in the meeting supplement to the journal Biological Psychiatry, Volume 73, Number 9S, and was also published in the Archives of General Psychiatry in 2013.
Slowing Down Ketamine Infusions to Reduce Side Effects
Ketamine is commonly given in 40-minute intravenous infusions. Timothy Lineberry from the Mayo Clinic reported in Abstract #313 from the meeting that slower infusions of ketamine over 100 minutes were also effective in producing antidepressant effects in patients with treatment-resistant depression. Lineberry’s research group used the slower infusion in order to increase safety and decrease side effects, such as the dissociative effects discussed above. In the 10 patients the group studied, they observed a response rate of 80% and a remission rate of 50% (similar to ketamine’s effects with 40-minute infusions).
Family or Personal History of Alcohol Dependence Predicts Positive Response to Ketamine in Depression
Mark J. Niciu and collaborators at the NIMH reported in Abstract #326 that a personal or family history of alcohol dependence predicted a positive response to IV ketamine in patients with unipolar depression.
Ketamine Acts on Monoamines in Addition to Glutamate
Ketamine’s primary action in the nervous system is to block glutamate NMDA receptors in the brain. In addition to its effects on glutamate, it may also affect the monoamines norepinephrine and dopamine. Kareem S. El Iskandarani et al. reported in Abstract #333 that in a study of rats, ketamine increased the firing rate of norepinephrine neurons in a part of the brain called the locus coeruleus and also increased the number of spontaneous firing dopamine cells in the ventral tegmental area of the brain.
Editor’s Note: These data showing that ketamine increased the activity of two monoamines could help explain ketamine’s ability to induce rapid onset of antidepressant effects, in addition to its ability to immediately increase brain-derived neurotrophic factor (BDNF, important for long-term memory and the creation of new synapses) and to restore healthy mushroom-shaped spines on the dendrites of neurons in the prefrontal cortex.
At the 10th International Conference on Bipolar Disorders in 2013, Congressman Patrick J. Kennedy addressed the combined audience of the Depression Bipolar Support Alliance (DBSA) and members of the International Society of Bipolar Disorders. He gave an inspiring speech about de-stigmatizing advocacy, and the need to have a unified message that promotes parity in the care of mental illnesses and physical illnesses. He suggested that mental disorders should be compared to heart attacks, with the mantra, “We want no more, and we should demand no less.”
Kennedy revealed his own dual diagnosis of bipolar disorder and alcohol abuse and the need to come out of the shadows, such as the basements of churches where people seeking treatment from Alcoholics Anonymous all too often remain unknown and anonymous.
Kennedy framed the issue of parity in the care of mental illnesses as a new civil rights battle. People with mental illness have been grossly discriminated against, stigmatized with derogatory epithets, and treated with indignity in the past. He stressed the need for all to advocate not so much for themselves, but for others, and to join in community to solve our current problem of isolation and alienation.
Kennedy indicated optimism for the parity mission and suggested that a good way to achieve it would be to join forces with another isolated group of young people—veterans returning from Iraq and Afghanistan. While many veterans return with brain injuries and post-traumatic stress syndrome (PTSD), seventy-two percent of veterans never go to the Veteran’s Affairs hospitals, many are ignored, and too many are locked up in prisons. Kennedy called them “prisoners of their war injuries” and “walking prisoners of war.” Twenty-two die each day by suicide.
Kennedy said we in the mental health community must stand with them and their hidden brain injuries. They are wounded, but they never receive a purple heart. He quoted a speech his uncle Robert F. Kennedy gave in Cape Town, South Africa in 1966 before anyone thought that apartheid would end. “It is from numberless diverse acts of courage and belief that human history is shaped. Each time a [person] stands up for an ideal, or acts to improve the lot of others, or strikes out against injustice, [that person] sends forth a tiny ripple of hope, and crossing each other from a million different centers of energy and daring, those ripples build a current that can sweep down the mightiest walls of oppression and resistance.”
In the mental health community we need each other and can’t afford different messages or fragmentation. Mental health advocates joining with veterans and their search for good care will be our salvation, as will our connectedness, togetherness, mutual respect, and these will yield solutions for both groups.
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, his colleague Jules Angst discussed some recent findings. Angst is perhaps the world’s leading authority on the long-term course of unipolar and bipolar disorders based on his multiple prospective follow-up studies, some lasting 20-30 years.
The Sensitization-Kindling Model
Angst described evidence that supports the sensitization-kindling model of recurrent mood disorders, which this editor (Robert Post) described in 1992. Episodes tend to recur faster over time, i.e. the well interval between episodes becomes progressively shorter. While stressors often precipitate initial episodes, after multiple occurrences, episodes also begin to occur spontaneously (in the absence of apparent stressors).
This type of progressive increase in response to repetition of the same stimulus was most clearly seen in animal studies, where repeated daily electrical stimulation of the amygdala eventually produced major motor seizures (i.e. amygdala kindling). Daily electrical stimulation of rodents’ amygdala for one second initially produced no behavioral change, but eventually, minor and then full-blown seizures emerged. Once enough of the stimulated full-blown amygdala-kindled seizures had occurred, seizures began to occur spontaneously (i.e. in the absence of the triggering stimulation).
The analogy to human mood disorders is indirect, but kindling provides a model not only for how repeated triggers eventually result in full-blown depressive episodes, but also for how these triggered depressive episodes may eventually occur spontaneously as well.
Long-Term Treatment of Mood Disorders
Angst also discussed long-term treatment of mood disorders. He has found that long-term lithium treatment not only reduces suicides in patients with bipolar disorder, but also reduces the medical mortality that accompanies bipolar disorder.
Angst noted his previous surprising observations that in unipolar disorder, long-term maintenance treatment, even with low doses of tricyclic antidepressants, prevents suicide. Previously, researchers Ellen Frank and David Kupfer of Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center had found that when patients with recurrent unipolar depression who had been stable for 5 years on the tricyclic antidepressant nortriptyline were blindly switched to half their original dose, about 90% rapidly relapsed into a new episode of depression. Their data helped establish the prevailing view that maintenance treatment with the full-dose regimen required to achieve a good initial acute response is also the optimal approach to long-term continuation and prophylactic treatment.
Angst found good results even at low doses, but his data may not be in conflict with Frank and Kupfer’s, as a person who responds well acutely to low doses may also be able to maintain good enough response to them to prevent recurrences in the long term.
Incidence of Bipolar Disorder in Adolescents Similar to Incidence in Adults
Angst also presented data from the Adolescent Supplement to the National Comorbidity Study (NCS-A), which analyzed interviews with approximately 10,000 adolescents (aged 13-17) in the US. He found a 7.6% incidence of major depression, a 2.5% incidence of bipolar I or II disorder, and a 1.7% incidence of mania. There was an even higher incidence of sub-threshold bipolar disorder, when there are not enough symptoms or a long enough duration of symptomatology to meet diagnostic criteria for bipolar I or II disorder. These data published by Merikangas et al. in 2009 provide clear epidemiological data that there is a substantial incidence of bipolar disorder in adolescents in the US, roughly similar to that seen in adults.
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, this editor (Robert Post) discussed progress in the treatment of bipolar disorder over the past 40 years. Despite the availability of lithium; many new mood stabilizers (carbamazepine, valproate, lamotrigine); and many atypical antipsychotics, all of which are anti-manic and some of which are antidepressant (quetiapine and lurasidone), there is still a very high rate of continued illness and treatment resistance, especially in the US.
In fact, research from the Bipolar Collaborative Network, a treatment research network including sites around the US (one run by this editor) and in Germany and the Netherlands, shows that almost everything about bipolar disorder is worse in the US. Americans have more genetic vulnerability because more of their parents have bipolar disorder, and they are more likely to have environmental vulnerability as a result of childhood adversity. Patients in the US also reported having had more stressors at the onset of their illness and more stressors prior to the last episode they had before entering the network at an average age of 40.
Age at illness onset is much lower in the US than in the Netherlands and Germany. About two-thirds of American patients had onset in childhood or adolescence (under 19 years), while only about one-third of the European patients in this study showed these early onsets.
The course of illness is also more difficult in the US. There is more anxiety, substance abuse, and medical comorbidity, and there are more episodes and more rapid cycling. All this resulted in more US patients than European ones who did not respond to naturalistic treatment in our treatment network despite being prescribed multiple medications.
The implication of these data is that we need a new and more concerted approach to bipolar disorder in the US, beginning with early diagnosis and treatment during childhood and adolescence, instead of the 10- to 15-year average delay that was typical about twenty years ago. The duration of the delay to first treatment with a drug to treat mania or depression was an independent predictor of a worse outcome in adulthood. Early intervention should also include therapy and education.
Family-Focused Treatment (FFT), a method pioneered by researchers David Miklowitz and Kiki Chang, has been shown to be much more effective than treatment as usual in children who are at high risk for developing bipolar disorder because they have a family history of the illness and symptoms of an anxiety or depressive disorder or bipolar not otherwise specified (BP-NOS). In this way it may even be possible to head off the full-blown illness before it starts in those children at highest risk.
In adults with bipolar disorder, adversity in childhood has been associated with an earlier onset of bipolar disorder compared to those who did not experience some form of adversity such as verbal abuse, physical abuse, sexual abuse, loss of a parent, abandonment, or neglect. At the 2013 meeting of the Society of Biological Psychiatry, Nancy Low et al. reported that the number of these stressful life events a child experienced was associated with the number of their anxiety symptoms, psychiatric disorders, and lifetime substance abuse. Having experienced 3 or more adversities was associated with a 3.5-fold increased risk for developing a mood disorder and a 3-fold increase in anxiety disorders and alcohol or drug abuse.
While the study has not yet been published in a peer-reviewed journal, the abstract (#194) may be found in the meeting supplement, Volume 73, Number 9S of the journal Biological Psychiatry.
Editor’s Note: Low’s study is the first to report that childhood adversity is a risk factor for the onset of bipolar disorder in the general population.
Given the increasing evidence for the persistence of epigenetic marks on DNA and histones (which can’t change the sequence of genes but can change their structure) in those who have experienced such stressors in childhood, this could provide a mechanism for the long-term vulnerability of these children to the development of mood disorders and a variety of physical illnesses.