No Need for Blood: Nine Alternatives to the Antidepressant Debate

Jan 23, 2014

There is very little evidence for the efficacy of antidepressants in bipolar disorder, particularly for longer-term use. However, there are at least 9 alternatives to conventional antidepressants.

“More blood on the stage,” one attendee jokingly requested. At the recent International Society for Bipolar Disorders (ISBD) meeting, 2 experts debated the role of antidepressants in the treatment of bipolar disorder.

Both sides of the debate presented rational interpretations of existing literature (thus the jest about more blood). Both speakers agreed there is very little evidence for the efficacy of antidepressants in the treatment of bipolar disorder, particularly for longer-term use. They disagreed regarding evidence for the capacity of antidepressants to exacerbate bipolar disorder. The risk of inducing manic symptoms was their main focus, although one should also consider risk of inducing mixed states and the risk of “mood destabilization,” ie, inducing cycling such that more mood-stabilizing medications are required than would be needed without the antidepressant. For all of these risks, there remains room for debate.

Yet such debate may be moot. Look closely at the benefit to risk ratio for treatment of manic episodes in bipolar depression. Imagine a competition, based on this ratio, between antidepressant modalities. In this competition, any treatment that can leap over the bar of efficacy can be compared on the basis of its potential to exacerbate bipolar disorder. If the efficacy bar is set close to zero, which both speakers agreed appears to be the case for antidepressants, then virtually any treatment with evidence of antidepressant effects in some form of depression can be considered for the treatment of bipolar depression. The competition comes down to evidence of exacerbation and other adverse effects and risks-not efficacy.

Looked at this way, there are at least 9 alternatives to conventional antidepressants, which for ease of recall can be thought of as “3 columns of 3” as shown in the Table. Most of them have no evidence at all of exacerbating symptoms of bipolar disorder (cost, difficulty, hassle, potential adverse effects, yes; but not the potential for making the condition worse). In this respect, they easily exceed the benefit to risk ratio of conventional antidepressants.

Rare induction of manic symptoms has been reported for 4 of these treatment approaches. Although findings from a secondary analysis by Goldberg and colleagues1 indicate that lamotrigine is no more likely to induce hypomanic/manic symptoms than a placebo is, case reports suggest that at least a few patients can clearly get worse.2 There is only one old case report of omega-3 fatty acids inducing hypomania.3 For quetiapine, a case report and literature review conclude that induction of hypomania is possible but rare.4 Otherwise, there are no data-such as the data that were the focus of the ISBD debate-for this risk from the 9 options shown in the Table.

Therefore, the relative value of the 9 options in comparison with antidepressants for the treatment of bipolar depression should be evaluated on the basis of their other risks and adverse effects (and in some cases, additional benefits).

Not pills

Given the image of psychiatry as portrayed in the media, it is useful to have a list of treatment options that demonstrate that we are not simply “pill pushers.” Granted, the first item on the list-physical activity-is difficult to maintain routinely even for those of us who are not depressed. Given the profound anergy that often accompanies bipolar depression, advocating exercise as an antidepressant tool can have an opposite demoralizing effect if not presented carefully. Acknowledge that it will be extremely difficult, and keep the initial “dose” extremely low, almost laughably achievable. For example, Harvard’s Gary Sachs explains their program’s exercise recommendation: “put your shoes on, go to the door, and open it. Walk in any direction for 7.5 minutes, and then walk home.” One might explore the viability of just 3 to 5 minutes of some activity and build from there.

Several types of psychotherapy have randomized trial evidence of efficacy in bipolar depression. Note that in this respect, psychotherapy is clearly superior to antidepressants. In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, for example, outcomes of psychotherapy as an adjunct to medications were superior compared with a moderately sophisticated control condition.5 In the same study population, adjunctive antidepressants were equivalent to placebo.6

Conventional light therapy can cause mixed states, just as antidepressants do.7 By comparison, “dawn simulators” only shift and hold circadian rhythm, and so are unlikely to have any capacity to worsen symptoms. They have not been directly studied in bipolar depression, which leaves them in the same category of evidence of efficacy as conventional antidepressants-basically none. Use of either antidepressants or dawn simulators is based on an extrapolation from efficacy data in other conditions. In addition, dawn simulators can treat comorbid seasonality, if present.8 At a net cost of $25 for some models (eg, the imaginatively named “Lighten Up!”), they would seem to deserve wide use. At the very least, they should be strongly considered before turning to an antidepressant.

ECT, with an excellent track record of efficacy in bipolar depression, could also be included in this column. I omit it only to maintain symmetry (3 columns of 3) and to reflect the preferences of patients I treat, for whom ECT is generally a very last option. Even antidepressants, with so little evidence for efficacy, are generally preferable in their eyes than this procedure, even though it is generally more benign than they think.

“Natural” pills

Data on omega-3 fatty acids clearly demonstrate efficacy relative to placebo in both unipolar and bipolar depression, when the dose exceeds 1 g of eicosapentaenoic acid (EPA) daily.9 Thus, as with psychotherapy, the evidence base for efficacy substantially exceeds that of antidepressants. Moreover, omega-3 fatty acids have additional cardiovascular benefits (lowering triglyceride levels, raising high-density lipoprotein levels-particularly useful in patients with metabolic syndrome). The recent concern about prostate cancer was only an observed association with serum omega-3 levels, although it does raise a safety question.10 A recent meta-analysis suggests that the risk, if any, of prostate cancer in men exposed to EPA is minimal (not significant in the aggregate data).11 For women, the benefit to risk ratio of fish oil strongly suggests a trial of fish oil before prescribing an antidepressant.

Thanks to the research efforts of Berk and associates12 in Australia, a small evidence base supports the use of N-acetylcysteine in bipolar depression. Here, too, evidence for risk appears to be low. Again the benefit to risk ratio exceeds that of antidepressants. However, I have had several patients for whom N-acetylcysteine clearly made them worse, so it may be too much like an antidepressant. Perhaps consistent with that concern is that it did not maintain separation from placebo in a maintenance trial design.13 Nevertheless, so far it has no published evidence of significant risks, making it (at least for now) superior in this respect to conventional antidepressants. I include it here in part because of the remarkable array of conditions it appears to address, and it is more effective than placebo in the treatment of trichotillomania, pathological gambling, and several substance use disorders. For patients with one of these conditions and comorbid bipolar depression, the benefit to risk ratio of N-acetylcysteine clearly exceeds that of antidepressants.

There are 2 forms of thyroid therapy to consider. Triiodothyronine (T3) has a substantial evidence base for efficacy as an adjunct in unipolar depression, but like many of the above modalities, it has been little studied in bipolar depression. A large case series was recently published.14 Broad experience has accumulated for levothyroxine (T4) as an antidepressant in bipolar depression.15 There is no randomized trial evidence as yet for either of these. Nevertheless, 2 rarely cited studies of bipolar depression treatment response demonstrated that patients with thyroid levels lower than the median were less likely (and slower) to respond to antidepressant treatment than those above the median thyroid levels.16,17

Moving a patient from a high-normal thyroid-stimulating hormone (TSH) level to a low-normal TSH level is a zero-risk maneuver, as long as one does not overshoot. Taking all the above data into account, does it not make sense to consider augmentation with levothyroxine in a patient with bipolar depression before using antidepressants? T4 may be preferable to T3 in this role because of more extensive experience with it in the UCLA trials, including 5-year data on bone density (no decrease relative to controls).18


The 3 medications in column 3 of the Table appear in most reviews as the main alternatives to antidepressants for bipolar depression. Quetiapine is usually placed well ahead of lamotrigine because of the more robust evidence for its efficacy. Yet consideration of these two options presents a difficult risk to benefit analysis, surprisingly absent from many expert recommendations. What is worse: a low risk of a dangerous skin reaction (a busy psychiatrist might see one or two in her practicing lifetime), or a high risk of metabolic syndrome and diabetes (to which modern lifestyle and bipolar disorder itself already predispose patients)?

When presented with these considerations, the vast majority of my patients seem to be making their decisions on the basis of risk, not relative potential benefit. Because fears can lower the likelihood of response, one can no longer expect response rates like those seen in placebo-controlled clinical trials. (For example, see the interesting reanalysis of the St John’s wort vs sertraline trial, in which what patients thought they were taking had more impact than what they were actually taking.19) In clinical terms, this tilts the risk to benefit scales in favor of lamotrigine, relative to quetiapine.

However one decides to rank-order the pharmacological options in column 3, evidence for their efficacy in bipolar depression is at least as strong as the evidence for efficacy of antidepressants. So again it comes down to comparing risks: a 1 in 1000 risk of Stevens-Johnson syndrome, weight gain, thyroid dysregulation, and toxicity risk with lithium; metabolic syndrome and diabetes with quetiapine; or a switch to mania? (What if the Stevens-Johnson syndrome risk was nearly 3 times lower, as suggested by a large German analysis?20) Clearly, risk analyses must be individualized for each patient: How bad have his manic episodes been? Can she afford a risk of manic symptoms? Is the risk of inducing hypothyroidism with lithium a better risk right now? Have the alternatives in columns 1 and 2 been thoroughly explored?

Bipolar II studies

Data from a study by Amsterdam and colleagues21 appear to demonstrate that fluoxetine monotherapy is superior to lithium over a 1-year follow-up. But before randomization, the study design selected a group of patients who could tolerate and benefit from fluoxetine monotherapy, so the randomized group may be quite unrepresentative of patients seen in routine clinical practice. The researchers emphasized that the fluoxetine group did not exceed the predefined Young Mania Rating Scale threshold for induced manic symptoms. Yet over the continuation phase, the fluoxetine group was easily distinguished from the placebo group, and especially the lithium group, by a very uneven mood course. The study becomes even more suspect when the very low completion rates are taken into account.22


This antidepressant debate, however rational, was moot before it began. Clinicians have at least 9 alternatives to antidepressants, all of which have as much evidence for efficacy in bipolar depression as antidepressants do. All 9 alternatives have less risk of inducing hypomania/mania, and at least 5 have very little risk at all-and most of them have additional benefits. The pharmacotherapies have significant risks and warrant careful discussion with patients and individualized decision making. But for the benefit to risk ratio for mania, there is no need for further debate-or blood.


1. Goldberg JF, Calabrese JR, Saville BR, et al. Mood stabilization and destabilization during acute and continuation phase treatment for bipolar I disorder with lamotrigine or placebo. J Clin Psychiatry. 2009;70:1273-1280.

2. Raskin S, Teitelbaum A, Zislin J, Durst R. Adjunctive lamotrigine as a possible mania inducer in bipolar patients. Am J Psychiatry. 2006;163:159-160.

3. Kinrys G. Hypomania associated with omega-3 fatty acids. Arch Gen Psychiatry. 2000;57:715-716.

4. Khalil RB, Baddoura C. Quetiapine induced hypomania: a case report and a review of the literature. Curr Drug Saf. 2012;7:250-253.

5. Miklowitz DJ, Otto MW, Frank E, et al. Intensive psychosocial intervention enhances functioning in patients with bipolar depression: results from a 9-month randomized controlled trial. Am J Psychiatry. 2007;164:1340-1347.

6. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.

7. Swartz HA, Frank E, Cheng Y. A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression. Bipolar Disord. 2012;14:211-216.

8. Terman M, Terman JS. Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder [published correction appears in Am J Psychiatry. 2007;164:529]. Am J Psychiatry. 2006;163:2126-2133.

9. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.

10. Brasky TM, Darke AK, Song X, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT Trial. J Natl Cancer Inst. 2013;105:1132-1141.

11. Chua ME, Sio MC, Sorongon MC, Morales ML Jr. The relevance of serum levels of long chain omega-3 polyunsaturated fatty acids and prostate cancer risk: a meta-analysis. Can Urol Assoc J. 2013;7:E333-E343.

12. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder-a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475.

13. Berk M, Dean OM, Cotton SM, et al. Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial. BMC Med. 2012;10:91.

14. Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord. 2009;116:222-226.

15. Bauer M. Thyroid hormone augmentation with levothyroxine in bipolar depression. Bipolar Disord. 2002;4(suppl 1):109-110.

16. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159:116-121.

17. Frye MA, Denicoff KD, Bryan AL, et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry. 1999;156:1909-1914.

18. Bauer M, Fairbanks L, Berghöfer A, et al. Bone mineral density during maintenance treatment with supraphysiological doses of levothyroxine in affective disorders: a longitudinal study. J Affect Disord. 2004;83:183-190.

19. Chen JA, Papakostas GI, Youn SJ, et al. Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J Clin Psychiatry. 2011;72:1669-1676.

20. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64:1134-1138.

21. Amsterdam JD, Luo L, Shults J. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Br J Psychiatry. 2013;202:301-306.

22. Xenitidis K, Campbell C, Eppel AB. Antidepressants in rapid-cycling bipolar disorder. Br J Psychiatry. 2013;203:75.