Coping with Diagnostic Uncertainty in Mixed States: Comparing Treatment Risks

“Marissa” has a history of trauma and major depressive disorder (MDD). She reports feeling anxious and struggling with insomnia. Her partner gently notes that Marissa can be pretty angry sometimes. Marissa could have comorbid MDD and posttraumatic stress disorder (PTSD), or she could have a depressive mixed state (and perhaps PTSD as well). As described in the first essay in this 3-part series, Marissa’s symptoms alone will not differentiate these diagnoses. The last of 4 ways of coping with this diagnostic uncertainty discussed in Part 2, comparing the risks of treatment options, is presented here through Marissa’s case.

The Figure presents the spectrum of mixed states,¹ the diagnostic dilemma, and a way of thinking about treatment options.

Suppose Marissa, who is 28 years old, has a cousin with possible bipolar disorder, had her first episode of depression at age 20 and 2 episodes since, one of which occurred shortly after the birth of her 2-year-old daughter. Sertraline made her insomnia much worse, so she stopped it. These features raise the probability of bipolarity, but only weakly vs (for example) a strong family history, earlier age of onset, more frequent episodes, and a more adverse response to sertraline. The diagnostic question remains: mixed depression or depression with PTSD?

After patient education (discussed in Part 2), Marissa understands this differential and prefers a medication approach over psychotherapy (even after digital options are presented). A direct comparison of treatment approaches is warranted.

Antidepressants or Lamotrigine?

Antidepressants are an obvious option for Marissa. They have modest benefits in both depression² and PTSD.³ Lamotrigine is not so obvious. Here’s the logic.

Treatment guidelines for mixed states4 are based primarily on efficacy in short-term RCTs funded by pharmaceutical companies in their pursuit of US Food and Drug Administration approval. Older medications are less studied. No randomized trials have been conducted for broadly defined mixed states (see Part 1).

Tolerability (adverse effects and long-term risks) frequently determines patients’ choice, rather than highest efficacy, particularly if symptoms are chronic not acute. Lamotrigine has the best tolerability amongst the mood stabilizers with antidepressant effects. (Lurasidone lacks decades of use to fully understand its long-term risks; likewise for lumateperone, cariprazine, and iloperidone. Quetiapine can cause insulin resistance, which appears to contribute to treatment resistance.⁵ Even low doses of lithium can cause hypothyroidism.⁶)

Extrapolating Treatment Options

As shown in the Figure, by extrapolating from experience in MDD, antidepressants can be considered for mixed depressions. Likewise, by extrapolating from experience in bipolar II, lamotrigine can also be considered.

Many practitioners are hesitant to consider lamotrigine unless a history of hypomania or mania is obtained. Indeed, while it makes sense to consider antidepressants for depression comorbid with PTSD or generalized anxiety disorder; there is no obvious reason to consider lamotrigine for these conditions—except when a depressive mixed state is equally likely the correct diagnosis.

Marissa has surely heard of antidepressants. The patient education discussed in Part 2 will help her understand why lamotrigine is also an option. Now, compare their risks.

Comparing Major Risks

The efficacy of antidepressants vs lamotrigine in broadly defined mixed states has not been studied. But two tolerability concerns are well known: antidepressant withdrawal and lamotrigine allergy. Understanding these risks may have a strong impact on treatment choice when diagnosis is uncertain.

Patients often weigh these risks very differently. For some, hearing the risk of Stevens-Johnson Syndrome (SJS) precludes any further consideration, regardless of how one explains its incidence. For others who may have known someone who struggled to discontinue their antidepressant, concerns about withdrawal might strongly affect their treatment choice.

Incidence of Severe Antidepressant Withdrawal

Different sources estimate very different rates of severe withdrawal. In one podcast interview, academic psychiatrist Michael Thase suggested an incidence of 1% to 2%.⁷ Other authors, including those of a review of data published through 2022,⁸ believe the rate is much higher, at least 10% (Mark Horowitz, personal communication). That review notes important effects of dose, duration of treatment, and differences between antidepressants. Obviously, the definition of “severe” also affects rates.

A 2024 review of 79 studies found a 3% rate of severe withdrawal (higher for venlafaxine, desvenlafaxine and escitalopram).⁹ Lastly, a post-hoc analysis of a recent randomized trial of antidepressant discontinuation found a rate of significant withdrawal of 16% (4 or more emergent symptoms, but not necessarily “severe”; see Response to a Comment by Horowitz).¹⁰

Withdrawal vs Stevens-Johnson Syndrome

Comparing antidepressant withdrawal and extreme allergic reactions to lamotrigine is obviously like comparing apples and oranges. Nevertheless, for a very rough impression of relative risk, comparing their rates may be useful. Consider first their lowest respective estimates: 1% for withdrawal; a 0.05% incidence of SJS¹¹; and a 0.05% incidence of death among patients with SJS.¹² Using these figures, the rate of severe antidepressant withdrawal is 20 times that of SJS and 400 times the SJS death rate.

Or consider the highest respective estimates: 10% for severe withdrawal, and 1% for SJS (inaccurate, but oft cited on internet sites). Using these figures, severe withdrawal is 100 times more common than SJS and 500 times the SJS death rate. Severe withdrawal has been associated with suicidal ideation, but not death by suicide.¹³ On the other hand, very severe withdrawal can be life-limiting for months to years, as attested by thousands of online accounts.¹⁴

Marissa has yet to make her decision between these 2 options. You will have to be prepared to assist her.

Concluding Thoughts

When patients present with depression and “The 4 A’s” (anxiety, anger, agitation, and/or attention problems), differential diagnosis is challenging. Clinicians should maintain an open mind regarding alternative explanations until good outcomes are obtained. Four means of coping with the resultant diagnostic uncertainty have been presented in this 3-part series.

Dr Phelps is retiring from 30 years of treating complex mood disorders, and recently founded another website, DepressionEducation.org. He is the bipolar disorder section editor for Psychiatric Times® and the author of A Spectrum Approach to Mood Disorders for clinicians and Bipolar, Not So Much for patients and their families.

References

1. Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22(2):203-219.

2. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.

3. Guidetti C, Feeney A, Hock RS, et al. Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis. Int Clin Psychopharmacol. 2024.

4. Natale A, Mineo L, Fusar-Poli L, et al. Mixed depression: a mini-review to guide clinical practice and future research developments. Brain Sci. 2022;12(1):92.

5. Calkin CV, Chengappa KR, Cairns K, et al. Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial. J Clin Psychiatry. 2022;83(2):21m14022.

6. Phelps J, Coskey OP. Low and very low lithium levels: thyroid effects are small but still require monitoring. Bipolar Disord. 2024;26(2):129-135.

7. Thase M. Webinar, Psychopharmacology Institute. Response to Listener Question. May 7, 2020.

8. Horowitz MA, Framer A, Hengartner MP, et al. Estimating risk of antidepressant withdrawal from a review of published data. CNS Drugs. 2023;37(2):143-157.

9. Henssler J, Schmidt Y, Schmidt U, et al. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. Lancet Psychiatry. 2024;11(7):526-535.

10. Kendrick T, Stuart B, Bowers H, et al. Internet and telephone support for discontinuing long-term antidepressants: the REDUCE cluster randomized trial. JAMA Netw Open. 2024;7(6):e2418383.

11. Bloom R, Amber KT. Identifying the incidence of rash, Stevens-Johnson syndrome and toxic epidermal necrolysis in patients taking lamotrigine: a systematic review of 122 randomized controlled trials. An Bras Dermatol. 2017;92(1):139-141.

12. Hsu DY, Brieva J, Silverberg NB, Silverberg JI. Morbidity and mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis in United States adults. J Invest Dermatol. 2016;136(7):1387-1397.

13. Kostic M, Plöder M, Hengartner M, Buzejic J. Suicidality emerging from rapid venlafaxine discontinuation: a challenge–dechallenge–rechallenge case report. J Clin Psychiatry. 2024;85(1):23cr14930.

14. Surviving Antidepressants. Accessed November 7, 2024. https://www.survivingantidepressants.org