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Antidepressants “have the propensity to destabilize mood, precipitating both hypomanic and manic episodes”—a phenomenon called antidepressant associated hypomania (AAH).1 Although this condition is most frequently associated with bipolar depression, it has also been reported in unipolar depression and in non-affective conditions, such as anxiety disorders.1 The potential for AAH has made antidepressant use controversial in patients with bipolar disorder (BP).2
A new review examines AAH in people diagnosed with unipolar depression, examining risk factors, conceptual models, and management.1 The authors define AAH as “hypomania occurring shortly after commencement or dose increase of antidepressant medications in individuals being treated for a unipolar depressive disorder without a previous diagnosis of BP.”
Lead author Nav Gill, MB, BS, psychiatry registrar, St. Vincent’s Hospital, Sydney, Australia explained that the review was motivated by ”seeing numerous patients in clinical practice who developed hypomanic symptoms following antidepressant initiation and the subsequent clinical dilemma surrounding initial and longer-term management, moreover diagnostic uncertainty.”
Dr Gill told Psychiatry Advisor that this dilemma takes place “in the context of limited local and international clinical guidelines and consensus as to whether these cases are reflective of true bipolar spectrum disorders or transient adverse drug effects.”
Coauthor Adam Bayes, MB, BS (Hons), MPsychiatry, PhD, senior lecturer, School of Psychiatry, University of New South Wales, Australia, elaborated.
“The review was sparked by my clinical practice as a psychiatrist who works in the field of mood disorders. I would not infrequently see patients with a history of seemingly unipolar depression who became hypomanic on antidepressants,” he told Psychiatry Advisor.
Dr Bayes continued, “In some cases, there was family history of bipolar disorder, but not always, [so] it was unclear to me how next to proceed. Would a mood stabilizer be a better option? Or was it just an idiosyncratic effect of that particular antidepressant in that particular patients, and would a trial of another antidepressant be okay?”
Six Explanatory Models
The authors state that AAH has been attributed to several different causes.
- An “iatrogenic, reversible affect of antidepressants, which abates on cessation of the drug”;3,4
- A “discrete form of BP” (sometimes labeled bipolar III disorder) in which hypomania or mania only occur in the setting of antidepressant treatment;4
- Conversion from unipolar depressive disorder to BP attributable to the antidepressant;5
- “Acceleration in the natural course of an underlying but then emerging bipolar condition”;6
- A “coincidental phenomenon” unrelated to antidepressant treatment, which might occur in someone with “pseudobipolar” disorder, as part of a “nascent” bipolar I disorder (BP1) or bipolar II disorder (BPII).7,8
Epidemiology of AAH
Estimates of the incidence of AAH vary from 0.3% to 22.4%, with the wide range attributable to a number of potential explanations, including different in study sample characteristics, antidepressant class, diagnostic criteria, and study duration.1 Estimates of the timing of AAH onset likewise differ, ranging from 4 to 12 weeks following initiation or dose increase of the antidepressant.1
Female gender and younger age of depression onset are risk factors for developing AAH—on the other hand, it is possible that the higher rate of AAH in young people might be “an artifact that represents the impact of an incipient BPD,” since the peak age of BPD onset is between 15 and 19 years of age.9
Family history of BPD may raise the risk for AAH because antidepressants may “precipitate a switch in those genetically predisposed” to develop a BPD.1
Nevertheless, Dr Bayes does not think that clinicians should hesitate to prescribe antidepressants to patients with unipolar depression who have a family history of BP, with the caveat that these patients “need to be carefully screened to determine if they themselves have a history of hypomania or mania.”
Moreover, even if these patients have no personal history of hypomania or mania, they should be “monitored closely for any affective switch,” Dr Bayes added.
Neurobiological Mechanisms of AAH
Antidepressants can inadvertently activate dopaminergic pathways.10 Moreover, certain antidepressants (eg, tricyclic antidepressants [TCAs], monoamine inhibitors [MAOIs], selective norepinephrine reuptake inhibitors [SNRIs], and certain selective serotonin reuptake inhibitors [SSRIs], such as high-dose paroxetine and sertraline) may increase inhibition of dopamine reuptake. SNRIs may also increase inhibition of noradrenaline uptake. Both can lead to “elevated mood states.”1
Although all classes of antidepressants may potentially induce hypomania or mania, some classes carry more risk than others. (Table 1)
Table 1
Risk of Mania by Antidepressant Class
| Class | Risk |
| SSRIs | Low· Paroxetine Sertraline Fluvoxamine Fluoxetine Citalopram |
| SNRIs | Low Duloxetine High Venlafaxine |
| MAOIs | Low Tranylcypromine High Phenelzine |
| TCAs | High Risk did not differ between agents |
| Supplements (based on case reports) | High St. John’s wort Omega-3 fatty acids |
SSRIs=selective serotonin reuptake inhibitors; SNRIs=selective norepinephrine reuptake inhibitors; MAOIs-monoamine oxidase inhibitors; TCAs=tricyclic antidepressants
Gill N et al. Curr Psychiatry Rep. 2020;22(4):20.
The authors note that a “reverse phenomenon” may occur when hypomania or mania follows antidepressant discontinuation or dose reduction, especially in patients who have taken SSRIs, TCAs, SNRIs, and MAOIs.
“AAH likely consists of a number of differing mechanisms,” Bayes commented. “A small number of studies have described AAH as a self-limiting iatrogenic reaction that abates with antidepressant cessation. However, the majority of studies support the concept that AAH more closely resembles an intrinsic bipolar disorder.”
AAH in Unipolar vs Bipolar Depression
The authors compare the quality of depressive episodes in patients who have experienced AAH, noting similar rates of melancholic and psychotic features as well as depression severity across AAH and BP groups. However, one study found more severe AAH depressive features in BPII.11
A study that used cluster analysis methodology compared 4 groups of patients: those with BPI those with BPII, unipolar depression with AAH, and recurrent unipolar depression.12 The cluster consisting of AAH with BPI and BPII exhibited greater depression severity, more suicide attempts, melancholic features, and greater chance of hospitalization.12 “Thus, many of the depressive features in those experiencing AAH appear more closely linked to the presence of a nascent or extant bipolar disorder than to unipolar depression,” Gill et al comment.1
Some research has suggested that an episode of AAH may precede eventual “conversion” to BP.13 It is possible that AAH is “most likely an acceleration of the natural course of an underlying but then emerging bipolar condition.”6
However, the authors state, “it appears that, rather than having a distinct and predictable course, AAH may reflect several differing models, with some expressions transient and self-limited and other indicative of the development of a BP disorder.”1
The Need for Diagnostic Accuracy
The authors suggest that one of the explanations for AAH in individuals with unipolar depression is that underlying BP was never accurate. In fact, one meta-analysis found an almost 6-year delay between onset of BP and initial management,14 “highlighting the need for clinicians to carefully exclude the presence of an underlying BPD in those presenting with AAH.”1 Reasons for this frequent misdiagnosis include:
- Clinicians do not ask about symptoms of “highs”
- Individuals do not report “highs”
- In BPII, elevated mood states are less severe and also non-psychotic
- The first mood episode may be in the depressed phase
Treatment Options for AAH
The authors explore several different treatment pathways for AAH, recommending “pre-emptive identification and management of mood-destabilizing factors (eg, substance use, sleep disturbance, and psychosocial stressors)” to clarify the picture prior to choosing a strategy.1
“The differing models suggest that AAH may be a “phenomenon and, yes, depending on the scenario management may differ,” Dr Bayes noted.
“For example, if it appears the hypomania is more consistent with a transient iatrogenic side effect, then dose reduction or trial of another antidepressant would be a reasonable strategy. However, if there are risk factors suggestive of an underlying bipolar disorder, then consideration could be given to pursuing or adding a mood stabilizer.”
Antidepressant Dose Reduction or Discontinuation
There is a dose-dependent relationship between antidepressants and the emergence or remission of hypomania, so some research suggests dose reduction or discontinuation with close observation and monitoring for emergence ether of further depression or mood elevation. Even in the context of ongoing hypomania, the dose should be reduced gradually to offset potential withdrawal effect that may exacerbate the elevated state.15
Mood Stabilizing Agents
The use of mood stabilizing agents is controversial. On the one hand, in patients with BP, antidepressants have been associated with both rapid-cycling episodes and poorer long-term illness outcome,8 so a mood stabilizer may be an “optimal treatment” in that setting.1 On the other hand, an individual with true unipolar depression and AAH may risk being subjected to unnecessary medications. Thus the initial diagnosis must be carefully evaluated.
Risk factors for “polarity conversion” (eg, family history of BPD, psychotic features, an earlier age of onset) should be taken into account when considering treatment duration. Use of a mood stabilizer prior to future antidepressant trials may reduce the risk of further AAH.8 Another strategy is to provide a “time-limited” prescription of an atypical antipsychotic that targets hypomania, reserving mood stabilizer therapy only for those with more severe mood disturbances.16
Atypical antipsychotics can be used in combination with antidepressant dose reduction, and may be informed by hypomania severity (as measured by the Young Mania Rating Scale [YMRS]). The authors quote the recommendations of Navarro et al.3
Further recommendations are listed below.1
· If remission is achieved by antidepressant dose reduction or cessation, replace the original antidepressant with an alternative in the same class at the lowest dose, at least 2 weeks following remission of hypomanic symptoms
· If remission is achieved by antidepressant withdrawal and atypical antipsychotic initiation, reduce the antipsychotic dose by 50% after 2 weeks of remission, discontinuing it 1 week later and replacing the original antidepressant with an alternative from the same class at the lowest dose.
Coauthor Gordon Parker, MD, PhD, DSc, Scientia Professor of Psychiatry, University of New South Wales, Australia, told Psychiatry Advisor that it has “long been held that antidepressants should not be prescribed at all—or any after an individual has been stabilized on a mood stabilizer—due to risks of causing a depressed bipolar patient to switch into a high, experience a mixed state, and/or have a worse illness course over time.”
He disagrees with this view, “believing that all such risks are over-inflated and such outcomes more reflect the natural history of the condition.”
In the event of severe bipolar depression, Dr Parker regards it as “completely appropriate and generally necessary to prescribe an antidepressant immediately and also introduce a mood stabilizer, if the patient is not on one, and warn the patient of the risks noted earlier, as bipolar depression has a high suicide risk.”
Limitations and Future Directions
The authors point to several limitations of their review, including the fact that the majority of randomized controlled trials of major depression did not include “operationalized criteria by which hypomanic episodes were diagnosed” and did not always not distinguish between hypomanic and manic states. Moreover, the use of differing time frames in AAH definition led to inconsistencies in comparing studies.
“There is some indicative guidance on how to manage AAH, but greater clarity is required regarding underlying biological mechanisms and the best treatment approaches,” Dr Bayes said. “Improving the nosological clarity of AAH should assist with clinical decision-making.”
References
1. Gill N, Bayes A, Parker G. A Review of Antidepressant-Associated Hypomania in Those Diagnosed with Unipolar Depression-Risk Factors, Conceptual Models, and Management. Curr Psychiatry Rep. 2020;22(4):20. doi:10.1007/s11920-020-01143-6
2. Gitlin MJ. Antidepressants in Bipolar Depression: An Enduring Controversy. Focus (Am Psychiatr Publ). 2019;17(3):278-283. doi:10.1176/appi.focus.17306
3. Navarro V, Gastó C, Guarch J, Penadés R, Pintor L.Treatment and outcome of antidepressant treatment associated hypomania in unipolar major depression: a 3-year follow-up study. J Affect Disord. 2013;155:59–64. doi:10.1016/j.jad.2013.10.024
4. Baldissarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: A review. J Affect Disord. 2012;148:129–35. doi:10.1016/j.jad.2012.10.033
5. Tondo L, Vazquez G, Baldessarini R. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121:404–14. doi:10.1111/j.1600-0447.2009.01514.x
6. Akiskal HS, BourgeoisM, Angst J, Post R, Möller H, Hirschfeld R. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of Bipolar Disorders. J Affect Disord. 2000;59:5–30. doi:10.1016/S0165-0327(00)00203-2
7. Reichart CG, Nolen WA. Earlier onset of bipolar disorder in children by antidepressants or stimulants? A hypothesis. J Affect Disord. 2004;78:81–4. doi:10.1016/S0165-0327(02)00180-5
8. Chun B, Dunner DL. A review of antidepressant-induced hypomania in major depression: suggestions for DSM-V. Bipolar Disord. 2004;6:32–42. doi:10.1046/j.1399-5618.2003.00084.x
9. National Institute for Health and Care Excellence (NICE). Bipolar disorder: assessment and management: NICE Guideline [CG185]. London, NICE; 2016. https://www.nice.org.uk/guidance/cg185. Updated February 11, 2020. Accessed: August 25, 2020.
10. Ramasubbu R. Dose–response relationship of selective serotonin reuptake inhibitors treatment- emergent hypomania in depressive disorders. Acta Psychiatr Scand. 2001; 104:236–9. doi:10.1034/j.1600-0447.2001.00383-2.x
11. Tondo L, Vazquez G, Baldessarini R. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121:404–14. doi: 10.1111/j.1600-0447.2009.01514.x
12. Dumlu K, Orhon Z, Özerdem A, Tural U, Ulaş H, Tunca Z. Treatment-induced manic switch in the course of unipolar depression can predict bipolarity: Cluster analysis based evidence. J Affect Disord. 2011;134:91–101. doi:10.1016/j.jad.2011.06.019
13. Barbuti M, Pacchiarotti I, Vieta E, Azorin JM, Angst J, Bowden CL, et al. Antidepressant-induced hypomania/mania in patients with major depression: evidence from the BRIDGE-II-MIX study. J Affect Disord. 2017;219:187–92
14. Dagani J, Signorini G, Nielssen O,et al. Meta-analysis of the interval between the onset and management of bipolar disorder. Can J Psychiatr. 2017;62:247–58. doi:10.1016/j.jad.2017.05.035
15. Wada K, Sasaki T, Jitsuiki H, Takaishi Y. One-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment. Int J Psychiatry Clin Pract. 2013;17:219–22. doi:10.3109/13651501.2013.793359
16. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407–20. doi:10.1046/j.1399-5618.2003.00067.x
