"They found in the STAR*D that about a third of patients will respond andexperience a full remission to the first drug, and about another one thirdwill have a partial response, so from the start two thirds of people willget about 50% better or more," said Richard Alan Friedman, MD, the Directorof the Psychopharmacology Clinic, Department of Psychiatry, at WeillCornell Medical Center, NewYork-Presbyterian Hospital. "That still leaves athird of patients who don't respond, but if you keep treating them, youpick up an additional successful fraction with each new treatment. So thosewho don't respond to three or four antidepressant treatments probably aregoing to equal about 15% of the depressed sample. In my experience, andthat of my colleagues, if you are very persistent and methodical over timeand do not give up, you can get almost anybody better. In the past, manypeople who were called treatment-resistant just didn't get really goodtreatment." Dr. Friedman is also a Professor of Clinical Psychiatry atWeill Cornell Medical College.

David A. Kahn, MD, Clinical Professor and Vice Chair for Clinical Affairs,Department of Psychiatry, Columbia University Medical Center,NewYork-Presbyterian Hospital and the New York State Psychiatric Institute,agreed. "The rates in the STAR*D study of response when medications werecombined were slightly greater than when medications were simply switchedfrom one to another. So there is often a reason to combineantidepressants." Clinicians will look to combine medications if thepatient with depression has tolerated the initial drug well, and a mix ofdifferent mechanisms of action is often preferable. Dr. Kahn offered anexample: "Most commonly an SSRI [selective serotonin reuptake inhibitor]might be the first medication, but the second addition might be acombination with buproprion, or even a combination with such medications aslithium, thyroid hormone, or buspirone, none of which would be used as asolitary antidepressant agent, but all three of which can augment theresponse to antidepressants." Other options, like an SNRI (serotoninnorepinephrine reuptake inhibitor), nefazodone, mirtazapine, the tricyclicantidepressants, MAO inhibitors, and others, all have their place and allcan be extraordinarily valuable, although several require a great deal ofexpertise because of the significant burden of side effects. Promisingpharmacologic clinical trials on new agents are, of course, ongoing.

Another recent development is a renewed appreciation for the role thatpsychotherapy and other nonpharmacologic treatments can play in treatingdepression. "The evidence for the value of psychotherapy was developedlater than the scientific evidence supporting medication," Dr. Kahn said.The result is that psychotherapy has been underutilized by people withdepression, despite there being excellent forms of psychotherapy -- e.g.,cognitive behavioral therapy and interpersonal therapy -- that research hasfound are effective in treating these patients. Further, the evidence seemsto suggest that the best treatment for depression incorporates bothpsychotherapy and pharmacologic treatment.

Electroconvulsive therapy is still the gold standard in nonpharmacologicsomatic treatment, though other brain-stimulation treatments are nowemerging. One is transcranial magnetic stimulation, recently approved bythe FDA, which applies focused magnetic stimulation to certain areas of thebrain of the patient, who is awake yet experiences no subjective sensationswhile receiving treatment. Response rates so far have rivaled those foundwith medication, but without serious side effects. Whether and how it canbe combined with pharmacologic therapy, and whether it is successful inmedication-refractory patients, are questions that are still subject toresearch.

Vagal nerve stimulation, also FDA-approved, is used for patients withmedication-resistant depression. Small amounts of electricity are used tostimulate the vagus nerve with a surgically implanted electrode. Althoughsuccess rates for this modality are not high, some responses can bedramatic. Another form of somatic treatment, which is still experimental,is deep brain stimulation in which surgically implanted electrodesstimulate the ventral tegmental area, located deep at the base of thebrain.

The promising nature of these developments underscores, however, that carefor major depression is multifactorial, complicated, and specialized. It isvital that primary care providers -- who by dint of sheer numbers treatmany more cases of depression than the nation's psychiatrists -- know whento refer their patients with major depression. Both Drs. Friedman and Kahncited a few specific signs:

-- If, at initial evaluation, the patient says they want to hurt or kill themselves or appears to be suicidal. (There are screening instruments for depression specifically designed for primary care providers, such as the PRIME-MD Patient Health Questionnaire, that the physician should not hesitate to use.)-- If the patient is psychotic, having delusions or hallucinations, or shows signs of a marked thought disorder.-- If the patient has a history of manic episodes or a diagnosis of bipolar disorder.-- If there is a history of complicated psychiatric problems like substance abuse disorder or a personality disorder.-- If the patient has a history of a failed treatment for depression.

Treatment for these patients is often quite complicated and requires theexpertise of a psychiatrist's care.

Dr. Kahn summarized the attitude at NewYork-Presbyterian: "What excites meis making sure that patients who come here are not going for one treatmentjust because they walked in the door of a doctor who knows how to do onething well, but that they instead meet an expert who is familiar with awide range of clinical and research treatments so that we can designtherapy using all that is available -- sophisticated psychopharmacology,expertly delivered psychotherapy, the possibility of brain stimulationtechniques -- all of which rest on the foundation of an accurate diagnosisand gaining a full understanding of that person as a human being, knowingwhat he or she experiences in life, what their hopes and dreams are, whattheir family is like, what the context of their work is like -- all thethings that we need to know to try to make that individual feel better."

Treatment for depression has come a long way. Those interested in learningthe state of the art on the care of the patient with depression shouldwatch this webcast featuring Drs. Friedman and Kahn, leaders in psychiatryand examples of the expertise available at NewYork-Presbyterian Hospital.

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