A Guide to Treating Unipolar and Bipolar Depression

Stephen M. Strakowski, MD


November 14, 2016

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Hello. I am Dr Stephen Strakowski, from the University of Texas at Austin. Those of you who have seen any of my videos before know that this is a new location for me. I am here now as the founding chair and professor of psychiatry, where we are building the brand-new Dell Medical School. In future videos, I will talk about how we are thinking about building this new medical school, and how psychiatry plays a major role in its creation.

But today, I'm going to talk about something else: differences and similarities in managing unipolar and bipolar depression. This is a common clinical problem. Information has evolved over the past few years, and we are really starting to think about these two conditions differently.

Unipolar Depression: Incidence, Heritability, and Causes

Major depression is among the most common conditions affecting humankind. In the United States, about 7% of people will develop depression in any given year; there is around a 17%-20% lifetime risk.

The genetic risk for depression is relatively low among psychiatric disorders. Heritability runs in the 30%-40% range—meaning that in a collection of people, depression genetics explain only about one third of the variants. If the depression is recurrent, and commonly recurrent, however, the impact of genetics raises to about 66%.[1]

However, many cases of depression (we have talked about this in other venues[2]) may simply be representative of an insult to the brain and the kinetic current, [or from] a whole variety of conditions. In fact, if you look at medical, neurologic, and psychiatric disorders, virtually anything that affects the brain is associated with higher levels of depression. So part of managing depression, as we will talk about, is trying to identify the potential cause.

Bipolar Depression: Incidence, Heritability, and Diagnosis

In contrast to unipolar major depression, bipolar disorder and subsequently bipolar depression is much less common, affecting somewhere in the neighborhood of 1%-2% of people over a lifetime. Type I bipolar disorder is defined by the occurrence of mania and cannot be diagnosed in the absence of mania. We will discuss how that affects thinking about depression in a moment. In bipolar disorder type II, there has to be episodes of hypomania that are also then accompanied by depressive episodes.

The heritability of bipolar disorder is much higher than unipolar depression, and runs in the range of about 85%.[3] Bipolar disorder is the most heritable condition in psychiatry. The diagnostic reliability of bipolar disorder tends to be higher (at least of mania) than unipolar depression, but the diagnostic reliability of hypomania is relatively low. The two types of bipolar disorder can be differentially examined; it is often harder to make a diagnosis of type II that someone else will agree with. Nonetheless, because of this high heritability, environmental factors are probably less important, at least in the initiation of episodes of bipolar illness, including depression. However, stress and other environmental factors (eg, drug abuse) certainly can affect the course of either illness.

Depressive Episodes: Do They Look Different?

In general, the depressive episodes of bipolar individuals and unipolar individuals look very similar. From a strict kind of cross-sectional clinical assessment perspective, it's really not possible to distinguish them without other information.

That said, there are some types of presentations that are suggestive of an evolving or emerging bipolar illness. These include depression at an early age (particularly prepubertal or early teens), postpartum mood changes, and [depression associated with] seasonality. Bipolar depression may have more severe anhedonia, hypersomnia, and psychomotor slowing—"melancholic" types of variants. The presence of catatonia, often in fact a mania syndrome in severe cases, is probably the best predictor despite all of those suggestive symptoms—which again, in a given individual, are often not particularly helpful.

In contrast to that, a family history of bipolar disorder in someone who is young and developing recurrent depressive episodes might suggest that this may be a bipolar individual. However, until mania or hypomania occurs, a diagnosis of bipolar disorder would be premature.

Unipolar Depression: Antidepressant Therapy

When we start talking about treatment, you can see that there are a large number of antidepressants for unipolar depression approved by the US Food and Drug Administration (FDA). There are many different classes, with the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) being the most commonly prescribed today. Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) tend to be used increasingly less, primarily because of tolerance. There are some other good antidepressants that do not fit neatly in a class, such as bupropion or mirtazapine.

The take-home [message] from this slide is that there are a lot of good established antidepressant therapies. In general, something can be found that is tolerated and effective in any given patient.

Unipolar Depression: The Role of Psychotherapy

In addition to medications, psychotherapy is helpful in major depressive episodes. Cognitive-behavioral therapy (CBT), particularly in mild to moderate cases, is well established, and the evidence suggests it is as good as any antidepressants and may actually help better in some cases with relapse prevention. It does appear to save money when administrated with antidepressants. Even though there are some initial upfront costs for the therapy, costs get evened out over time by better recovery.

Interpersonal therapy also has a strong evidence base. This is not the same as psychodynamic therapy—it is a focus on interpersonal interactions without assumptions of causality. It essentially bases its "core" on the fact that interaction with other humans represents a major part of our stressors and social supports. This therapy focuses on improving those [interactions] and leads to improvement in depression. In fact, for psychodynamic psychotherapy in the purest sense, there is really only limited evidence that it is efficacious in depression.

There is also a strong interest right now in nutraceuticals and lifestyle management. But so far, unfortunately, those have not been able to hold up in studies particularly well for the treatment of depression. That said, however, they are generally good for you, and so there is no reason not to include them in a treatment paradigm.

Bipolar Depression: Medications

In this chart of medications commonly used in bipolar disorder, only three products at the moment are FDA-approved for treatment of bipolar depression: the combination of olanzapine and fluoxetine, quetiapine, and more recently lurasidone. As you can see, there are a number of other medications, such as lithium and lamotrigine, that have apparent antidepressant efficacy. In general, mood stabilizers that are effective for maintenance seem to be effective for treating depression.

Recently, there have been some interesting studies. Historically, we have often used antidepressants in the treatment of bipolar depression. However, as shown in this chart from Gary Sachs and colleagues in the New England Journal of Medicine in 2007, the STEP-BD study[4] showed us that the addition of an antidepressant to a good mood stabilizer in patients with bipolar disorder really added very little improvement of depression. It also did not increase the risk for switching or adverse effects.

The take-home messages were that antidepressants add very little to effective use of mood stabilizers, and that the treatment of bipolar depression is very different from unipolar depression. Antidepressants appear to be much less effective for bipolar depression than unipolar depression. This helps us think differently about treatment guidelines and algorithms.

Bipolar Depression: Switch Risk

There is still an ongoing discussion on what the risk [associated with] antidepressant therapy is of switching into mania from depression. Again, in that previous slide from Sachs and colleagues, it really looked like the antidepressants, at least in the setting of a mood stabilizer, did not increase the risk at all. The risk in studies has ranged from as high as 30%-40% with the older tricyclics to as low as placebo rates with SSRIs and newer antidepressants.[3] Probably somewhere in [between] there is a true rate.

Unfortunately, the natural switch rate of depression into mania in the absence of treatment may be as high as 40%, which was observed in the collaborative depression study in the 1980s.[5] The confounder is that even though we tend to think of patients moving from depression through euthymia through mania, that is not actually how it happens. It's more of a toggle from one state to the other, and depression itself increases the risk for mania. So the effects of antidepressants just remain confounded because typically, people do not get antidepressants until they are depressed.

That said, certainly with the older antidepressants, there may be a switch risk. The newer antidepressants in the setting of a mood stabilizer seem to have a fairly low risk. Regardless, from STEP-BD and other studies, the benefit of adding an antidepressant appears to be low. SSRIs may be better anxiolytics long-term than antidepressants—they may have an anxiolytic role in bipolar disorder, and we need more studies to determine whether that is true and whether they are safe [in that setting].

Bipolar Depression: Role of Psychotherapy

Psychotherapy is very important. In bipolar depression, CBT has a good evidence base. Interpersonal therapy and social rhythm therapy that came out of Pittsburgh[6] also have a good evidence base, as do family-focused therapies. All of these have been shown to decrease relapse, improve functioning, and help with treatment compliance. They are all used in conjunction with mood-stabilizing drugs, which are necessary in bipolar disorder as a first step. Psychotherapy is a nice second addition.

Management of Unipolar Depression

With that in mind, I have included brief guidelines for treatments on each of these conditions. With unipolar depression, the first key is to either start or optimize the antidepressant. Treatment failures are often simply from not waiting long enough, or not using a high enough dose. Again, it's important to remember that these are not rapidly-acting agents, and it often takes 3-6 weeks to even see the initial response.

The first-line therapies that most people are familiar with are SSRIs, SNRIs, bupropion, and CBT. Then there are what I call "1b" options, which are a little less established—you can read those on the slide. If there is literally no response in 4-6 weeks—the patient is no better, or even worse—probably switching rather than maintaining the current antidepressant is the best step.

If there is a partial response, think about augmentation strategies—which is adding another antidepressant, ideally from a different class. Other things, such as psychotherapy, thyroid hormone, or perhaps one of the approved atypical antipsychotics, have been shown to be helpful augmenting agents. Lithium augmentation continues to be the best-studied augmenting strategy.

Eventually, we get to such things as ketamine, which is experimental but maybe something to consider; repetitive transcranial magnetic stimulation (rTMS); or electroconvulsive therapy (ECT). If ECT had less stigma and was easier to administer, particularly in severe cases, I would move it up this chart to be used earlier.

With recurrent and even single-episode patients, try to use three or fewer drugs and be systematic. Take your time making changes, and [achieve] an adequate dose. Do not chase symptoms. I have talked about this in another video.

Managing Bipolar Depression

The guideline for treating bipolar depression is very different. The first step is optimizing current mood stabilizers or starting mood stabilizers—ideally, those that have some evidence of maintenance efficacy. Those typically roll into being reasonable antidepressants.

Lithium and CBT are good things. It's a good idea to add CBT to an existing mood-stabilizer program that has generally been effective. If you are not using lithium, consider it. These FDA-approved agents are also good choices: olanzapine, olanzapine in combination with fluoxetine, lamotrigine, lurasidone, and quetiapine.

Maximizing mood stabilization appears to be the best intervention. ECT in severe cases should not be delayed too long. I have it as third-line in my chart—but again, only because it's not widely available. If it's available, then it's a good choice to move up the chart.

Again, like unipolar depression where there are similarities, if it's not working in 3-6 weeks, get rid of the drug that is not working and add a new one. If it's working partially, consider augmenting. But keep in mind, you need to keep your mood stabilizer base on board. Augmentation approaches that are listed here are not terribly dissimilar from [those for] unipolar depression. [Remember] the three-medication maximum, and make systematic changes.


With these approaches, I think it's possible to come up with an ideal program for your individual patient. It is important to keep in mind, though, that the treatments are very different and that antidepressants have an increasingly limited role in the treatment of bipolar depression. A good diagnosis is going to be really important for a good treatment outcome.

Much of what I have talked about here, can be found in a couple of books[1,3] we have published, which you might find useful. I hope this is helpful for everyone. From my new place in Texas, I appreciate your time, and thank you all for listening.

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