When is pharmacotherapy necessary for the treatment of seasonal affective disorder?

KEYWORDS:

• Antidepressants
• Bright Light Therapy
• Fluoxetine
• Bupropion
• Seasonal Affective Disorder

1. Introduction

Seasonal affective disorder (SAD) is a psychiatric entity defined by recurrent depressive or (hypo)manic episodes that occur and remit following a specific seasonal pattern [1]. Lifetime prevalence in Western countries has been reported between 1.9% and 9%, depending on latitude, with a predominance for younger age and the female gender [1].

SAD consists of two subtypes, of which winter depression is the most common. This type is characterized by the onset of recurrent episodes of unipolar depression in the fall or winter with a remission in fall or spring [1,2]. Much less common, the summer type of SAD is defined by depressive episodes beginning in the spring or summer and remitting during fall or winter [1,2]. Beyond seasons, it has been demonstrated that summer depression is connected to a raise in temperature. Meaning that the time of the year when depression occurs is linked to the months with the highest temperatures [3]. Additionally, using comprehensive data from multiple decades for both the United States and Mexico, recent research found a rise in suicide rates for an increase in monthly average temperature, further emphasizing the impact of higher temperatures on depressive mood and behavior [4]. Besides their temporal aspects, winter and summer SAD do also differ by their clinical manifestations. Patients with winter depression experience hypersomnia, increased appetite, and weight gain, while patients with summer depression usually present with agitation, irritability, insomnia, as well as decreased appetite and weight loss [1,2]. In the Diagnostic and Statistical Manual of Mental Disorders, 5th version (DSM-5), SAD is included as a ‘seasonal pattern specifier,’ which can be applied to not only major depressive disorder but also to bipolar I and II disorder [2]. In clinical practice, summer depression and bipolar mood episodes with seasonal pattern are treated in the same way as nonseasonal episodes; thus in this editorial, we will only discuss unipolar winter type SAD, hereafter mentioned to as ‘SAD.’ While specific SAD-oriented trials are sparse, antidepressant medications have demonstrated efficacy [5]. Beyond antidepressants, bright light therapy (BLT) is considered an effective and well-tolerated treatment for SAD as well [5]. We consider these different therapeutic options for SAD and propose an expert opinion based on the existing evidence and our clinical experience treating SAD patients.

2. Acute treatment

2.1. Antidepressants

Various insufficiently powered and open-label trials demonstrated some efficacy for escitalopram, duloxetine, agomelatine, reboxetine, nefazodone, bupropion, tranylcypromine, and mirtazapine [5]. Moscovitch et al. investigated the efficacy of sertraline in a study with a strict double-blind randomized controlled trial (DB-RCT) design and found that sertraline was significantly superior to placebo [6]. However, as this is the only sertraline trial, results should be replicated and cannot be considered conclusive until then. Five studies focused on fluoxetine and demonstrated all a significant positive effect on SAD [5]. Lam et al. [7] explored the effectiveness of fluoxetine in a DB-RCT. However, while there were significantly more patients who achieved response in the fluoxetine group compared to the placebo group, a recent update of the Cochrane Collaboration qualifies this finding as low-certainty evidence as the confidence interval for this finding included both a potential benefit as well as no benefit of fluoxetine and no significant differences in the continuous outcome measures (a modified Hamilton Depression Rating Scale) were observed [8]. Finally, it should be noted that up to 25% of the participants treated with antidepressants for SAD withdrew from the clinical trials early due to adverse events.

2.2. Bright light therapy

Beyond antidepressants, BLT is a well-established treatment for SAD. Both the Cochrane Collaboration [8,9] and the Council on Research of the American Psychiatric Association [10] did assess the efficacy of bright light therapy in the treatment of SAD. These meta-analyses found that bright light was superior to control conditions. Further, a recent meta-analysis carried out by the Cochrane collaboration based on two RCT ‘s showed that light therapy is as effective as fluoxetine for the treatment of SAD [9]. Although generally no side-effects are reported when using BLT, it should be noted that the rate of switch into mania after BLT in bipolar depression is lower than that observed with drugs or other chronotherapeutic techniques. As a matter of fact, switching rates are closely similar to the 4% switch rate expected during the placebo treatment of bipolar depression [11]. However, a somewhat increased rate of switch has been observed when considering patients with rapid-cycling bipolar depression [11].

3. Prevention

Given the well-known morbidity of a depressive episode and the predictability of these episodes inherent to the SAD diagnosis, preventive treatment may be necessary, especially for those individuals who are known to experience severe depressive episodes. Until today, bupropion extended release (XR) is the only antidepressant with a proven prophylactic efficacy for SAD and is as such approved by the US FDA. Three double-blind randomized controlled trials demonstrated bupropion’s superior prophylactic efficacy to placebo [12,13]. Recurrence of depressive episodes was significantly lower in the bupropion group when started in autumn, before the onset of symptoms and continued until spring [12,13]. However, side-effects of bupropion include headaches, insomnia and nausea and affect around 20–30% of patients [12,13]. While an efficacious intervention for the prevention of recurrence of depressive episodes, the Cochrane working group stated that the numbers needed to treat for additional beneficial outcomes (NNTB) will vary strongly by baseline risks [14]. For a population with a yearly recurrence rate of 30%, the NNTB is 8, while for populations with yearly recurrence rates of 50% and 60%, NNTBs are 5 and 4 [14].

A few studies evaluated the preventive efficacy of light therapy, group-based cognitive behavior therapy and melatonin. They found a significant effect for prevention, but given the limited number of studies and, in certain cases, methodological limitations, the recent Cochrane reviews concluded that no adequate conclusion could be drawn [15–17].

4. Expert opinion

Given the absence of robust evidence and the lack of comparative studies, the decision for or against initiating a treatment with fluoxetine or BLT should be strongly based on patient-centered criteria, such as preferences, tolerability, contraindications, and costs [5]. In our opinion, since BLT is supported by somewhat more robust evidence, it is less invasive and more cost-effective [18], before starting an antidepressant such as fluoxetine, BLT should be the first treatment option when considering the acute treatment of SAD [5]. It should be noted that to avoid relapse, the treatment should be sustained at least 2 weeks beyond the spontaneous remission of the depressive symptoms in spring/summer [19].

Beyond these aspects, severity of illness is an important clinical factor to consider. While patients with a mild or moderate depressive episode may benefit from BLT alone, we believe that this may be insufficient for patients with a severe depressive episode, f.i. with melancholic features, who may benefit from fluoxetine, eventually combined with BLT [19]. As for BLT, the use of the antidepressant should be maintained at least 2 weeks beyond the spontaneous remission of the depressive symptoms in spring/summer [19].

In case of a partial response to first-line treatment with fluoxetine or BLT, we propose continuing the first-line treatment of choice and adding BLT or fluoxetine, respectively. In case of minimal or non-response to fluoxetine and BLT combination therapy, the clinician can consider augmentation and switching fluoxetine for another antidepressant [19]. This is consistent with multiple practice guidelines for managing a (non-SAD) treatment-resistant depression. Further steps could – in line with the existing guidelines on treatment resistance – consist of combining antidepressants of even neuromodulation, e.g. electroconvulsive therapy.

Bupropion is and remains the first choice when a preventive treatment for SAD is considered. Taking into consideration the high prevalence of side-effects, in our opinion bupropion should only be considered for patients with high yearly recurrence rates and/or patients suffering from severe depressive episodes. It should be noted that while robust evidence supports the preventive properties of bupropion, its therapeutic effect during acute treatment is only supported by one insufficiently powered open-label study [5].

In addition, during both acute and preventive treatment, patients should be encouraged to incorporate positive behavioral attitudes such as sleep hygiene and aerobic exercise. It should however be noted that while the majority of hospitals recommend these lifestyle changes, the actual evidence on efficacy and harm is fairly limited [20].

It should be stressed that the evidence on the treatment of SAD remains too limited, given the prevalence, the suffering from patients and families, the repercussions on functioning and quality of life, and the societal costs. For now, our clinical decision-making for the treatment of SAD should be based on patient-centered decision criteria and the choice for any treatment should include a well-considered risk–benefice evaluation. As we noted earlier, the last pharmacotherapeutic trial was conducted in 2007 [3]. Further research and especially larger RCTs are required to guide patients and clinicians on the effectiveness of antidepressants, BLT and their combination in the general population and in different subgroups, on combining these therapies with chrono- and psychotherapy, on the start, duration, and ending of treatment, and on prevention and treatment resistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.