Patients with Bipolar Depression Have a Higher Mortality Rate, Especially if They Also Have Cardiovascular Disease
In a large longitudinal study of depressed patients in Taiwan that was published in the Journal of Psychiatric Research this year, Chang et al. found that after 10 years, patients with bipolar depression (N=1,542) had significantly higher mortality rate than those with other types of depression (N=17,480). Patients with bipolar depression were twice as likely to have died from suicide or accidental death than were patients who had other types of depression. When cardiovascular disease was also present in both groups, patients with bipolar disorder were also four times more likely to have died from suicide or accidental death than those with other types of depression.
Editor’s Note: These data again emphasize the critical importance of patients with bipolar disorder carefully looking after their medical and cardiovascular health both early on and throughout the entire course of their illness.
Much of the excess medical mortality in bipolar disorder is attributed to cardiovascular disease, and now those with cardiovascular disease also appear more prone to suicide. This should be a call to action to improve the long-term treatment of both bipolar disorder and its common comorbidity, cardiovascular disease.
Get your medical illness treated!
It will improve your health and longevity. Especially treat these signs of the metabolic syndrome, a major risk factor for cardiovascular disease:
- Cholesterol–Increase “good” cholesterol (high-density lipoproteins or HDLs) and lower “bad” cholesterol (low-density lipoproteins or LDLs)
- High Triglycerides–Triglycerides should be below 150 mg/dL
- Blood Pressure–Aim for 130/85 mmHg or lower
- Blood Sugar–Fasting blood sugar (glucose) should stay below 100 mg/dL
- Overweight & Obesity–Keep waist circumference under 40” for men or 35” for women
Exercise is good for all of these!
How Illness Progresses In The Recurrent Affective Disorders
This editor (RM Post) in collaboration with Jacqueline Fleming and Flavio Kapczinski published the article “Neurobiological mechanisms of illness progression in the recurrent affective disorders” in the Journal of Psychiatric Research this year. The article built on several themes about the progression of bipolar illness that had been explored in previous research.
These themes include:
- The likely acceleration of repeated episodes as a function of the number of prior episodes (episode sensitization)
- The increased responsivity of the illness to repeated stressors (stress sensitization)
- The increased behavioral reactivity to repeated use of psychomotor stimulants such as cocaine (stimulant-induced behavioral sensitization)
Not only are these observations well documented in the scientific literature, but recent observations also suggest that each type of sensitization can show cross-sensitization to the other two types. That is, individuals exposed to repeated stressors are more likely both to experience affective illness episodes and to adopt comorbid substance abuse. In a similar way, episodes of an affective disorder and stressors may also be associated with the relapse into drug administration in those who have been abstinent.
In addition to these mechanisms of illness progression in the recurrent affective disorders, the new article reviews the literature showing that the number of affective episodes or the duration of the illness appear to be associated with a variety of other clinical and neurobiological variables.
The number of affective episodes a patient experiences is associated with the degree of cognitive dysfunction present in their bipolar illness, and experiencing more than 4 episodes of unipolar or bipolar depression is a risk factor for dementia in late life. A relative lack of response to most treatments is also correlated with the number of prior episodes, and this holds true for response to naturalistic treatment in general. While most of these data are correlational and the direction of causality cannot be ascertained for certain, it is likely that the number of affective episodes and/or their duration could account for and drive difficulties with treatment and with cognitive function.
If this were the case, one would expect to see a variety of neurobiological correlates with the number of prior episodes or duration of illness, and in the article we summarize those that have been found in unipolar and bipolar disorder. Considerable data indicate that cortical volume and degrees of prefrontal cortical dysfunction can vary as a function of number of prior episodes. There is evidence that increased activity of the amygdala and the nucleus accumbens are also related to episodes or duration of illness. In those with unipolar depression, the volume of the hippocampus is decreased with longer duration of illness. Read more
Earlier Age of Onset of Bipolar Illness in the US Compared to Europe
As we have previously reported in the BNN, the Bipolar Collaborative Network (including this editor Robert M. Post) found that patients from 4 sites in the United States had significantly earlier ages of onset of their bipolar illness compared to 3 sites in the Netherlands and Germany). These findings have been replicated by Frank Bellivier et al., who used a broader sample of European participants.
Bellivier’s research group studied two large samples of bipolar I patients from the US (n= 2275) and from 14 countries in Europe (n= 3616). The researchers found 3 different distributions of age of onset, and patients from the US had a greater representation in the early age of onset subgroup. Sixty-three percent of the sample from the US fell into the early-onset group versus 25% of those from Europe. The mean age of onset of the early-onset subgroup was significantly lower in the US sample (14.5 +/- 4.9 years) than in the European sample (19 +/- 2.7 years).
Editor’s Note: It is time that we took these geographical differences in the frequency of early age of onset of bipolar disorder seriously. While some controversy has surrounded the diagnosis of bipolar illness in children, it becomes increasingly important to recognize that this bona fide, well-diagnosed illness is more common in children from the US than from many other countries. Affected children should have careful clinical evaluation and, if the diagnosis warrants, definitive treatment. This should include both psychoeducational approaches; focused psychotherapies, including the family-focused therapy pioneered by Dave Miklowitz; and psychopharmacological intervention. When this kind of combined treatment is implemented, young patients who are treated with lithium, another mood stabilizer, or an atypical antipsychotic do much better than those who do not receive these consensus-based treatments.
Treatment algorithms for children of different ages with bipolar disorder are still being developed. However, it appears that in young and very young children, the atypical antipsychotics are often more effective than lithium or valproate monotherapy, as suggested in recent large randomized clinical trials. Initiating appropriate treatment is extremely important, since the duration of the untreated interval (that is, the time from illness onset to first treatment) is directly related to worse outcomes in adulthood. The longer the duration of untreated illness, the greater the severity of depression, the longer the duration of depression, and the greater the number of episodes an adult experiences.
As might be expected from the earlier age of onset of bipolar disorder, US patients also have a higher incidence of the major vulnerability factors for early onset—more genetic vulnerability (parents with bipolar disorder), more childhood stressors, and more stressors in the year prior to illness onset. Patients from the US also had a variety of other poor prognosis factors, including a higher degree of anxiety comorbidity, alcohol and substance abuse problems, a higher incidence of having more than 20 episodes over their lifetime, and a higher incidence of rapid cycling. All of these characteristics combine to produce worse outcomes in adult patients from the US compared to those from Europe. Earlier and more judicious treatment of the illness in the United States is needed to help ward off this more pernicious course of bipolar illness.
Sunlight Could Be a Geographic Risk Factor for Pediatric-Onset Bipolar Disorder
A number of factors appear to be associated with age of onset of bipolar disorder. Several studies have replicated the finding that those who experienced some adversity in childhood and who have a parent or parents with bipolar disorder are at increased risk for earlier onset of the illness. These risk factors are more prevalent in the US than in many western European countries, and considerable data support the observation that the age of onset of bipolar illness is earlier in the United States than in several European countries. However, childhood onsets of the illness are prevalent in Turkey and in Norway.
Researcher Mike Bauer raises another possibility in an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders. He examined the association between age of onset and sunlight in the environment in 24 different sites in 13 different countries. Solar insolation refers to the amount of electromagnetic energy striking the surface of the earth. Bauer found that larger springtime maximum monthly increases in solar insolation were associated with younger ages of onset of bipolar disorder (p= 0.006). These calculations were derived from NASA Surface Meteorology and Solar Energy databases for each location. The largest maximum monthly increases in solar insolation occurred in varied climates, including in Norway, Chile, and arid parts of California.
Genetic Risk Factors for Onset of Bipolar Disorder
A Genetic Risk Factor For Bipolar Disorder: The CACNA1C Gene
In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, Sophia Frangou reported on the CACNA1C polymorphism, a genetic variation that has been associated with the risk of developing bipolar disorder in several genome-wide association studies that search for links between genes and illnesses. Frangou found that those people with the genetic variation had increased volume in some parts of the brain, including the right hypothalamus and the right amygdala, and decreased volume in others, including the putamen, as well as alterations in the functional connectivity of different cortical areas.
Location of the CACNA1C gene
These data may be related to findings that calcium influx may play a role in bipolar disorder. In people with the genetic variation, the risk allele binds to a subunit of the voltage-dependent calcium channel, which modulates the influx of calcium from the outside to the inside the neuron.
Increased amounts of calcium are consistently found in the white cells and platelets of patients with bipolar disorder compared to controls. Moreover, the drug nimodipine, a dihydropyridine L-type calcium channel blocker, is effective in the prevention of manic and depressive episodes in a subgroup of patients, particularly those with cycling patterns that are ultra-rapid (4+ episodes per month) or ultradian (including a mood switch within a 24-hour period 4+ times per month). A large randomized study of patients with bipolar disorder presented by H.R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry also found that while lithium was associated with a 50% response rate, the combination of lithium and nimodipine was associated with a 73% response rate, again suggesting the additional efficacy of blocking L-type calcium channels.
Immune Abnormalities May Predict Onset of Bipolar Disorder in Children at High Risk
At the 5th Biennial Conference of the International Society for Bipolar Disorders E. Mesman discussed connections between immunity and bipolar disorder. Mesman and colleagues followed offspring of parents with confirmed bipolar disorder for 12 years and compared them to children in the general population. In the children of bipolar parents they found higher levels of immune markers called cytokines (PTX3 and sCD25) in circulating monocytes, a type of white blood cell. In the children of bipolar parents they also found a high inflammatory setpoint in the monocytes. T-effector and T-regulatory cells were also different in the offspring of bipolar parents.
While these findings were present in children who had already become ill with bipolar disorder, they were also present in those who had yet to experience a mood disorder, suggesting that these immune and inflammatory markers may ultimately be an important risk marker for the onset of bipolar disorder.
Editor’s Note: These are among the first studies suggesting that immune and inflammatory abnormalities may precede the onset of bipolar disorder. Many studies have shown that patients with active bipolar disorder show more inflammation, including increases in inflammatory markers interleukin 1 (IL-1), interleukin 6 (IL-6), C reactive protein (CRP), and tumor necrosis factor alpha (TNFa). The new data are of considerable importance not only because inflammation could serve as a marker of illness onset, but also because inflammation could become a potential target for therapeutics (i.e. using anti-inflammatory and immune-suppressing agents to treat bipolar disorder).
The Unfolding Story of Poor Response to Antidepressants in Bipolar Depression
The role of the traditional antidepressants in the treatment of depression in bipolar illness remains controversial. Despite mounting evidence that they are not efficacious in the treatment of bipolar depression, they are still among the most widely used treatments for that condition. At the first biennial conference of the International Society for Bipolar Disorders held in Istanbul this past March, Mark A. Frye and Shigenobu Kanba chaired a symposium on antidepressant-induced mania and individualized treatment for bipolar depression.
This editor (Robert M. Post) discussed factors influencing antidepressants’ effects on patients with bipolar depression. In a recent meta-analysis, researchers Sidor and MacQueen reviewed data from studies encompassing 2373 patients with bipolar depression and found that antidepressants had no significant benefits over placebo on measures of response or remission. Pooled estimates for a thousand patients showed no increase in patients’ risk of switching into mania after treating with antidepressants. However, in a smaller sub-analysis, the risks of switching into mania following treatment with the older tricyclic antidepressants (43%) and venlafaxine (15%) was greater than the risk of switching after being treated with SSRIs (7%) or bupropion (5%).
There is a conundrum in the literature. While antidepressants don’t work very well in bipolar depression, there is a small subgroup of patients who, having responded well to antidepressants for two months, benefit more from continuing the antidepressant treatment than from discontinuing the drug. Continued treatment with adjunctive antidepressants (added to regular treatment with a mood stabilizer or an atypical antipsychotic) was associated with fewer relapses into depression over the next year when the antidepressants were continued compared to when they were discontinued. Lori Altshuler et al. have published two uncontrolled studies to this effect, Russell Joffe et al. have published one, and a more recent randomized study of this by Nassir Ghaemi replicated some of the results in patients who had non-rapid-cycling bipolar disorder. At the same time, the literature shows that there are number of risk factors for switching into hypomania during antidepressant treatment in bipolar depression.
Risk factors for switching into mania upon treatment with an antidepressant include: younger age, bipolar I compared to bipolar II, rapid cycling in the past year, mixed depression, use of older tricyclic antidepressants compared to newer second-generation antidepressants, use of noradrenergic active antidepressants compared to those that act on serotonin or dopamine, and a history of substance abuse. Read more
Study Calls Into Question FDA Black Box Warning about Suicide Risk in Youth Taking Antidepressants
In 2004, the Federal Drug Administration issued a “black box warning” about increased risk of suicidal thoughts and behavior in children and adolescents taking selective serotonin reuptake inhibitors (SSRIs). See here for an overview from the National Institute of Mental Health.
An article published in the Archives of General Psychiatry earlier this year analyzed data from studies of fluoxetine and venlafaxine in youth, adults, and geriatric patients to determine if antidepressant use is linked to suicide. The drugs decreased both depressive symptoms and suicidal thoughts and behavior in adults and the geriatric population. They seemed to have no effect on suicidal thoughts or behavior in the youth.
For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication.
Weight Gain and Metabolic Risks of Antipsychotic Drugs in Children and Adolescents
A study published in the Journal of Child and Adolescent Psychopharmacology in late 2011 reviewed the various weight and metabolic side effects of drugs like olanzapine, clozapine, risperidone, quetiapine, and aripiprazole.
Across 34 published head-to-head and placebo-controlled studies in youth with psychotic and bipolar disorders, weight gain ranged from 3.8 to 16.2 kg with olanzapine (n=353), 0.9-9.5 kg with clozapine (n=97), 1.9-7.2 kg with risperidone (n=571), 2.3-6.1 kg with quetiapine (n=133), and 0-4.4 kg with aripiprazole (n=451).
Exercise and Brain Health: Some Good Points to Remember
In a review article in the Neuroscientist published in February of this year, Kirk I. Erickson and collaborators wrote that “[m]ajor depressive disorder is considered a risk factor for Alzheimer’s dementia and memory impairment and is associated with less BDNF and greater hippocampal atrophy, possibly through a BDNF pathway. However, exercise and effective treatment for geriatric depression increases BDNF levels, increases serotonin fibers, is associated with greater hippocampal volumes, and reduces the risk for Alzheimer’s dementia.”
Editor’s note: Not a bad set of benefits from exercise! The researchers suggest that exercise is extremely important in reversing the decreases in brain-derived neurotrophic factor (BDNF) associated with depression, helping to improve depressed mood, increasing cardiovascular fitness, and maintaining healthy cognition.
Hippocampal volume and BDNF levels in blood both decrease with age. Yet exercise increases both BDNF and the formation of new neurons (neurogenesis) in animals. New data in humans suggest that aerobic fitness is associated with the size of the hippocampus, both in both children and adults. It is not clear yet whether this increase in hippocampal volume is directly driven by increases in BDNF and/or neurogenesis. However, since a smaller hippocampus is a risk factor both for depression and for mild cognitive impairment progressing to Alzheimer’s dementia, attempting to enhance hippocampal volume in any way possible is probably a good idea.
Methods of increasing hippocampal volume include treatment with antidepressants or with lithium. In the 2012 paper Erickson and collaborators also wrote, “Anaerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway.”
Erickson and collaborators conducted a longitudinal study published in 2010 that quantified the amount of physical activity subjects engaged in by calculating the total number of blocks walked per week. Individuals reporting greater amounts of physical activity at the beginning of the study had, upon examination nine years later, greater gray matter volume in several parts of the brain, including the hippocampus. This effect was “dose-dependent,” meaning that only those individuals who walked at least 72 blocks per week (roughly equivalent to 1 mile per day) had significant sparing of brain tissue nine years later. The study found increased gray matter volume in the prefrontal cortex and in the temporal lobe.
After a further follow-up of four more years, greater gray matter volume with physical activity was associated with a two-fold reduced risk of cognitive impairment. The researchers concluded that “physical activity patterns earlier in life were linked to brain volume and cognitive impairment later in life.”
There are a number of important points to remember about cognitive impairment. One is that increasing hippocampal volume and preventing its decrement with aging may help prevent age-related memory loss and potentially the rapidity at which mild cognitive impairment progresses. Read more
Keep Your Heart and Cardiovascular System Healthy
Middle aged folks, watch your risk factors for cardiovascular disease. These include: high blood pressure, cholesterol, weight, and blood sugar (diabetes).
According to Heartwire, an article in the New England Journal of Medicine indicates that having any of these risk factors increases the likelihood of cardiovascular disease later in life. The more risk factors one has, the greater the increase in risk.
Across the whole meta-analysis, participants with no risk factors at age 55 (total cholesterol level: <180 mg/dL;
blood pressure: <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking; nondiabetic) had drastically better odds
of avoiding death from cardiovascular disease through the age of 80 than participants with two or more major risk
factors (4.7% vs 29.6% among men and 6.4% vs 20.5% among women).People with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal MI (Editor’s Note: myocardial infarction, or heart attack) (3.6% vs 37.5% among men, <1% vs 18.3% among women) and fatal or nonfatal stroke (2.3% vs 8.3% among men,
5.3% vs 10.7% among women), compared with those with two or more risk factors.
What this article does not mention is that depression is a risk factor for coronary artery disease, and should be treated just as aggressively and persistently as the other cardiovascular risk factors.
Also as we’ve written before in the BNN, exercise is one element of a healthy life style that can positively affect all of these risk factors. Starting a healthy diet and exercise regimen in middle age will have long-term positive effects and reduce risks later in life.
