Antidepressants And Sleep: Unpacking Insomnia And Sleepiness Side Effects

Depression, Sleep Problems, And Antidepressants

Sleep problems are one of the most common challenges for people with major depressive disorder (MDD) - with studies finding 60 - 90% of MDD patients experiencing insomnia (sleeplessness) and 15 - 40% experiencing hypersomnia (excessive sleepiness) (Nutt et al., 2008). 

But what if the most common treatment for depression - antidepressant medications - actually stir up new sleep issues, like increased sleepiness (somnolence) or, importantly, treatment-emergent insomnia?

This isn’t a minor annoyance; sleep issues can seriously impact how well a person sticks to treatment, how effectively the medication works, complicate the depression with new problems (what we tend to see at The Better Sleep Clinic), and even increase the risk of depression returning (Zhou et al., 2023).

So, which antidepressants are most likely to interfere with sleep and cause insomnia? And does the dose make a difference?

Luckily for all those wondering, a recent study by Zhou et al. (2023) set out to answer these very questions by synthesizing data from the best trials available, providing a clearer picture for both patients and doctors, especially those struggling with insomnia. 

So what did they find? Read on.

Why Look at the Effects of Antidepressants On Sleep?

It may seem surprising, but while we know antidepressants can cause side effects like digestive issues or sexual dysfunction, the impact on sleep hasn't always received the same level of careful comparison (Zhou et al., 2023). This is a big deal because, as the researchers highlight, sleep-related side effects can undermine adherence, or sticking with an antidepressant medication, and hinder recovery.

Persistent insomnia, in particular, can worsen mood and make it harder to function during the day (Wichniak et al., 2017). On the other hand, feeling constantly sleepy (somnolence) can be dangerous if your job requires alertness, like driving or operating machinery (Eugene, 2020). 

Understanding which medications are more likely to cause these specific sleep problems, and how dosage plays a role, is crucial for making informed treatment choices. Prior meta-analyses had looked at second-generation antidepressants (Alberti et al., 2015), but a comprehensive comparison across many drugs including dose-effect relationships was needed.

The researchers aimed to directly compare many common antidepressants, rank their likelihood of causing somnolence or insomnia based on pooled data, and explore the relationship between the dose of the medication and the risk of these sleep disturbances, noting that dose-response isn't always linear for efficacy or side effects (Hamza et al., 2022; Cheng et al., 2020).

Investigating Antidepressants and Sleep Problems 

To get the most reliable answers, Zhou et al. (2023) conducted a systematic review and network meta-analysis, following standard reporting guidelines (Liberati et al., 2009). Think of it like combining the results of many high-quality studies to get a bigger, more robust picture. 

Importantly for our interest in sleep, the researchers:

• Used Strict Criteria: They only included double-blind, randomized controlled trials (RCTs) – the gold standard in medical research. These studies focused on adults (18+) with MDD who were taking a single antidepressant (monotherapy) during the acute phase of treatment.

• Focused on Sleep: The studies had to report on sleep-related side effects, specifically treatment-emergent somnolence and insomnia. They used the Cochrane risk of bias tool (RoB2.0) to assess study quality.

• Maintained an MDD only focus: They excluded studies focusing on specific populations like postpartum or post-stroke depression, or those where a large percentage of participants had bipolar or psychotic depression, to keep the results focused on MDD.
  
  

All up, they ended up analyzing data from 216 trials involving 64,696 patients. The average age was around 45.5 years, and about 63.2% were female.

They also did some other fancy statistical stuff to allow them to compare between different studies done in different ways, and to examine how the dose of each antidepressant related to the risk of insomnia or sleepiness, building on methods used in prior dose-effect research (Hamza et al., 2022).

This comprehensive approach allowed them to rank the antidepressants based on their likelihood of causing these sleep side effects and map out the dose-response curves.

Antidepressants And Insomnia: Which Antidepressants Might Give You Trouble Sleeping?

Which antidepressants are most likely to give you insomnia symptoms or worsen them? The study compared the odds of experiencing sleeplessness on each medication versus taking a placebo. An Odds Ratio (OR) greater than 1 suggests a higher risk compared to placebo.

Here’s what the researchers found:

• Many Increase Risk: Compared to placebo, 11 antidepressants showed significantly higher ORs for causing insomnia.

• The Top Insomnia Inducers: The antidepressants most strongly linked to insomnia were:

1. Reboxetine: OR = 3.47 (95% CI: 2.77 to 4.36) (nearly 3.5 times the odds of insomnia compared to placebo)

2. Vilazodone: OR = 2.99 (95% CI: 1.78 to 5.03)

3. Desvenlafaxine: OR = 2.12 (95% CI: 1.50 to 2.99)

• Others Causing Insomnia: Other drugs significantly increasing insomnia risk included duloxetine (OR=1.96), bupropion (OR=1.83), venlafaxine (OR=1.77), sertraline (OR=1.67), citalopram (OR=1.67), fluoxetine (OR=1.65), paroxetine (OR=1.47), and escitalopram (OR=1.37).

• One Exception: One drug stood out for having a lower risk of insomnia compared to placebo: amitriptyline (OR = 0.63; 95% CI: 0.42 to 0.92).

How Does Antidepressant Dose Affect Insomnia Risk?

The relationship wasn't always linear:

• Flat then Increasing: For bupropion, citalopram, escitalopram, paroxetine, sertraline, and vortioxetine, the risk of insomnia didn't change much between low and moderate doses but then increased at higher doses.

• Increasing then Flat: For desvenlafaxine, duloxetine, fluoxetine, venlafaxine, and vilazodone, the insomnia risk increased gently at lower doses and then seemed to level off at higher doses.

This suggests that for some drugs, pushing the dose higher might increase insomnia, while for others, the risk might plateau.

Which Antidepressants Increase Sleepiness (Somnolence)?

While we are mostly interested in which antidepressants might cause insomnia, it's also useful to know which antidepressants might cause the opposite problem – excessive sleepiness or drowsiness (somnolence). This can also impact daily functioning and treatment outcomes.

Here’s what Zhou et al. (2023) discovered from their network meta-analysis with respect to sleepiness:

• Many Increase Risk: Compared to placebo, 13 out of the 21 antidepressants studied showed significantly higher odds ratios (ORs) for causing somnolence.

• The Top Sleepiness Inducers: The antidepressants with the highest risk for somnolence were:

1. Fluvoxamine: OR = 6.32 (95% CI: 3.56 to 11.21)

2. Trazodone: OR = 5.23 (95% CI: 3.49 to 7.84)

3. Mirtazapine: OR = 4.83 (95% CI: 3.09 to 7.56)
   
   

• Others Causing Somnolence: Other antidepressants significantly associated with higher somnolence risk included amitriptyline (OR=4.01), duloxetine (OR=3.20), escitalopram (OR=3.42), paroxetine (OR=3.01), nefazodone (OR=2.30), sertraline (OR=2.31), fluoxetine (OR=2.24), venlafaxine (OR=2.04), desvenlafaxine (OR=2.23), and agomelatine (OR=1.41). 

• One Exception: Interestingly, bupropion stood out with a lower risk of somnolence compared to placebo (OR = 0.50; 95% CI: 0.30 to 0.82).

Does Changing the Dose Of An Antidepressant Increase Drowsiness?

This is where things get particularly interesting. Zhou et al. (2023) found that the relationship between the dose of an antidepressant and the risk of somnolence isn't always straightforward, echoing findings about non-linear dose-responses in antidepressant treatment more broadly (Hamza et al., 2022; Johnson et al., 2022).

It wasn't simply a case of "higher dose equals more sleepiness." They observed different patterns:

• Linear Increase: For some drugs, the risk of somnolence increased steadily as the dose went up within the usual therapeutic range. This was seen with fluoxetine, milnacipran, nefazodone, and sertraline (Zhou et al., 2023).

• Increase then Decrease: For another group of drugs, the risk of somnolence increased from low to moderate doses but then surprisingly decreased at higher doses. This pattern was observed for amitriptyline, desvenlafaxine, duloxetine, escitalopram, paroxetine, toludesvenlafaxine, trazodone, and venlafaxine (Zhou et al., 2023).

• Inverted U-Shape: Two antidepressants showed a distinct "inverted U-shape" curve. The risk of somnolence increased steeply up to a certain point and then decreased again at higher doses.

• Mirtazapine: Maximum somnolence effect was at approximately 30 mg (Dose-effect model OR = 4.89; 95% CI: 3.12 to 9.40). This aligns with clinical observations and suggestions that its sedation might be attenuated at higher doses (Atkin et al., 2018). This means for someone taking mirtazapine 30mg daily who complains of sleepiness, both decreasing or increasing the dose might potentially reduce that side effect

• Fluvoxamine: Maximum somnolence effect was at approximately 150 mg (Dose-effect model OR = 6.41; 95% CI: 3.45 to 15.92).

These varied dose-response curves highlight that managing somnolence isn't always about lowering the dose; sometimes, adjusting it upwards (for certain drugs) might be an option, guided by a clinician (Zhou et al., 2023).

What Does This Mean for You? Key Takeaways

This large-scale analysis provides valuable information for anyone taking or considering antidepressants. It is also especially useful information to discuss with your doctor or prescriber if you’re experiencing sleep problems while on an antidepressant. Knowing the specific profile of your medication and how dose changes might impact sleep can help you work together with your prescriber to find the best approach for your treatment and your sleep.

• Most Antidepressants Affect Sleep: The study confirms that the majority of commonly prescribed antidepressants carry a higher risk of causing either sleepiness or insomnia compared to taking nothing (placebo).

• Know Your Risk Profile: Different drugs have different tendencies, based on the Zhou et al. (2023) rankings:

• High Somnolence Risk: Fluvoxamine, trazodone, mirtazapine.

• High Insomnia Risk: Reboxetine, vilazodone, desvenlafaxine.

• Lower Somnolence Risk: Bupropion.

• Lower Insomnia Risk: Amitriptyline.

• SSRIs/SNRIs: Most drugs in these commonly prescribed classes (like fluoxetine, sertraline, venlafaxine, duloxetine) showed increased risks for both somnolence and insomnia in the meta-analysis, consistent with previous observations (Wichniak et al., 2017). Fluvoxamine was notably high for somnolence but not significantly for insomnia. Zhou et al. (2023) suggest that if an SSRI/SNRI causes daytime lethargy when taken in the morning, trying it at bedtime might be appropriate, except perhaps for fluvoxamine where nighttime dosing seems logical given its high somnolence risk.
  
  

• Dose Isn't Simple: The relationship between dose and sleep side effects is complex and varies by drug. The non-linear and inverted U-shape curves seen with drugs like mirtazapine and fluvoxamine are particularly important. It means dose adjustments need careful consideration and discussion with your doctor – simply lowering the dose might not always be the answer for sleepiness with certain medications.
  
  

• Drugs Often Used for Sleep: The study confirmed the higher somnolence risk of drugs sometimes used off-label for insomnia, like trazodone and mirtazapine, whose effects on sleep architecture have been studied (Zheng et al., 2022; Mi et al., 2020). Agomelatine also showed higher somnolence risk but may have less oversedation compared to mirtazapine in some settings (Leung, 2021). Trazodone's side effects are linked to its complex receptor profile (Jarema et al., 2011), and its use as a first-line insomnia therapy remains debated (Pelayo et al., 2023). Mirtazapine has also been associated with restless leg syndrome (Revet et al., 2020) and may have optimal acceptability around 30 mg (Furukawa et al., 2019).
  
  

• Newer Antidepressants: The study included newer drugs like vilazodone (high insomnia risk, consistent with rates reported by Deardorff & Grossberg, 2014) and vortioxetine (no significantly higher risk for either somnolence or insomnia compared to placebo in this analysis, aligning with safety data reported by Baldwin et al., 2016). Bupropion's insomnia risk is a known side effect, potentially related to its metabolites (Costa et al., 2019). Toludesvenlafaxine showed a low absolute risk for somnolence in the limited data available (Zhou et al., 2023).

Clinical Comment On Sleep And Antidepressant Medications

Our observations in the clinic generally aligns with these findings with the key reminder being that we have to be taken with a grain of salt as we only see those with insomnia and on the sleeplessness side of the sleep problem equation.

Of the common antidepressants we see in New Zealand, we would stack their insomnia inducing risk in exactly the same way - venlafaxine and sertraline being the most activating, with escitalopram the most gentle on sleep (for most).

Venlafaxine appears to be very activating, with many reporting “being on the edge of sleep” but “unable to quite get there”. But we’ve also observed that some people are on low doses of venlafaxine for quite some time with no issue, but insomnia emerges when the dose is increased - that’s similar to what this study noted.

Of all the SSRI/SNRI’s, we’ve noted that escitalopram may be the least impactful on sleep and in hindsight, we typically don’t see people on high doses, so this has generally been at low to moderate doses, similar to what the study suggests.

Of those antidepressants that are most sleepiness inducing, we still see some people prescribed Amitriptyline, an older generation tricyclic class of antidepressant drug, and it tends to increase sleepiness, especially at low doses, 10-20mg (where it primarily acts as a drowsy antihistamine). This may not fully show in the study as the doses for depression are typically much higher, starting at 50mg. 

Mirtazapine can seem like it will be helpful for sleep, but we don’t always see this. Part of the issue may stem from its long half-life (time in the body) of 20 - 40 hours. This long time in the body means it may make it easier to sleep at night, but then people feel lethargic and sedated during the day. 

The study was published in the journal Sleep (Zhou et al., 2023).

Frequently Asked Questions About Antidepressants and Sleep Problems

Can antidepressants cause sleep problems like insomnia or sleepiness?

A: Yes, many commonly prescribed antidepressants can affect sleep. This large review (Zhou et al., 2023) found that most antidepressants studied carried a higher risk of causing either treatment-emergent insomnia (difficulty sleeping) or somnolence (excessive sleepiness/drowsiness) compared to a placebo. The specific effect often depends on the individual drug.

Which antidepressants are most likely to cause insomnia?

A: According to the analysis by Zhou et al. (2023), the antidepressants with the statistically highest risk of causing insomnia compared to placebo were Reboxetine, Vilazodone, and Desvenlafaxine. Several others, including bupropion, venlafaxine, and common SSRIs/SNRIs like sertraline, fluoxetine, and escitalopram, also showed a significantly increased risk. Amitriptyline was found to have a lower risk of insomnia.

Which antidepressants are most likely to cause sleepiness or drowsiness (somnolence)?

A: The study (Zhou et al., 2023) identified Fluvoxamine, Trazodone, and Mirtazapine as having the highest risk of causing somnolence. Other medications like amitriptyline, duloxetine, escitalopram, paroxetine, and sertraline also showed significantly increased risks. Bupropion was associated with a lower risk of somnolence.

Q4: Does the dose of my antidepressant affect sleep side effects like insomnia or sleepiness?

A: Yes, the dose often matters, but the relationship is complex and varies by drug (Zhou et al., 2023). It's not always a simple case of higher dose = more side effects.

• For insomnia, some drugs showed increased risk mainly at higher doses (e.g., bupropion, sertraline), while others showed risk increasing early then plateauing (e.g., desvenlafaxine).

• For somnolence, some drugs showed a linear increase with dose (e.g., fluoxetine, sertraline), while others had an "inverted U-shape" where moderate doses caused the most sleepiness (e.g., mirtazapine, fluvoxamine).

What should I do if I think my antidepressant is causing insomnia or other sleep problems?

A: Do not stop taking your antidepressant abruptly. Suddenly stopping can cause withdrawal symptoms or worsen your depression. The most important step is to talk to the doctor who prescribed the medication. They can help determine if the sleep issue is related to the drug, discuss potential strategies like adjusting the timing of your dose, changing the dose (based on the complex relationships mentioned above), or considering a switch to a different antidepressant if necessary.

Are there any antidepressants less likely to cause insomnia?

A: Based on the Zhou et al. (2023) analysis, amitriptyline had lower odds of causing insomnia compared to placebo. Other antidepressants known for sedation, like trazodone and mirtazapine, are less likely to cause insomnia (though they carry a high risk of drowsiness). It's a trade-off, and the best choice depends on individual needs and discussion with a doctor.

Can The Better Sleep Clinic help if my antidepressant is affecting my sleep?

A: Yes, we can help. While we don't prescribe or manage antidepressant medication directly (that's done by your prescribing physician or psychiatrist), we can:

• Conduct a thorough sleep assessment to understand the nature of your sleep problem (e.g., insomnia, excessive sleepiness).

• Help differentiate between medication side effects and other potential sleep disorders or contributing factors.

• Provide evidence-based, non-drug treatments for insomnia, such as Cognitive Behavioral Therapy for Insomnia (CBT-I), which can be effective even when medication side effects are present.

• Collaborate with your prescribing doctor (with your permission) by providing detailed sleep assessment results to help inform their medication management decisions.

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Written By The Better Sleep Clinic

Reviewed By Dan Ford, Sleep Psychologist