Immune Response in Mania

February 18, 2014 · Posted in Course of Illness, Risk Factors · Comment 

antibodies

While the reasons why one person develops bipolar disorder and another does not remain mysterious, the current thinking is that genes contribute some risk while immunological abnormalities contribute other risks. Researchers have identified certain antibodies whose levels spike during an episode of mania, as if the patient is having an immune reaction. These are referred to as biomarkers or inflammatory markers.

While various biomarkers for mania have been identified, until recently their effects had only been examined independently. A 2013 article by Dickerson et al. published in the journal PLOS ONE examined four biomarkers in combination. Each was a type of antibody: to the NR peptide of the NMDA receptor, to gliadin (a protein derived from gluten), to Toxoplasma gondii (a parasitic protozoan), and to Mason-Pfizer Monkey Virus. Measures of these four types of antibodies made up a combined inflammation score for participants in the study.

The study compared 57 patients presenting with a manic episode with 207 non-psychiatric controls and 330 patients who had had recent onset of psychosis, schizophrenia, or bipolar depression. The combined inflammation score of the mania group was significantly higher than the other groups at the time of hospital admission and at the time of evaluation several days later. It had returned to normal (i.e. not different from the other groups) at followup six months later, although those with the highest combined inflammation scores were at risk for re-hospitalization during that period.

The findings of this study suggest that hospitalization for mania is associated with immune activation, and the level of this activation predicts subsequent re-hospitalization. Treatments for mania that target this inflammatory response should be investigated.

Longitudinal Trajectory of Childhood Bipolar Disorder

December 19, 2013 · Posted in Course of Illness · Comment 

teens getting older

Most children recover from an episode of bipolar disorder after a considerable period of time, but the majority eventually relapse. At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Boris Birmaher of the University of Pittsburgh presented new data on the long-term prospective course of bipolar disorder in 255 children with bipolar I, 30 children with bipolar II, and 153 children with bipolar NOS (not otherwise specified), who together had an average age of onset of 9.3 +/- 3.9 years. The children participated in the study for an average of 8 years. Most of the children (81.5%) recovered from their episode, but only after an average of 2.5 years of follow up treatment. Yet 62.5% of those who recovered experience a recurrence after an average of 1.5 years.

Editor’s Note: It takes a long, long time to achieve recovery, and longer for bipolar NOS (more than 2 years on average) than for either Bipolar I or II (about 1.8 years). However, the high rate of relapse within 1 to 2 years is equally disturbing. These data are similar to those in many other prospective follow up studies of children, and suggest that it is important for parents to be aware that this illness is difficult to treat, and good results within weeks are not likely to be the norm. At the same time, 43% of the children with a bipolar diagnosis eventually achieved euthymia (wellness) in the longer term, so there is cause for some optimism.

Four Trajectories in Children with Bipolar Illness

Birmaher described four different long-term,trajectories observed over an average of 8 years of follow up with 438 children with bipolar disorder.

  1. Predominately euthymic (24%)
  2. Ill early then much improved (19%)
  3. Mild to moderately ill—euthymic only 47% of the time (34.6%)
  4. Predominantly ill—euthymic 11.5% of the time (20.3%)

Explaining Wellness

The predominantly well group (1) was associated in a univariate analysis with a later onset of illness, higher socio-economic status, less conflict, fewer stressors, less sexual abuse, fewer anxiety and ADHD comorbidities, and less medication (including stimulant use).  In a multivariate analysis, this group was independently associated with less severe depression/mania, less suicidal ideation, less substance use, less sexual abuse, and less family history of mania and substance abuse.

This group had the best functioning, almost to 80 on the Children’s Global Assessment Scale (C-GAS). In comparison, despite considerable time euthymic for groups 2 and 3, these children still had considerable functional impairment, in the realm of 65 on the C-GAS scale. Even in Group 1, about half of the children had low C-GAS scores.

Birmaher suggested the importance of trying to find ways to delay the onset of the illness (to graduate more children into the good prognosis group) and allowing them time to develop socially and educationally and graduate from high school. Potential preventive strategies could include omega-3 fatty acids, more time spent exercising, good sleep hygiene, family focused therapy (FFT), dialectic behavior therapy, treating subsyndromal depression, and even treating parents with mood disorders to complete remission (which has been shown to improve behavioral health in offspring).

Editor’s Note: As this editor Post, Chang, and Frye wrote in the Journal of Clinical Psychiatry in 2013, beginning to study the effectiveness of these kinds of early primary and secondary prevention strategies in children who can now be readily identified clinically as at risk for a mood disorder, should be given the highest priority.  

Children who have at least one parent with a bipolar or unipolar disorder, some further environmental risk factors (such as adversity in early childhood), and early symptoms of depression, anxiety, or prodromal bipolar disorder are at very high risk for bipolar disorder, and there is an urgent need for randomized studies (even open ones) of safe potential preventive strategies for these children. 

Omega-3 fatty acids in particular have a strong record of safety, compelling rationale for use in bipolar disorder, and have already been shown to have significant preventive effects in decreasing the transition from early prodromal psychosis to full-blown schizophrenia.

Worsening Comorbidities Relate To Adverse Bipolar Outcomes

December 18, 2013 · Posted in Course of Illness · Comment 

anxious teenMany children with bipolar disorder also present with other comorbid Axis I psychiatric illnesses. Now it seems that the worsening of these comorbidities, such as attention-deficit hyperactivity disorder (ADHD) or an anxiety disorder, can signal a more difficult course of bipolar illness itself. At a symposium on the course of bipolar disorder in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Shirley Yen from Brown University discussed findings on comorbidities of childhood onset bipolar disorder from COBY, the Collaborative Child Bipolar Network. Upon study entry, 60% of children with bipolar disorder also had ADHD, 40% had oppositional defiant disorder (ODD), 39% had an anxiety disorder, 12.5% had both oppositional defiant disorder and a conduct disorder, and 9% had a substance abuse disorder.

The prevalence of most of these comorbid illnesses increased over time (e.g. anxiety disorder rates increased from 39% to 62%). The illnesses were also related to the time it took participants to achieve recovery (eight consecutive weeks well), and the time until a recurrence of a depressive or manic episode.

Increases in anxiety were linked to longer time to achieve recovery and a shorter time to a recurrence. Increases in ADHD were linked to a more rapid onset of a depressive recurrence. Increases in oppositional defiant disorder and conduct disorder had no relationship with either remission or recurrence. Increases in substance abuse disorders were linked to a longer time to recover from a manic episode. Thus, worsening of the comorbid conditions had definite consequences for both recovery and recurrence.

Depression in Youth Is Tough to Treat and Requires Persistence and Creativity

November 27, 2013 · Posted in Course of Illness, Current Treatments, Risk Factors · Comment 

teen boyAt a symposium on ketamine for the treatment of depression in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, David Brent, a professor at the University of Pittsburg, gave the opening talk on the fact that as many as 20% of adolescents who are depressed fail to improve, develop chronic illness, and are thus in need of alternatives to traditional treatment. Predictors of non-improvement include substance use, low-level manic symptoms, poor adherence to a medication regimen, low blood levels of antidepressants, family conflict, high levels of inflammation in the body, and importantly, maternal depression. In adolescents insomnia was associated with poor response, but in younger children insomnia was associated with a better response.

Brent suggested using melatonin and sleep-focused cognitive behavioral therapy for insomnia in youth, but not using trazodone (which is commonly prescribed). Trazodone is converted to a compound called Meta-chlorophenylpiperazine or MCPP, which induces anxiety and dysphoria. MCPP is metabolized by hepatic enzymes 2D6, and fluoxetine and paroxetine inhibit 2D6, so if trazodone is combined with these antidepressants, the patient may get too much MCPP.

Surprisingly and contrary to some data in adults about the positive effects of therapy in those with abuse histories, in the study TORDIA (Treatment of SSRI-Resistant Depression in Adolescents), if youth with depression had experienced abuse in childhood, they did less well on the combination of cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) compared to SSRIs alone.

Emotional Abuse in Childhood is a Risk Factor for Bipolar Disorder

November 11, 2013 · Posted in Course of Illness, Risk Factors · Comment 

Boy hearing emotional abuseEvidence 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.

Jules Angst on the Long-Term Progressive Course of Mood Disorders

October 31, 2013 · Posted in Course of Illness, Current Treatments · Comment 
Jules Angst

Jules Angst

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.

Bipolar Illness is Worse in the US than in Germany and the Netherlands

October 31, 2013 · Posted in Course of Illness, Risk Factors · Comment 

sad girl with US flag

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.

U.S. Patients with Bipolar Disorder Have More Stressors in Childhood and Prior to Illness Onset

September 23, 2013 · Posted in Course of Illness, Risk Factors · Comment 

verbal abuse of a child

In research published since 2008, our Editor-in-Chief Robert M. Post and colleagues in the Bipolar Collaborative Network have compared patients with bipolar disorder in the United States to those in Germany and the Netherlands. Compared to the European sample, patients in the US have more genetic vulnerability to bipolar disorder (by having a parent with bipolar disorder), earlier onsets of their illness, more complicated courses of illness, greater treatment resistance, and more medical comorbidities. Patients in the US also have more psychosocial stress.

The researchers are now turning their attention to these psychosocial vulnerabilities, and in a new paper that will be published in Psychiatry Research (late in 2013 or early in 2014), the authors show that patients in the US had more stressors both in childhood and just prior to the onset of their illness. Childhood stressors analyzed in the study were verbal abuse, physical abuse, and sexual abuse. Stressors in adulthood included indicators of a lack of social support, troubles with finances or employment, lack of access to health care, and medical comorbidities.

The stressors patients experienced just prior to their most recent episode of bipolar illness were related to: stressors in childhood, an earlier age of illness onset, anxiety and substance abuse comorbidity, lower income, both parents having an affective illness such as depression, and feeling more stigma.

The new research suggests that for patients with bipolar disorder in the US, adverse life events in childhood and later in life are more prevalent than they are for patients in the Netherlands or Germany. Earlier and more effective approaches to these stressors, such as the Family-Focused Therapy developed by David Miklowitz and Kiki Chang, could potentially slow the onset or progression of bipolar illness in this country.

Long-term Course of Bipolar Illness is Most Difficult

February 1, 2013 · Posted in Course of Illness · Comment 

Bipolar

While the 4 major childhood-onset psychiatric illnesses we discussed this week (bipolar, unipolar, ADHD, and anxiety disorders) show long term difficulties into adulthood in the majority of instances, it appears that the most severely impacted are those with bipolar disorder. These data are also consistent with retrospective data from multiple cohorts of adults with bipolar disorder, which indicate that those whose illness began in childhood fared more poorly in adulthood than those with adult-onset illness. Thus, while there has been a modicum of treatment research in childhood depression and anxiety disorder and a plethora of treatment studies in ADHD, the dearth of treatment studies in children with bipolar disorder is all the more disconcerting.

Bipolar disorder is common, occurring in some 2 to 3% of children and adolescents, and carries a relatively grave prognosis into adulthood in the majority of instances, especially when it is inadequately treated. Virtually all of the investigators in the area of childhood-onset bipolar who presented at the AACAP meeting have pleaded for increased treatment research for bipolar disorder in children, and one can only hope that their message is soon heard.

Long-term Outcomes for Childhood-Onset Disorders: Anxiety Disorders

January 31, 2013 · Posted in Course of Illness · Comment 

anxiety

A symposium at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) examined long-term outcomes of childhood onset disorders, including bipolar disorder, unipolar depression, ADHD, and anxiety disorder.

Course of Childhood Onset Anxiety Disorders

Danny Pine presented a study of 191 adolescents with an anxiety disorder, among whom 36% showed no anxiety disorder in adulthood, while 62% continued to have an anxiety disorder. Among a control population, 390 adolescents without an anxiety disorder remained so in adulthood, while 36 developed new onset of an anxiety disorder in adulthood. Sixty-two of the 98 participants who had anxiety disorders in adulthood had had the disorder continuously from its onset in adolescence. Thus, it appears that approximately two-thirds of adults with an anxiety disorder show a persistence of their childhood onset anxiety disorder, while approximately 1/3 had a new anxiety disorder diagnosis.

Editor’s Note:  While all 4 of these major childhood onset psychiatric illnesses (bipolar, unipolar, ADHD, and anxiety disorders) show long term difficulties into adulthood in the majority of instances, it appears that the most severely impacted are those with bipolar disorder. These data are also consistent with retrospective data from multiple cohorts of adults with bipolar disorder, which indicate that those whose illness began in childhood fared more poorly in adulthood than those with adult-onset illness. Thus, while there has been a modicum of treatment research in childhood depression and anxiety disorder and a plethora of treatment studies in ADHD, the dearth of treatment studies in children with bipolar disorder is all the more disconcerting.  

Bipolar disorder is common, occurring in some 2 to 3% of children and adolescents, and carries a relatively grave prognosis into adulthood in the majority of instances, especially when it is inadequately treated. Virtually all of the investigators in the area of childhood-onset bipolar who presented at the AACAP meeting have pleaded for increased treatment research for bipolar disorder in children, and one can only hope that their message is soon heard.

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