Combination therapy for severe depression

Severe depression is life threatening. So it is worth every effort to get depression under control and make life more manageable. For most people, that means some combination of antidepressant drugs and talk therapy.

Jessica Bosari has seen the consequences of severe, untreated depression in her own family: it ended in suicide for her father, his father and her maternal grandmother. So when the now-37-year-old freelance writer found that she hadn't outgrown what she'd thought was teen angst by her early 20s and became worried about how her moods could affect her new child, she began seeking treatment for depression, starting with psychotherapy and then adding medication.

One big challenge is that even the most effective treatments typically take four to six weeks to improve depression. But anti-depressant medications tend to have their worst side effects immediately, before it becomes clear whether they will work.

Antidepressant drugs are classified or grouped by how they affect a patient's brain chemistry. Their ingredients are designed to address specific areas of brain functioning. These are the major classes of antidepressants now on the market:
--Selective serotonin reuptake inhibitors (SSRIs)
--Serotonin-norepinephrine reuptake inhibitors (SNRIs)
--Norepinephrine and dopamine reuptake inhibitors (NDRIs)
--Monoamine oxidase inhibitor (MAOIs) or MAO inhibitors

"Unfortunately, we have no way of telling which drug will do what for what person," says John W. Williams, M.D., a professor of medicine and psychiatry at Duke University.
Peter Shapiro, M.D, a professor of clinical psychiatry at

Columbia University, says that with a new drug, ideally, people show some improvement within two to three weeks—but if not, and if raising the dose and waiting another few weeks doesn't work, "you're probably not magically going to have headway eight to 10 weeks later."

For Bosari, the first medication prescribed was an early SSRI drug. "It did improve my mood but it was not what I would call a cure," she says. "It helped me to function better. It was not as hard to get out of bed. I did kind of have a sense of 'Oh, this is different."

Bosari took the drug for a few years, eventually stopping because it didn't seem to be helping much.

Tracking Your Recovery

"The aim for treatment is not reduced misery; it is normalcy," says Eric Goplerud, a professor of health policy at George Washington University.

He recommends using a questionnaire called the Patient Health Questionnaire-9 (PHQ-9). If treatment is working, research shows that you should see about a 50 percent reduction in symptoms within six weeks.

Mark Zimmerman, M.D., director of outpatient psychiatry at Rhode Island Hospital and his colleagues developed another method to track depression and anxiety symptoms.

"Any patient can use it as long as their doctor registers and it's free for doctors to register," he says.

According to the largest trial of multiple medication treatment for depression, conducted by the National Institute of Mental Health, about one-third of patients will completely recover with the first drug they try and up to 93 percent will recover by the time they've tried four different medications.

If multiple medications fail, see an experienced psychiatrist rather than a general practitioner—or even a psychopharmacologist, who is a psychiatrist specializing in the use of medications.

In Bosari's case, when her depression returned, she ultimately found the right drug combination for her. "I finally felt 'normal,'" she says. "It clicked, like it was the missing piece of the puzzle."

How Long?

"There has been a consensus for a while that if you have had a significant episode of depression and been treated and gotten better, you should stay on your effective dose for at least six months," Shapiro says. "And the more episodes of depression you have had in the past, the more likely it is that if you not on maintenance medication, you will have a relapse going forward."

Bosari has decided to stick with this combination indefinitely—and given her life and family history, it's clear that her depression is chronic and requires long-term treatment. She says that finding the right therapist and exercising have also been critical to her recovery.

Center for Advancing Health

Sound Familiar?
Some common antidepressants:
SSRIs: Prozac (fluoxetine), Lexapro (escitalopram oxalate), Zoloft (Sertraline hydrochloride), Paxil (paroxetine)
SNRIs: Effexor (venlafaxine), Cymbalta (duloxetine)
NDRI: Wellbutrin (bupropion)
Tricyclics: Pamelor (nortriptyline)
MAOIs: Nardil (phenelzine), Parnate (tranylcypromine)

Sidebar: Dealing With Side Effects

Antidepressants have many side effects—but most are manageable, though extremely variable from person to person. "Probably the most common side effects are gastrointestinal symptoms, which can be nausea, upset stomach, gas, or diarrhea. They tend to be worse at the beginning—a lot of people have them only for the first day or two," Shapiro says.

Sexual side effects also occur frequently and tend to last longer. SSRIs can particularly reduce sexual desire and sensation. This can often managed by lowering the dose, or adding an antidepressant like Wellbutrin (buproprion), which tends to have positive effects on sexual experience or even switching to another SSRI.

Antidepressants can also affect sleep. If a medication produces tiredness, it should be taken at bedtime and if it has a stimulant effect, it should be taken in the morning. "A lot of people have agitated, jittery hyper-caffeinated feelings the first day or so, but that usually goes away," Shapiro says.

However, if a sense of agitation becomes extreme or intolerable—or if it is associated with thoughts of harm to yourself or others—call your doctor immediately, as this is obviously a potentially severe problem and you will probably need a different treatment.

Although antidepressants can either increase or lower weight, Remeron (mirtazapine) is especially likely to cause weight gain, according to Zimmerman. If doses are not tapered, many antidepressants can cause withdrawal symptoms—and this problem tends to be more severe with Effexor (venlafaxine) and Paxil (paroxetine). Since Paxil is also the SSRI most clearly linked with birth defects when taken by pregnant women, it should not be the first medication tried.

Source: Columbia University


  1. Nadine Mally Nadine Mally United States says:

    I have been on antidepressants medication since 1994. I never had any problems with most of the medications except, Paxil, which made me dizzy and nauseated. Now that I am in my late 50's, my medications have stopped working for me. In the last 3 years My father, my husband and recently my mother passed away. I really didn't have time to grieve until something happened at work, and I lost it. I couldn't stop crying.  My Psychiatrist ordered me an anxiety medication called Buspar which, I take 1 pill basically at night. I still don't feel any better as far as my depression so she ordered me Abilify. After reading up on it, the side effects scared me. I declined taking it. Is there some medication that can stabilize my mood. I don't want to feel tired anymore, as I have no energy to begin with.  I can't get out of bed to begin with. Any suggestions?

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