Bipolar disorder is a complex, often debilitating and potentially life threatening illness in which the patient goes from episodes of depression to episodes of mania or hypomania, most often with periods of relative euthymia in between these episodes. The most common way to conceptualize the treatment of bipolar disorder is by phase. The ideal goal would be preventing the distinct manic and depressive episodes. This is done mostly with medications although psychotherapy, lifestyle modifications and even neuromodulation potentially have a role. A particularly difficult aspect of bipolar disorder is treating the acute phase of bipolar depression. Each is treated mostly with psychotropic medication. In this Episode, Dr. DePietro will focus on treating acute bipolar depression.
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References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
Bipolar disorder is a complex, often debilitating and potentially life threatening illness in which the patient goes from episodes of depression to episodes of mania or hypomania, most often with periods of relative euthymia in between these episodes. The most common way to conceptualize the treatment of bipolar disorder is by phase. The ideal goal would be preventing the distinct manic and depressive episodes. This is done mostly with medications although psychotherapy, lifestyle modifications and even neuromodulation potentially have a role. A particularly difficult aspect of bipolar disorder is treating the acute phase of bipolar depression. Each is treated mostly with psychotropic medication. In this Episode, Dr. DePietro will focus on treating acute bipolar depression.
Please leave feedback at https://www.psydactic.com.
References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
This is not a direct transcript, but instead is a script that helped to guide the content of this episode. The content the actual recorded episode will differ.
Bipolar disorder is a complex, often debilitating and potentially life threatening illness in which the patient goes from episodes of depression to episodes of mania or hypomania, most often with periods of relative euthymia in between these episodes. This is an oversimplification, but despite the difficulties in defining bipolar disorder, I want to focus on treatment.
The most common way to conceptualize the treatment of bipolar disorder is by phase. The ideal goal would be preventing the distinct manic and depressive episodes. This is done mostly with medications although psychotherapy, lifestyle modifications and even neuromodulation potentially have a role. Treating residual inter-episode symptoms as well as comorbid conditions like substance use and anxiety disorders actually has an integral role in changing the overall course of bipolar disorder.
The other aspect of treating bipolar disorder is treating the acute phase of both mania and depression. Each is treated mostly with psychotropic medication. Today, I want to focus on treating acute bipolar depression.
//I love it. Lets focus on bipolar depression because it seems harder to treat than mania.//
Treating bipolar depression is somewhat complex and also mystifying to clinicians, students and patients alike. I think the confusion begins with the fact that bipolar depression is not treated with antidepressants, at least never alone.
A second problem is that the treatments we do have for bipolar maintenance do not always work for the depressive phase of the illness. This can be confusing because we often ask “what drugs work for bipolar disorder?” and while there are many answers that are correct, we cannot simply assume that this means the drug treats bipolar depression. For example, the antipsychotic Haldol can effectively treat mania and probably prevent it too; but it does not treat or prevent depression and may in fact induce it.
//Agreed. Haldol is not the most motivating drug and can also interfere with executive functioning.//
The third point of confusion is the word “mood stabilizer.” It is common in psychiatry and I know we are stuck with it, but I really hate that term. It is not a chemically or pharmacologically valid construct. It isn’t even defined clearly from a clinical point of view. For example, antipsychotics are used to treat bipolar disorder, but they are not really “mood stabilizers.”
Moreover, in someone with mood lability from other disorders, for example borderline personality disorder, there is evidence for certain drugs helping to “stabilize” the mood. I mean things like topiramate and high dose omega-3 fatty acids, but these have no proven role in bipolar disorder. Giving a "mood stabilizer," is misleading as it pertains to treating bipolar disorder because it neglects the fact that the illness is treated in phases. Another point of confusion with bipolar depression treatment is the reality that the treatments we have are not slam-dunk options. The tools we have are controversial and understanding the data is complex. I hope to help clear up some confusion.
//Then, to be clear, let's be clear.//
So to be clear, I am going to talk about the acute treatment of bipolar depression.
Bipolar depression is defined by the DSM the same as unipolar depression. It is the same clinical syndrome, but that doesn’t mean it responds to the same treatments. Before getting into the specific options, it is important to talk about the general approach to treatment. We have to be mindful of patient safety. Depression can be life-threatening. Suicide is the obvious culprit, but there is risk from other severe problems such as self-neglect, substance use (often as self-medication), and secondary syndromes like catatonia. Even when it is not life-threatening, depressive episodes can impact a patient beyond the time of the episode itself, causing more future dysfunction.
//What do you mean by future dysfunction? I thought we were talking about the acute phase.//
Right. The goal of treating a bipolar depressive episode, like unipolar, is to treat to remission. Remission means complete or near complete resolution of symptoms. Having residual symptoms in between episodes of mood disorders tend to predict future episodes and worse prognosis. Therefore, treating to remission is the best approach to long-term mood stability.
It is important to note that when treating the acute episode, we must be mindful of long-term maintenance treatment. Will we continue this particular medicine? What will our strategy be long-term? Sometimes in choosing a particular treatment in the acute setting, we are actually thinking more about the patient’s long-term function rather than the immediate episode. In any case, as with any disorder, we have to apply what we know about the individual in front of us and come up with a treatment plan that works best for them.
//You mean we can't just follow a protocol?//
Right. Patients don't follow protocols.
AND, since placebo rates are high in bipolar depression, getting patient buy-in, establishing therapeutic rapport, and offering encouraging words and support are all important in the treatment of the individual.
When choosing to treat bipolar depression, as with unipolar depression, we can make use of psychotherapy. Continuing psychotherapy as maintenance is important in managing the disease.
//I agree. Keeping patients engaged in therapy as a lifestyle is critical in bipolar disorder.//
There are several pharmacologic options for treating bipolar depression. In general, the approach should be to start a medication, titrate to an effective dose range as tolerated, and then wait several weeks for response if possible. Although it may take 4 or more weeks to fully kick in, a complete lack of response within 1-2 weeks may indicate that response is unlikely in the future and it is time to consider switching treatments.
//So then you think you should have a check in at least 2 weeks later to assess for response?//
Yes, but having only a partial response in 1-2 weeks does not mean the patient will not get better by weeks 4-6 and it is reasonable to continue the treatment until an adequate trial of 4-6 weeks is completed.
Many pharmacologic studies in bipolar disorder are with one medication so I’ll mostly talk about each medication individually. In reality though, bipolar patients often present on a variety of medications. Therefore, I either have to switch to a new regimen entirely by switching them to monotherapy with a new medication, OR I have to extrapolate from the data for particular medication and assume that if a medication is effective as monotherapy for bipolar depression, I can add it and it will be effective in combination with other drugs. While there is some data for combination therapy, it is limited.
Also, keep in mind many studies focus on bipolar I depression and do not necessarily discuss bipolar II. Although many experts believe that data in one of these two versions of the illness counts as some evidence for the other version, we should note that this is not established, and is in fact a gap in the evidence.
//So what are our options for treating bipolar depression, specifically?//
The FDA has approved 5 options. In no particular order they are.
Lumateperone is approved for bipolar II depression as well and quetiapine’s label is open ended.
Notice all of these medications are antipsychotics. Olanzapine plus fluoxetine can be given as two generic medicines. Quetiapine is also generic. These are the cheapest options. The others are relatively new and cost a lot.
Olanzapine plus fluoxetine is an interesting drug combination. The study that got this combination approved by the FDA was a large study that had about 350 people in the placebo arm, 350 in the olanzapine arm, and 70 in the olanzapine+fluoxetine arm. This is because the makers of the drug were actually hoping to show olanzapine alone had efficacy in bipolar depression, which it did. The problem, according to the FDA, was despite the definite efficacy of olanzapine in reducing symptoms of the MADRS, it seemed like the main effects were in anxiety, appetite and sleep sub-scales, not those dealing with the core symptoms of depression. While these are important symptoms, they are non-specific and the FDA thought that olanzapine alone did not show sufficient evidence that it worked as an antidepressant in bipolar disorder.
Olanzapine+fluoxetine was better than olanzapine by a little bit, and was a lot better than placebo. There are obvious downfalls of this combination though. As a long term option, olanzapine has several serious side effects of which we are all familiar, most notably metabolic derangements. Fluoxetine as an SSRI presents long term concerns with mood destabilization and increased treatment resistance that isn’t necessarily mitigated by the fact that olanzapine is anti-manic. Since bipolar is a chronic illness, these are factors to be mindful of.
Quetiapine is the most evidence-based drug for bipolar depression. Lots of data supports its efficacy in bipolar depression alone and notably in combination with, although I hate the word, traditional “mood stabilizers” like lamotrigine and lithium. The efficacy of quetiapine in bipolar depression is similar to that of antidepressants in unipolar depression depending on which study you look at, with numbers-needed-to-treat in the 4-7 range and a moderate effect size.
Also, quetiapine has good data in preventing bipolar depression, as well as treating mania, making it useful in maintenance as a monotherapy. It does of course have significant side effects including sedation, orthostasis and weight gain.
//So tell me about Lurasidone, a more expensive option.//
Lurasidone is a drug recently approved for bipolar depression alone and also in combination with lithium or valproate. An excellent study about 2 years ago in the AJP showed it was very effective in treating unipolar depression with subsyndromal manic symptoms. But lurasidone has less of an evidence base than quetiapine. The few studies in favor of this drug show a similar effect to quetiapine.
//What about head to head trials with quetiapine?//
Not that I am aware of.
There were also no head to head trials that I am aware of comparing Lurasidone alone vs lurasidone plus lithium or valproate. In individual trials, the reduction in depressive symptoms was greater with lurasidone alone compared to placebo than mood stabilizers compared with lurasidone plus mood stabilizers.
To the extent that we can make comparisons across studies, this could indicate two things. One possibility is that the net effect of lurasidone combinations or lurasidone alone are the same but lithium and valproate have a different antidepressant effect, making the difference between mood stabilizers alone vs in combination with lurasidone look smaller than that of lurasidone vs placebo. Another potentially concerning possibility is that lithium and valproate actually somewhat decrease the efficacy of lurasidone. It is impossible to draw conclusions from the data we have.
Lurasidone does have important draw-backs including extrapyramidal symptoms and it isn’t well-studied in the maintenance phase.
The fourth drug for bipolar depression is cariprazine. It has data that in my view is less compelling than the previous drugs. Its number-needed-to-treat for remission vs placebo in one major study was 10, which is relatively weak. The drug markets itself as one of only two bipolar depression treatments that also treats mania (the other being quetiapine), a clever tactic but a misleading one.
//You mean drug companies are trying to fool us into prescribing their medications? Never!//
Unless the two poles are occurring at once, as in a mixed state, there is no inherent benefit from having one drug able to treat depression and mania. What we really need is something that prevents both depression and mania. Cariprazine does not have good maintenance data. Moreover, cariprazine treats the two poles at different dosages. In fact, one study found that the high dose of the drug necessary to treat manic symptoms was ineffective for treating depressive symptoms. This is not surprising given drugs behave differently at different doses. This does limit its usability as monotherapy in bipolar disorder which seems to be the marketing tool employed.
Cariprazine’s tolerability is limited mostly by extrapyramidal symptoms.
//That seems to be a theme.//
The last option is lumateperone. It has some positive data but is super new so the jury is still out on this one. I’ll leave discussing this drug for another time because it's so new. My educated guess is that it will probably be similar in efficacy to quetiapine and lurasidone but better tolerated. It has no maintenance data or studies in mania at this time.
//So does that mean we only have 5 options to treat bipolar depression? Please say yes, so I can solve all my patient’s problems with a quick pneumonic, like QuOCLL or QC LOL//
Lithium, valproic acid and carbamazepine all have some data in bipolar depression but it is limited. Lithium in particular has great maintenance data and many experts think it is effective for bipolar depression. Lithium helps prevent suicide. Long term studies, often retrospective, show that patients on lithium tend to do better overall in terms of their illness than patients without lithium. So it is certainly a reasonable option.
Lamotrigine is interesting. People often make the mistake in thinking it is an obvious choice for bipolar depression and even that it is approved by the FDA for this indication. These are myths. The truth is that lamotrigine is approved for maintenance because it may prevent bipolar depression. But, in several studies it failed to show any benefit at treating bipolar depression acutely. This may in part be due to the fact that the dose-titration for this drug takes so long that it is impractical. There is one study that I am aware of that actually does show an effect over placebo. And when several studies were pooled together, lamotrigine was more effective than placebo by a small margin, at least in cases of severe bipolar depression. But this is all based on the strength of one study, not the four others included in the analysis that showed no separation from placebo. There is some data however from small studies that lamotrigine plus quetiapine and lamotrigine plus lithium are effective combinations for acute bipolar depression. So if anyone tells you lamotrigine is a proven drug for bipolar depression, they aren’t really being entirely accurate. The truth is actually more nuanced and more uncertain.
Electroconvulsive therapy is a very effective option for acute bipolar depression and it works rather quickly.
//I’m glad you mentioned ECT, because it is such an effective option and is the topic of the first series in this podcast, to shamelessly self promote.//
ECT is the gold standard for treating the acute episode. It is still not established what to do for maintenance after ECT, including what role maintenance ECT may have, but this is a great option in severe or treatment resistant cases.
//So if you have a highly suicidal patient with severe bipolar depression, then ECT should be a the top of your list for treatment options?//
Definitely, if it is available.
Other less evidence based options include TMS, ketamine, pramipexole and T3 but these are still fairly speculative.
//You know Dr. DePietro. Of all the drugs you’ve mentioned so far, you’ve only mentioned one of the most common antidepressants (fluoxetine) and that was in combination with an antipsychotic (olanzapine). So what’s up with this?//
I have saved the most controversial part of this discussion for last: Antidepressants. Just because something is called an “antidepressant” doesn't mean it works for acute bipolar depression. One misunderstanding that I want to nip in the bud goes as follows: antidepressants are effective in bipolar depression, but they run the risk of inducing mania. When using them, you just have to monitor closely and have an antimanic drug on board. This understanding underestimates the risks and overstates the benefits of antidepressants in treating bipolar depression.
It is not established that any antidepressant works as monotherapy for bipolar depression or that any other than fluoxetine in combination with olanzapine works as part of a drug cocktail. Some weak and controversial evidence suggests that antidepressants work in bipolar depression but there are also many negative trials of a variety of drugs. Moreover, antidepressants can induce a manic-switch, some worse than others. Adding an antimanic drug can mitigate although probably not eliminate that risk. That said, we do not know the propensity to cause mixed features short of full-blown mania.
Another risk that is not often discussed is mood destabilization. There is some data that long-term antidepressant use in bipolar disorder leads to more rapid cycling and more treatment-resistant depressive episodes or mixed episodes. The problem is not only that antidepressants potentially cause mania, but that they might induce more frequent and harder to treat depression. At least that is the concern. This is not fully established although there is some evidence to support it.
//So then do you recommend never using antidepressants other than olanzapine plus fluoxetine?//
The jury is still out. Some say antidepressants should probably be used only rarely in bipolar disorder, others say that they probably do have a prominent role at least in the right patient, perhaps in bipolar II for example. My own opinion is that there probably are a small subset of patients that could benefit from antidepressants. There is probably another larger group that will be harmed by antidepressants. For the majority of bipolar patients, antidepressants probably have little or no benefit. I also have no way to identify which patient is which.
That answer may sound like a cop out, so if I have to commit to a side, I am more anti-antidepressants in bipolar disorder. There is really no convincing evidence that these drugs as a class treat acute bipolar depression. But I am open that some patients may benefit because there does seem to be some data that shows they have a small effect. The association between antidepressant use and rapid cycling is fairly strong as shown in numerous studies, so that gives me a lot of pause because rapid cycling is very difficult to treat. First do no harm, and it is not clear that antidepressants are doing no harm.
//So what would you say to folks who point out that there are some meta-analyses that show a small benefit of using antidepressants in bipolar disorder?//
Meta-analyses are only as good as the studies which they rely upon. Those that purport to show antidepressants work in bipolar disorder have some problems. Some of the studies that demonstrate efficacy are small and utilize monoamine oxidase inhibitors. Another problem is that they often include the olanzapine+fluoxetine study mentioned above with the caveats spoken of above. But if several metanalyses include some of the same positive studies, it will appear as if multiple analyses reinforce the conclusion when in reality, they all are dependent on a few problematic studies. In several of the famous randomized, placebo-controlled studies in which antidepressants have been tried, many have failed to beat placebo or other mood stabilizers alone. This includes imipramine, multiple SSRIs, and buproprion.
Now, all of this is a generalization. Much more could be said about how treating acute depression relates to the maintenance phase, how specifiers and specific symptom clusters affect treatment, and how to practice precision medicine with the patient in front of you. For now, I hope this was a helpful overview of the pearls and pitfalls of treating bipolar disorder and I hope some of the myths that you may have heard have been clarified. Thank you!
References and recommended readings:
General:
Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression. Bipolar Disord. 2020 Aug;22(5):472-489. doi: 10.1111/bdi.12860. Epub 2019 Nov 8. PMID: 31650675.
ECT:
Medda P, Perugi G, Zanello S, Ciuffa M, Cassano GB. Response to ECT in bipolar I, bipolar II and unipolar depression. J Affect Disord. 2009 Nov;118(1-3):55-9. doi: 10.1016/j.jad.2009.01.014. Epub 2009 Feb 14. PMID: 19223079.
OFC:
Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003 Nov;60(11):1079-88. doi: 10.1001/archpsyc.60.11.1079. Erratum in: Arch Gen Psychiatry. 2004 Feb;61(2):176. PMID: 14609883.
Quetiapine
Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005 Jul;162(7):1351-60. doi: 10.1176/appi.ajp.162.7.1351. PMID: 15994719.
Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, Calabrese JR; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006 Dec;26(6):600-9. doi: 10.1097/01.jcp.0000248603.76231.b7. Erratum in: J Clin Psychopharmacol. 2007 Feb;27(1):51. PMID: 17110817.
Lurasidone
Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, Sachs G. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014 Feb;171(2):160-8. doi: 10.1176/appi.ajp.2013.13070984. PMID: 24170180.
Cariprazine
Citrome L. Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2019 Oct;73(10):e13397. doi: 10.1111/ijcp.13397. Epub 2019 Aug 19. PMID: 31355510.
Earley WR, Burgess MV, Khan B, Rekeda L, Suppes T, Tohen M, Calabrese JR. Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study. Bipolar Disord. 2020 Jun;22(4):372-384. doi: 10.1111/bdi.12852. Epub 2019 Nov 6. PMID: 31628698; PMCID: PMC7318333.
Lumateperone
Calabrese JR, Durgam S, Satlin A, Vanover KE, Davis RE, Chen R, Kozauer SG, Mates S, Sachs GS. Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial. Am J Psychiatry. 2021 Dec;178(12):1098-1106. doi: 10.1176/appi.ajp.2021.20091339. Epub 2021 Sep 23. PMID: 34551584.
Lamotrigine
Geddes JR, Gardiner A, Rendell J, Voysey M, Tunbridge E, Hinds C, Yu LM, Hainsworth J, Attenburrow MJ, Simon J, Goodwin GM, Harrison PJ; CEQUEL Investigators and Collaborators. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016 Jan;3(1):31-39. doi: 10.1016/S2215-0366(15)00450-2. Epub 2015 Dec 11. PMID: 26687300.
Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008 Mar;10(2):323-33. doi: 10.1111/j.1399-5618.2007.00500.x. PMID: 18271912.
Valproic Acid
Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010 Aug;124(3):228-34. doi: 10.1016/j.jad.2009.11.008. Epub 2009 Dec 30. PMID: 20044142.
Lithium
Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, Paulsson B, Brecher M; EMBOLDEN I (Trial 001) Investigators. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010 Feb;71(2):150-62. doi: 10.4088/JCP.08m04995gre. Epub 2010 Jan 26. PMID: 20122369.
Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005 Oct;162(10):1805-19. doi: 10.1176/appi.ajp.162.10.1805. PMID: 16199826.
Antidepressants
Goldberg JF, Perlis RH, Ghaemi SN, Calabrese JR, Bowden CL, Wisniewski S, Miklowitz DJ, Sachs GS, Thase ME. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007 Sep;164(9):1348-55. doi: 10.1176/appi.ajp.2007.05122032. PMID: 17728419.
Antonietta Furio M, Popovic D, Vieta E, Stukalin Y, Hagin M, Torrent C, Azorin JM, Angst J, Bowden CL, Mosolov S, Young AH, Perugi G; BRIDGE-II-Mix Study Group. Characterization of rapid cycling bipolar patients presenting with major depressive episode within the BRIDGE-II-MIX study. Bipolar Disord. 2021 Jun;23(4):391-399. doi: 10.1111/bdi.12994. Epub 2020 Oct 8. PMID: 32959482.
Schneck CD, Miklowitz DJ, Miyahara S, Araga M, Wisniewski S, Gyulai L, Allen MH, Thase ME, Sachs GS. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008 Mar;165(3):370-7; quiz 410. doi: 10.1176/appi.ajp.2007.05081484. Epub 2008 Jan 15. PMID: 18198271.
Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 Apr 26;356(17):1711-22. doi: 10.1056/NEJMoa064135. Epub 2007 Mar 28. PMID: 17392295.