Sleep disturbances are a common symptom of seasonal affective disorder (SAD) (1, 2) and may potentially amplify the mood symptoms of SAD. Benzodiazepines (BZDs) and BZD-like drugs (the ‘Z-drugs’) are effective hypnotics and are widely prescribed for chronic insomnia (3). As such, their use should be considered for patients with insomnia associated with SAD. Lormetazepam is a BDZ with a well-established clinical efficacy and, like other drugs of this class, can potentially be used in a cyclical or intermittent regimen (4, 5). Due to its pharmacokinetic and pharmacodynamic characteristics is therefore particularly appropriate for a disorder such as SAD that has a seasonal course. In this review, we provide a brief overview of SAD followed by a more detailed discussion of insomnia in SAD and its management, with a focus on BDZs, and more specifically, lormetazepam.

The seasonal nature of mood disorders has been acknowledged since antiquity, with Hippocrates the first to describe the important link between seasons and mood changes. He believed that the proper study of medicine should first observe the development of the seasons (as described in his work ‘On Airs, Waters, and Places’). Chronobiological concepts link circadian rhythm disturbances to the seasonality of SAD (6), which has recently been acknowledged to have a distinct nosographic autonomy (7, 8). This mood disorder, specifically its depressive component, is closely linked to the periods of the year and to the time of light exposure; recurrent winter episodes alternate with periods of euthymia or hyperthymia in spring−summer (winter SAD) (9), while a summer disorder (summer SAD) shows clinical manifestations between May and September (Northern Hemisphere) and hypomanic phases in winter (10). Evidence suggests that winter SAD may be triggered in susceptible individuals by the reduced ambient light that occurs in winter, whereas summer SAD may be triggered by high temperatures (11).

Key risk factors for SAD include geographic latitude, age, gender, genetic predisposition, and lifestyle, which are discussed below.

Estimated worldwide prevalence rates of SAD vary between 1% and 10% of the population, depending on geographic location; regions further from the equator, which receive less sunlight in winter and more in summer, tend to have higher rates of SAD (1, 12). As a result, SAD is more common in northern populations, correlating with latitude. The prevalence of SAD is also affected by age. Although SAD can affect children, it tends to start around the time of puberty, worsening during adolescence, and becoming more severe in the third to fourth decade of life (13). The prevalence of SAD tends to be higher among women than men (1, 12). In Italy, the prevalence of SAD is estimated to be between 3.5% and 11.5% for the subsyndromal form (S-SAD), more commonly known as “winter blues”, and the ratio of women to men with SAD is about 3:1 (14).

There is a close association between depression and menopause (15). Menopausal women with SAD typically experience autumn/winter symptoms, including subjective dysphoria, sleep disturbance, severe asthenia, increased appetite, and carbohydrate cravings (13).

The seasonal pattern is added to the diagnosis in patients with recurrent affective disorders (unipolar major depression or bipolar I or II disorder) with seasonal depressive relapses (16). In addition, genetic predisposition can increase the risk of SAD (1, 17). Indeed, seasonal changes in mood and behavior tend to run in families, especially winter SAD. This is largely due to a biological predisposition that contributes at least 29% to the onset of SAD (11).

From a biological viewpoint, people with SAD have a dysregulated serotonergic system, which is one of the factors responsible for mood balance. Patients with SAD have shown seasonal fluctuations in binding to the serotonin transporter (SERT) protein in the brain (18). The SERT protein is responsible for transporting serotonin from the synaptic cleft to the presynaptic neuron. Thus, higher levels of SERT lead to lower levels of serotonin activity (19). SERT levels are kept low by sunlight throughout the summer, but they rise in the winter, causing depression and SAD (19).

In addition, patients with SAD may experience overproduction of melatonin, a hormone produced by the pineal gland that facilitates sleepiness and normalizes the circadian rhythm during hours of darkness. In healthy people with normal sleep-wake cycles, the physiological production of melatonin usually begins in the evening, 14 hours after spontaneous wakening (20). As winter days become darker, melatonin production increases, inducing sleepiness and lethargy in patients with SAD (19). The combination of reduced serotonin and increased melatonin disrupts the circadian rhythm (19).

Gamma−aminobutyric acid (GABA)-mediated signaling within the suprachiasmatic nucleus (SCN, the ‘master circadian clock’), is implicated in regulating the seasonal rhythm in animal models and the circadian rhythm in mammals (21, 22). However, seasonal variations in GABA levels in various brain regions implicated in the pathophysiology of SAD such as the putamen and insula (but not the SCN) could not be verified in healthy human volunteers in a recent study (22). Since there was no seasonal variation in GABA content in these brain regions, the study authors suggested future investigations should determine whether there are seasonal variations in GABA levels in patients with SAD, and whether there is seasonal variation in GABAergic neurotransmission attributable to changes in GABA receptor functioning (22).

SAD can become a chronic condition with cyclical depressive episodes. Winter and summer SAD are characterized by a lack of energy, a state of sadness, and reduced sociability (11). The most common symptoms of SAD include hypersomnia or insomnia, hyperphagia or hypophagia, mental fatigue, asthenia, concentration difficulties, and irritability (1). A specific feature of SAD is the presence of a depressed but reactive mood, which allows a significant change in mood (accentuated in the evening hours) following a positive event.

Symptoms starting in autumn and winter may include tiredness, fatigue, mood deflection, irritability, difficulty concentrating, musculoskeletal pain, decreased sexual desire, hypersomnia, increased appetite, and weight gain (10, 13). The acute phase usually occurs during the darker months, and, in severe cases, SAD may be associated with thoughts of suicide (19). Notably, winter SAD is frequently associated with an initial hypersomnia that is often underestimated, which can evolve into forms of secondary insomnia (2).

The most common symptoms of summer SAD are insomnia, loss of appetite, weight loss, irritability, difficulty concentrating, anxiety, psychomotor agitation, and mood swings (10).

Sleep disturbances, such as insomnia, are among the most common symptoms of SAD (2). In healthy individuals, light synchronizes the circadian clock with the Earth’s solar day and has downstream effects on sleep, alertness, and mood (2). Seasonality and light therapy suggest SAD is related to abnormal responses to low light levels in winter. Specifically, SAD is characterized by a delay in the circadian phase relative to the sleep-wake cycle (circadian misalignment); delayed circadian timing is thought to manifest behaviorally as early-onset insomnia and morning hypersomnolence, with difficulty falling asleep and waking up the next morning (23). Poor sleep quality associated with SAD manifests as fragmented sleep due to frequent awakenings during the night (2). Hypersomnolence is an atypical vegetative symptom of depression and is considered a cardinal symptom in the characterization and diagnosis of SAD, expressed as either excessive daytime sleepiness and/or increased sleep duration (2). A registry study based on data from clinical interviews reported that individuals with hypersomnia in SAD sleep 72 minutes longer in winter than summer (24).

Diagnostic criteria for chronic insomnia disorder note that it compromises the patient’s lifestyle, causes cognitive decline with a reduction of executive processes, loss of occupational productivity, and potential physical damage due to fatigue-related accidents (25). Insomnia is also considered to be an independent risk factor for cardiovascular and neurological disorders, as well as psychiatric comorbidities, increasing suicidal risk (25, 26). Of concern, many individuals with insomnia inappropriately self-medicate instead of seeking formal care, and Italy has a high rate of sedative-hypnotic misuse (26). Historically, insomnia was viewed as primarily a symptom associated with somatic or mental disorders, but the latest European Insomnia Guideline 2023 classifies insomnia as an independent disorder (25). Nevertheless, insomnia tends to be under-recognized in Italy, where most primary care physicians continue to consider insomnia to be a comorbid condition (26). Given the high prevalence of insomnia symptoms and their serious health implications, as well as its under-diagnosis, the recognition, diagnosis, and adequate treatment of insomnia represents an important unmet need.

Treating sleep disorders is crucial to alleviating the overall symptoms of SAD and improving quality of life. Bright light therapy (BLT) is considered a first-line treatment for SAD, despite the fact that while some studies have shown effectiveness, others have not (27). Exposure to bright light in the morning aims to redress the serotonin-melatonin balance to regulate the circadian sleep-wake rhythms and have an effect on both mood and sleep (28). Lifestyle modification offers a wide range of additional intervention options. Accordingly, some studies have shown a beneficial effect of exercise, with or without BLT, combined with sleep hygiene rules, dietary changes and the integration of supplements (including vitamin D), and melatonin (19, 29). Psychological support based on cognitive behavioral therapy (CBT) can help to manage negative thoughts about sleep and SAD (19). However, the use of CBT requires qualified personnel and is not widely available in all countries (30). Moreover, evidence-based insomnia management guidelines are not routinely used in mental healthcare (31). The emergence of fully-automated digital CBT (dCBT) may transform the insomnia treatment landscape, as this treatment delivery format can be efficiently integrated into both population health and clinical health service initiatives, optimizing treatment for people across all levels of complexity and need (30). A real advantage of dCBT products is that they could potentially deliver clinical guideline care for insomnia at a population scale (30).

Pharmacological treatments target the brain’s neurotransmitter systems and neurochemistry that regulate the sleep-wake cycle (Figure 1). Key neurotransmitters that regulate sleep and wakefulness include GABA, acetylcholine, and orexin (27): the binding of GABA to its receptor opens an ion channel that allows chloride ions to move into the cell and thereby exert a hyperpolarizing (inhibitory) function (33) which, in the late evening, facilitates the induction of non-rapid eye movement (NREM) sleep. The knowledge of neurochemical changes associated with NREM and rapid eye movement (REM) sleep, as well as those associated with awakening, together with an understanding of how pharmacotherapies may affect these systems, is crucial to help clinicians choose the most appropriate insomnia medications.

Hypnotic BZDs and the Z-drugs are the most widely used drugs prescribed for chronic insomnia (3), and are discussed in more detail in Sections 5.1 and 5.3. Importantly, these classes of molecules differ from each other, both in terms of their effects on the sleep and in terms of dosage and administration regimens.

More recently, dual orexin receptor antagonists (DORAs) have been approved to manage chronic insomnia in patients with a range of psychiatric disorders. DORAs reduce wakefulness by inhibiting the effect of orexin through binding to OX1 and OX2 receptors localized on monoaminergic and cholinergic neurons of different brain areas (34). Since activation of OX neurons by orexin also leads to activation of GABAergic neurons in the ventral hypothalamic preoptic area and consequently inhibition of sleep-promoting GABA/galanin-containing neurons in the same area (35), it could be hypothesized that the effect of DORAs is also mediated via this latter polysynaptic circuit. Some examples include suvorexant, lemborexant, and daridorexant, which can be used for ≥3 months and up to 1 year for chronic insomnia (34, 36, 37).

Melatonin receptor agonists (MRAs) including melatonin and ramelteon have been investigated for their effectiveness in treating insomnia, but results from two network meta-analyses were inconsistent (32, 38). Targeting the melatonergic pathway remains an area of active investigation however. Agomelatine is a melatonin MT₁ and MT₂ receptor agonist and neutral antagonist at the serotonin 5-HT_2C receptor usually used in patients with major depressive disorder (39). A recent proof-of-concept 24-week study of agomelatine in combination with CBT in patients with moderate to severe insomnia reported encouraging reductions in insomnia severity, whereas reductions in efficacy over the duration of the study were observed with the active comparator clonazepam (40).

Drugs such as antidepressants, antihistamines, and antipsychotics are often prescribed off-label, in particular the antidepressants (e.g., mirtazapine, trazodone), for their effective sedative action to patients with insomnia (25, 41, 42). However, the European Sleep Research Society 2023 guidelines recommend very careful use of antidepressants and antipsychotics to treat insomnia due to their contraindications and adverse effects (25).

Further, antipsychotic medications (e.g., quetiapine, olanzapine) are not recommended for the treatment of insomnia due to the lack of randomized controlled trial evidence on the use of these substances concerning insomnia disorder with or without comorbidities (25).

Insufficient evidence supports the use of antihistaminergic drugs in the short- or long-term treatment of insomnia (25). Not only are there no high-quality randomized placebo-controlled clinical studies, but these drugs are known to induce a marked sedative, not hypnotic, effect associated with a rapid development of tolerance (25).

A critical reconsideration of the therapeutic class of BZDs is appropriate, as these drugs continue to suffer the stigma of the development of dependence and tolerance. With regard to the latter in particular, although the mechanism of onset is still unknown, one of the hypotheses underlying its development could be the modification, after prolonged use of high doses, in the gene expression of the receptor subunits of the GABA_A receptor (4, 81, 83, 84).

It is important to consider BZDs within a specific clinical context in which the use of short-term hypnotics could help fill an “unmet need”, i.e., that of assisting patients with SAD and insomnia. In fact, alternative treatment options such as antidepressants do not cure insomnia and are not appropriate for some patients due to potential adverse effects. In contrast, BZDs used in compliance with treatment schemes such as those described above can constitute a useful resource in the therapeutic armamentarium available to the physician. Indeed, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) (85) considers tolerance and dependence − very recurrent when dealing with the issue of abuse − as phenomena that do not occur when BZDs are taken under medical supervision.

Among the fears associated with the use of BZDs is a possible link between their long-term intake and the onset of neurological disorders, such as cognitive decline and dementia (86, 87), but the data for dementia are not definitive (87). Furthermore, the occurrence of anterograde amnesia has been highlighted as a class effect of BZDs (64). For example, in a placebo-controlled trial involving healthy male volunteers comparing lormetazepam (1 or 2 mg) with flunitrazepam (2 mg), anterograde memory impairments were the largest with flunitrazepam, less marked with lormetazepam 2 mg than with the 1 mg dose, while memory impairments with lormetazepam 1 mg did not differ from those with placebo (88). Even if anterograde amnesia were to occur with BZDs, its duration would be limited, given the short-to-intermediate half-life of the drug.

Clinicians should be correctly trained and educated in the use of BZDs. A recent qualitative investigation into the long-term use or prescription of BZDs has highlighted the fact that physicians lack resources, time, and specific knowledge about available treatments when addressing sleep- and anxiety-related problems in older-aged patients (89).

Sleep disorders, including insomnia, hypersomnia, and circadian rhythm disruptions, are common in SAD and can worsen emotional symptoms. Effective management often involves light therapy to regulate sleep-wake cycles, maintaining good sleep hygiene, and, if needed, medical interventions such as targeted medications or psychological therapies. Based on our current understanding of the pathophysiology of insomnia and SAD, we propose that hypnotic BZDs, such as lormetazepam, could be used to treat sleep disturbances in patients with SAD. In this context, lormetazepam represents a rational choice thanks to its balance between hypnotic efficacy, preservation of sleep architecture, control of evening anxiety, and limited risk of residual sedation. These elements make it preferable to hypnotics with an excessively short half-life (which do not sustain sleep) or an overly long half-life (which worsens the lethargy and low energy typical of SAD). Based on our clinical experience, short-term use of BZDs or BZDs on an intermittent dosing schedule may improve sleep quality and overall well-being in these patients. Nevertheless, well-controlled clinical trials in patients with SAD are required. We consider that our experience may serve as a stimulus for a critical reflection on the use of BZDs in SAD.