Light therapy for bipolar disorder: Clinical advice from the international bipolar disorder group

People who live with bipolar disorder (BD) spend more time grappling with depressive symptoms than manic symptoms. Bipolar depression can diminish quality of life and lead to unfavourable outcomes, characterised by persistent functional and cognitive impairments, recurrent mood episodes, treatment-refractory illness, high burden of medication side effects and increased suicide risk (Judd et al. 2002, 2003a, 2003b). First line treatments for bipolar depression exhibit limited efficacy, while electroconvulsive therapy (ECT) and wake therapies, although highly effective, are not widely available (Vieta et al. 2010; Grunze et al. 2013; Gottlieb et al. 2019; Wirz-Justice and Benedetti 2020). Antimanic therapy or ‘mood stabilizers’ often falls short in treating depression, prompting the addition of conventional antidepressants. Such combination regimens are promising but may carry risks of affective mood switch, rapid cycling, and suicidality (Vieta et al. 2010; Grunze et al. 2013). Given the challenging therapeutic landscape, development of novel treatments tailored to manage and prevent bipolar depressive episodes is a public health imperative. Despite mounting evidence to support the clinical efficacy of bright light therapy (BLT) and newfound insights into the physiological mechanisms, BLT is largely underutilised and poorly understood by mental health clinicians (Wirz-Justice et al. 2004; Geoffroy et al. 2020). Bridging the gap between research findings and clinical application is essential to fully harness the benefits of BLT in BD.

The historical connection between light and mood dates back to ancient times (Geoffroy 2020). From Wong Tai’s venerable observations linking seasonal light variations to mood fluctuations, to Hippocrates’ advocacy of ‘heliotherapy’ in 400 BC, early scientists recognised the influence of sunlight on human well-being and posited the therapeutic potential of light interventions. Modern uses of BLT are informed by neuroscientific innovations launched in the 1980s and onward. Foundational discoveries and ground-breaking progression of this work are elaborating the putative mechanisms, that encompass the light detection, neural pathways and integrate with knowledge of chronobiology, homeostatic sleep processes, wake systems and monoaminergic neurocircuits to explain the pathophysiology of BD (Harvey 2008; McClung 2013; Geoffroy 2018; Wirz-Justice and Benedetti 2020).

Mood disorders are characterised by specific patterns, clinical features and comorbid conditions that point to manifestations of disturbances in circadian rhythms (delayed or advanced sleep phase disorders), abnormal sleep-wake cycles (hypersomnia in atypical depression), and altered mood traits predicted by infradian cycles (seasonal variation or premenstrual dysphoric disorder) (Harvey 2008; McClung 2011; Geoffroy 2018)). Chronotherapeutics has increasingly applied a versatile set of evidence based behavioral, environmental and pharmacological interventions to regulate sleep-timing, enhance alertness, improve sleep quality, and manage mood episodes. These chronotherapeutic interventions have received consensus recognition from the International Society for Bipolar Disorders (ISBD) (Gottlieb et al. 2019). Higher quality evidence supports adjunctive BLT as an acute treatment for bipolar depression (Gottlieb et al. 2019). Although generally well-tolerated, anti-manic prophylaxis in BD I subtype and clinical monitoring are recommended with initiation of and ongoing light treatment (Gottlieb et al. 2019). The position of maintenance BLT for relapse prevention awaits further investigation. Daily BLT is identified as an outstanding, primary treatment for seasonal depression (American Psychiatric Association, Practice Guideline for the Treatment of Patients With Major Depressive Disorder (American Psychiatric Association 2000); https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf↗ and (Maruani and Geoffroy 2019)). Protocols of effective BLT in bipolar depression are similar to parameters indicated for seasonal and non-seasonal major depressive disorder (Gottlieb et al. 2019; Geoffroy et al. 2020). In this evidence-based practice guideline, we aim to propose clinical practice recommendations and applications of bright light treatment in the management of BD.

We believe that a better understanding of the physiological and neurobiological mechanisms underlying BLT is critical for increasing its clinical use. Just as physicians expect to understand the pharmacodynamics of a drug before prescribing it, the mechanisms of light must also be integrated into medical knowledge to facilitate adoption and appropriate application (Geoffroy et al. 2020).

The circadian system is conceptualised as a hierarchical structure, with a master central clock pacemaker overseeing the rhythmic functions of peripheral clocks distributed throughout the body. The central circadian clock in humans, is located in the suprachiasmatic nucleus (SCN) of the hypothalamus (Moore and Lenn 1972; Stephan and Zucker 1972). This small, paired structure, consisting of approximately 20 000 neurons (10 000 x2), is located just above the optic chiasm and below the third ventricle. The SCN orchestrates the daily physiological rhythms by generating or synchronising cycles across nearly all bodily functions, through both direct neural connections with other brain centres (e.g., control of pineal melatonin) and indirectly through the release of humoral signals that influence the timing of the clocks found in most tissues (e.g., gut oscillator) (Dibner et al. 2010). Often described as the conductor of an orchestra, the SCN ensures that tissue-specific (peripheral) oscillators remain harmonised, enabling the precise temporal coordination of various physiological processes.

Alignment of the circadian clock in the SCN with the external light/dark cycle is primarily set by input from the retino-hypothalamic tract. This anatomical pathway (that functionally transmits photoreceptor signals from the retina to the SCN) consists of axons originating from a subset of retinal ganglion cells (RGCs) that receive inputs from rod-cone networks, and express the photopigment melanopsin, making them intrinsically photosensitive retinal ganglion cells (ipRGCs) (Baver et al. 2008). As photoreceptors in the retina, ipRGCs detect light through the melanopsin signalling pathway, which is particularly sensitive to blue light with a maximal peak at ∼480 nm. Within the SCN, neurons integrate light signals with non-photic inputs, such as those mediated by serotonin from the medial raphe nucleus (Hay-Schmidt et al. 2003), neuropeptide Y signals from the intergeniculate leaflet nucleus of the thalamus (Janik and Mrosovsky 1994), and melatonin from the pineal gland (Shibata et al. 1989). These photic and non-photic signals, collectively known as ‘zeitgebers’ (from the German ‘time giver’), help synchronise internal rhythms with the external environment. Under natural conditions, the detection and processing of regular zeitgebers leads to robust entrainment or synchronisation of the internal time-keeping mechanisms. However, when these time cues become irregular or desynchronised, the circadian clock’s timing can become erratic, and the amplitude of its oscillation may be reduced (Jewett et al. 1994). A weakened circadian amplitude can, in turn, lead to less effective synchronisation of downstream oscillators, disrupting physiological and behavioural rhythms (Souêtre et al. 1989; Dijk et al. 2012; Harfmann et al. 2017). Output signals from the SCN influence multiple brain circuits, orchestrating a wide range of physiological and behavioural processes. Melatonin production in the pineal gland is one of the best studied pathways of the SCN. In humans, endogenous melatonin circulates at low levels throughout the day. Melatonin production rises exponentially in the evening a few hours before habitual bedtime to a near square wave amplitude (or skewed cosine, (Van Someren and Nagtegaal 2007)) and ceases rapidly within one hour of habitual waketime. Basal levels of melatonin provide feedback onto SCN receptors and influence the timing of its own production, though this effect is much more pronounced during the daytime when circulating melatonin concentrations are typically quite low, as compared to the evening effect (Lewy et al. 1992). Likewise, exogenous melatonin can impact and possibly change the SCN rhythm when administered during the daytime (Lewy et al. 1998). The increased levels of melatonin at night has also been implicated as mechanistically associated with decreases in alertness (Cajochen et al. 2000). In addition to the timing of melatonin being under direct control of the SCN, exposure to light at night can also acutely suppress the production of melatonin in a spectral (Brainard et al. 2001; Najjar et al. 2024) and an intensity-dependent manner (Zeitzer et al. 2000; Prayag et al. 2019) (for review on the effects of light on melatonin and sleep, see: (Prayag et al. 2019)).

The proper timing of sleep emerges from a dual process that balances signals of the SCN circadian pacemaker with sleep homeostasis (Borbély 1982; Dijk and Czeisler 1994). Mediated by health, stress, social and cultural factors, the preferred time of sleep or more broadly, the subjective preference for sleep and wake is defined as ‘chronotype’ (Van Someren and Nagtegaal 2007). Individuals are ‘morning, intermediate, or evening’ types according to their sleep time preference. Homeostatic sleep is an appetitive process such that the more sleep one gets, the less sleep is needed and, conversely, the longer one stays awake, the more sleep is needed. The accumulation and dissipation of homeostatic sleep follows an exponential function (Franken et al. 1991). Operating in tandem with sleep homeostasis is the circadian clock, which is independent of sleep need. The SCN generates a ‘paradoxical’ signal for wake in the hours just before habitual bedtime, and a signal for sleep in the hours just before habitual waketime. While awake, the increased homeostatic drive for sleep is offset by the increased circadian drive for wake. During sleep, the decreased homeostatic drive for sleep is offset by the increased circadian drive for sleep. Together, wake and sleep are consolidated into single daily periods in humans by integrating signals from the SCN, sleep homeostat (Dijk and Czeisler 1995), and possibly from sustained direct light effects (mediated through the melanopsin pathway) (Hubbard et al. 2021).

Light treatment is a modality of chronotherapy, traditionally understood as operating through a circadian mechanism whereby light acts as a zeitgeber influencing the SCN (Gottlieb et al. 2019). However, with advancements in mapping the neural projections of ipRGCs in mammals (particularly studies in rodents), emerging evidence suggests that the antidepressant effects of light may be mediated through multiple brain centres, either in parallel with or bypassing the SCN (Maruani and Geoffroy 2022). One compelling example is the recent identification of the perihabenular nucleus (PHb) in the dorsal thalamus of the mouse brain, which has been shown to play a key role in mood regulation (Fernandez et al. 2018; Huang et al. 2019). PHb neurons are particularly responsive to changes in lighting conditions, such as transitions from darkness to light. Light signals processed by the PHb are subsequently routed to regions involved in mood regulation, such as the ventromedial prefrontal cortex, nucleus accumbens, and dorsal striatum (Fernandez et al. 2018).

Human studies using functional MRI have demonstrated the light-intensity–dependent activation in the prefrontal cortex (Sabbah et al. 2022). This effect is consistent with the intensity-dependent suppression of melatonin in response to light (Prayag et al. 2019). Preceding fMRI studies showed acute temporal changes in blood perfusion from blue-light exposure, with an immediate activation of the hypothalamic region and habenular region, followed by activation of the brain stem and monoaminergic brain stem nuclei, specifically the raphe nucleus (serotonin) and locus coeruleus (noradrenaline) (Vandewalle et al. 2009), and neuronal activation of the general cerebrum within 30 min of blue-light exposure. Intriguingly, the patterns of temporal and spatial spread of activity across the inter-connected regions, map onto the neural circuits of mood disorders (Price and Drevets 2010) and correspond with the onset and timing of antidepressant responses to BLT. Together, these findings point to a conserved retino-thalamic-frontocortical pathway in mammals that mediates the effects of light on neural pathways of mood and behaviours among patients with BD.

We must contend with a disproportionate lack of human data from light studies. Promising theories and investigations on light are often piloted in non-human models. Even so, novel findings from such basic science and pre-clinical studies are critical steps in the scientific process that serve to uncover the mechanisms underpinning the role of light in mood and behaviour, and to support the corresponding evidence from clinical studies on the clinical and functional outcomes of BLT in patients with BD.

The literature base on utilising adjunctive BLT (addition of BLT to an existing antimanic agent or ‘mood stabilizer’) for treatment of bipolar depression has expanded immensely across the years (Gottlieb et al. 2019; Lam et al. 2020). Evidence from recent higher quality clinical trials suggest that adjunctive BLT is effective in reducing bipolar depressive symptoms and improving global functioning without much risk for a manic switch (Takeshima et al. 2020). Furthermore, BLT may enhance other dimensions of BD, such as sleep quality, cognitive performance, and anxiety (Sit et al. 2018; Takeshima et al. 2020; Bisdounis et al. 2022). The ISBD Task Force on Chronobiology and Chronotherapy and others have made recommendations to utilise BLT for adjunctive treatment of acute bipolar depression (Gottlieb et al. 2019; Lam et al. 2020). These groups also declared the need for further research in consideration of the study limitations. Of note, the varying light treatment parameters, small sample sizes, brief durations of therapy and inconsistent quality across trials are possible short-comings that could limit generalisability (Gottlieb et al. 2019; Lam et al. 2020).

In a comparison of depression outcomes of light therapy, antidepressant drugs, and combined treatment (BLT with antidepressant)(Geoffroy et al. 2019) meta-analyses showed a clear superiority of combination therapy (standardised mean difference [SMD] = 0.56; p < 0.001) and no significant difference in treatment effect of BLT or drug in major depressive episodes (SMD = 0.19; p = 0.17) (Geoffroy et al. 2019). Utilising BLT or combination therapy are likely acceptable first-line treatments for depressed patients with a diagnosis of BD or MDD regardless of seasonality (Geoffroy et al. 2019). Lam et al. conducted a high quality meta-analysis of RCTs specific to bipolar depression and showed significant improvements in clinician-rated depressive symptoms (Hamilton Depression Rating Scale, HDRS; (SMD = 0.43; p = 0.03) and a clinical response in favour of BLT (odds ratio = 2.32; p = 0.024) (Lam et al. 2020). Similar results were found in subsequent meta-analyses (Franken et al. 1991; Dijk and Czeisler 1995; Brainard et al. 2001). Therefore, BLT emerges as an acceptable adjunctive treatment option for management of seasonal and non-seasonal bipolar depressive episodes.

To optimise the therapeutic benefits of BLT a comprehensive strategy is crucial (Figure 2). Delivery of BLT is ideally approached following a proper diagnostic evaluation, and complete assessment of the patient’s 24-hour exposure to light and darkness, sources of illumination, habitual sleep/wake times, exercise, sleep hygiene practices (Esaki et al. 2019; 2021a) and schedule constraints (school, work and social obligations) (Ballard et al. 2024). For patients with BD I, antimanic therapy is indicated during BLT and at least 2–4 weeks prior to initiating BLT (Pacchiarotti et al. 2013), to prevent (hypo)manic episodes and to avoid mood induction effects. In contrast for BD II patients, the need for mood stabiliser coverage may depend on the clinician’s discretion (Bahji et al. 2020). Broad consensus supports that treatment guidance and ongoing mood monitoring are provided by a trained clinician (Yatham et al. 2018).

See Tables 1 and 2.