Major depression and bipolar disorder; New treatments are on the horizon for serious depression

As director of the Mood and Anxiety Disorders Program and associate professor of psychiatry and neuroscience at Mount Sinai Hospital, Dr. Dan V. Iosifescu is a psychiatrist who specializes in treatment-resistant depression and bipolar disorder. His research looks for novel treatments and understanding the brain mechanisms of these severe conditions.

Who's at risk

Major depression and bipolar disorder are two of the most common disorders seen by psychiatrists.

"Depression affects between 10% and 15% of the population," says Iosifescu. "Bipolar disorder is less frequent, but still affects 2% to 4% of Americans at some point during their lifetime."

A subset of patients who do not improve after multiple treatments is termed "treatment resistant."

These mood disorders can appear similar, and depressive episodes are indistinguishable in bipolar disorder and major depression. "Depressive episodes are characterized by long periods of severe sadness and a lack of interest in doing things" says Iosifescu. "In bipolar disorder, patients experience episodes of depression alternating with episodes of extreme mood elevation called mania or hypomania, which often lead to dangerous behaviors."

Genetics and traumatic life events are the two primary risk factors for depression and bipolar disorder, which both have fairly early ages of onset.

"While bipolar typically begins early in life (50% of patients have their first episode by age 18), depression has a wider range of first onset. However, the majority of patients experience their first episode before age 30," says Iosifescu.

While some patients might have only one or two depressed or manic episodes during their lifetime and can maintain a high level of functioning, patients with treatment-resistant disorder have long, chronic episodes or a series of multiple recurrences and can be highly impaired.

Signs and symptoms

Both depression and bipolar disorder are characterized by multiple psychological and physical symptoms.

"Besides sadness and lack of interest, symptoms of depression include disrupted sleep, low self-esteem, guilt, low energy and fatigue, poor concentration and significant changes in appetite," says Iosifescu. "Importantly, some patients experience suicidal thoughts, and suicide is a cause of mortality in both depression and bipolar disorder."

While most patients can recognize their periods of depression, they are less able to recognize as abnormal the mood elevation (hypomania and mania) of bipolar disorder. "The periods of mania — an abnormally excited, hyper mood — can feel like positive energy to the patient, even as they are perceived as abnormal by those around the patient, and it impairs significantly the patients' ability to function," says Iosifescu.

"In this state, people tend to have excessive involvement in pleasurable activities, disregarding risks or potential negative consequences."

Mania is also associated with high irritability, distractedness, high self-esteem, decreased sleep without fatigue, high levels of activity and pressured speech (very rapid speech).

"Sometimes bipolar disorder is not recognized, as the patient does not remember manic episodes as abnormal. However, the most significant challenge for treatment-resistant patients is finding a treatment that does work, even if it's not standard," says Iosifescu. "A series of novel treatments currently researched, some of them in advanced development, could prove to be lifesaving for these patients."

Traditional treatment

The standard trifecta of treatment options are medications, psychotherapies (counseling or talking therapy) and somatic treatments like electric-shock therapy and transcranial magnetic stimulation.

"We have a good number of FDA-approved drugs for depression and a smaller number for bipolar disorder," says Iosifescu. "The problem is that a lot of these medications belong to the same families of chemicals and work in relatively similar ways. So while they're incredibly helpful for many people, they are ineffective for a minority of our patients."

Psychotherapies seek to improve the patient's sense of well-being and provide tools for overcoming problems.

"For instance, cognitive behavioral therapy focuses on the abnormal thinking patterns that patients develop and helps them recognize and correct their distorted perceptions," says Iosifescu.

Somatic therapies apply energy directly to the brain to cause positive changes in depression and mood.

"Along with electro-convulsive therapy, commonly known as electric shock therapy, more modern treatments include transcranial magnetic stimulation, a magnetic field that stimulates currents in the brain, and vagus nerve stimulation, which modulates electric signals in the brain," says Iosifescu. "While electric shock therapy tends to be very effective, it has significant side effects. Transcranial magnetic stimulation and vagus nerve stimulation have limited efficacy."

Research breakthroughs

Doctors are seeking new therapies to help patients who have proven resistant to treatment.
"One very important novel treatment is ketamine, a medication currently used for anesthesia," says Iosifescu. "Recent studies, including several from our group at Mount Sinai, showed that ketamine works reliably and much faster than other antidepressants, with significant improvement occurring after only a few days even in treatment-resistant patients."

The success of ketamine points to a potential whole new family of drugs for treating depression, with activity on glutamate brain receptors, in contrast to current antidepressants, which produce their effects via serotonin, norepinephrine and dopamine.

Questions for your doctor

If you're diagnosed and undergoing a new treatment regimen, ask: "How soon can I expect improvement?" "If it's not working after eight weeks, it's time to take another approach," says Iosifescu.

Another key question is, "How will we know that the treatment is working?"

Not all depression symptoms improve at the same pace. "We have a wide enough variety of treatments that even after you've tried a few, we can find something else that works on very different mechanisms to help you manage these disorders and improve your quality of life," says Iosifescu.