WASHINGTON (FRONTLINE MEDICAL NEWS) – A sea change is underway in how major depressive and bipolar disorders are diagnosed and treated.

Historically, the absence of an accurate, comprehensive nosology of depression has led to much suffering and confusion. People with bipolar disorder in particular are either not diagnosed early enough or are not diagnosed with the correct “flavor” of depression, according to Roger S. McIntyre, MD, author of updated treatment guidelines for bipolar depression, and the first-ever treatment guidelines for mixed features in major depressive disorder. “Twenty years ago, we would have described bipolar as episodic breakthroughs of mania and depression, with well intervals in between,” Dr. McIntyre said at Summit in Neurology & Psychiatry. “But now, we’ve really changed our fundamental thinking about bipolar disorder.”

Although reasons for the evolution in thinking are many, one of the strongest currents of change flows from the 2013 publication of the DSM-5, according to Dr. McIntyre, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit at University Health Network in Toronto.

“The DSM-5’s authors took a neo-Kraepelinian view that mood disorders are dimensional,” Dr. McIntyre said in an interview. As a result, there’s been a reversal of what he called the “social construct imposed upon the cosmos of mood disorders by the DSM-III that divided that world into either depression or bipolar disorder.”

This return to thinking of mood disorders as existing on a continuum, as psychiatrist Emil Kraepelin, MD, theorized around the turn of the last century, pivots on the decision to do away with mixed states and to instead add the mixed features specifier.

“The move to mixed features is the necessary bridge between bipolar disease and major depressive disorder,” Dr. McIntyre said in the interview.

Therefore, for a period of time between the 1980 publication of the DSM-III and the DSM-5, “real-world” presentations of subsyndromal, opposite-pole symptoms that are common in major depressive disorder (MDD) and in bipolar disorder were not accounted for.

In practical terms, the addition of mixed features means that a patient with mania who presents with subsyndromal depressive symptoms would be seen, for example, to have mania with mixed features. A patient with a depressive episode who presents with subsyndromal hypomanic symptoms would be seen to have depression with mixed features. Therefore, depression with mixed features can be present not only in MDD, but in both bipolar I and II.

New treatment algorithms

This dimensional approach of assessing mixed features along a continuum could lead to better and earlier diagnosis of bipolar depression and more targeted therapies, according to Dr. McIntyre. What he thinks it won’t do is lead to an overzealousness in the overdiagnosis of bipolar depression.

“That is false. We wouldn’t say we’re not going to diagnose bowel cancer because we hear it’s overdiagnosed. But to get the diagnoses right, what we need is fidelity to diagnostic criteria.”

Enter the state of Florida. As part of its best practices for psychotherapeutic use in adults, Florida is the first state to have published evidence-based guidelines for depression with mixed features. Dr. McIntyre is one of the guidelines’ coauthors.

Antidepressants bad, olanzapine worse

Some changes to treatment algorithms might come as a surprise. Despite being among the most commonly prescribed treatments for bipolar disorder, monotherapy with antidepressants is not approved in the guidelines. “Period,” said Dr. McIntyre. “Many patients do well on antidepressants, but the most common outcome is inefficacy.”

It might be better to combine an antidepressant with an atypical antipsychotic, or a mood stabilizer to avoid treatment-emergent mania, or, more commonly, destabilization in patients who are susceptible to subsyndromal mania, he said.

In addition to mitigating symptoms of a depressive episode, atypicals can help suppress hypomanic symptoms. Dr. McIntyre said this is critical to remember, because patients with these combinations of symptoms are “the very persons who shouldn’t get an antidepressant but are also the ones most likely to be prescribed them,” according to old ways of thinking.

As for maintenance in bipolar disorder, Dr. McIntyre believes the axiom, “What gets you well keeps you well,” is a good rule of thumb when going through the algorithm. “It’s not always true, but it’s almost always true.”

Management of MDD with mixed features includes the introduction of atypicals or mood stabilizers such as lithium or lamotrigine in patients with any prior history of hypomania or mania, something Dr. McIntyre said already is beginning to happen in practice.

Olanzapine monotherapy as a first-line treatment of bipolar disorder initially was “demoted” by Dr. McIntyre and his coauthors in Florida’s bipolar treatment guidelines. In the updated version, the atypical remains a second-line therapy behind lurasidone as the recommended first-line therapy because of olanzapine’s tendency to interfere with metabolic processes. Quetiapine also is a first-line therapy, but with the qualification that it, too, could interfere with metabolic processes. Combination therapy with olanzapine plus fluoxetine is second-line.

“Lurasidone does not have the metabolic changes of quetiapine. It doesn’t make sense to treat mania and then erase 25 years of a person’s life because of weight gain,” Dr. McIntyre said.

The average lifespan of people with bipolar disorder is about 20 years shorter than it is for those without serious mental illness.

Inflammation harms cognition

The changes are indicative of how seriously the field has begun to take metabolic disturbance as an adverse event in serious mental illness. Literature on obesity as a “psycho-toxin” is growing, and Dr. McIntyre is among the pioneers.

One study by Dr. McIntyre and his colleagues, currently in press, explores how obesity-related inflammation disturbs the brain’s dopamine system, resulting in interference with executive function. Because it is well established that people with bipolar disorder are more likely to be obese ( J Affect Disord. 2008 Sep;110[1-2]:149-55 ), they also are more susceptible to cognitive impairment than are people of normal weight, according to Dr. McIntyre.

In a 2013 study , Dr. McIntyre and his colleagues showed that a first episode of mania in a person with obesity creates the same level of cognitive impairment as that found in the brains of normal-weight individuals who have experienced five episodes of mania (Psychological Med. 2014 Feb;44[3]:533-41). “There is something about obesity that is brain toxic,” he said.

Proof of concept of this is that cognitive outcomes for people before bariatric surgery are worse than postsurgery outcomes ( Am J Surg. 2014 Jun;207[6]:870-6 ).

Systemic inflammation elevates levels of C-reactive protein, interleukin-1, and other cytokines, and interferes with insulin signaling; all have deleterious effects on cognition, as well as metabolic health. Those disturbances negatively affect emotional regulation, sleep, appetite, and sex drive, as well as executive function, he said.

“Inflammation is a convergent system, implicated across many brain- and body-based disorders. People with bipolar disorder not only have systemic increases in inflammation, but also neuroinflammation,” Dr. McIntyre said.

Accordingly, controlling inflammation becomes essential to chronic management of depression in general and bipolar in particular since, with each successive episode of untreated mania, patients’ ability to think clearly takes a hit. “Cognitive function is the principal determinant of psychosocial function, of workplace visibility, [and] of quality of life in most patient-reported outcomes,” Dr. McIntyre said.

Cognitive impairment also can lead to a worsening of the ability to balance reward and impulse control, leading to higher rates of substance abuse or other psychiatric comorbidities after onset of bipolar disease; a vicious cycle can ensue.

“As cognitive difficulties rise, comorbidities rise. But also, some of the comorbidities we see are reflections of cognitive impairment,” Dr. McIntyre said. To wit, binge eating disorder and bulimia nervosa are common in people with bipolar disorder ( J Affect Disord. 2016 Feb;191:216-2 ).

Citing a recent scientific statement from the American Heart Association recommending that bipolar disorder and MDD should be considered tier II risk factors for cardiovascular disease among youth, the Florida guidelines urge clinicians to regularly screen patients for cardiometabolic disorders – not only for their medical implications but for their potential to flag emergent psychiatric issues.

Pharmacotherapeutics specifically targeting neuroinflammation are not yet ready for clinical practice, but Dr. McIntyre said other, more conventional therapies are available for bipolar disorder that have anti-inflammatory properties, including selective serotonin reuptake inhibitors and lithium. “Lithium is also anti-amyloid and has an anti-suicide effect. It is a drug I would definitely use as first line.”

Some behavioral therapies also are protective against inflammation and are recommended in the guidelines. Those include attention to sleep hygiene, diet, and exercise. “Social rhythm therapy is underutilized. These patients need their day organized. They need aerobics; they need sleep,” Dr. McIntyre said.

Future is now

Although the “whole-person” approach is still nascent – seeing depression as a collection of what Dr. McIntyre said are alterations in the neural circuitry amounting to a series of “disconnection syndromes” – psychiatry already has entered a new era where disease models are more comprehensive, he said.

This new way of thinking can connect the dots between why, for example, so many people with bipolar depression also have drug and alcohol abuse. It also could help explain why in bipolar there is so much obesity, or why there is so much anxiety, he said. “We’ve moved away from the rather silly, overly simplistic notions that you have too much or too little serotonin. Or that there was too much or too little dopamine causing mania. It made for convenient sound bytes, but it was probably just superstition we were gravitating to.”

The guidelines have been peer reviewed and will be published in the Journal of Clinical Psychiatry later this year, Dr. McIntyre said.

The meeting was held by Global Academy for Medical Education. Global Academy and this news organization are owned by the same company.

Dr. McIntyre disclosed that he has numerous industry relationships, including with AstraZeneca, Eli Lilly, Janssen Ortho, Lundbeck, Pfizer, and Shire.

On Twitter @whitneymcknight


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