Obstructive Sleep Apnea (OSA) and Depression – Pathophysiology & Management

KEY TERMS IN POLYSOMNOGRAPHY

Apnoea

• Breathing stops for at least ten seconds while sleeping.

Hypopnoea

• Significant reduction in airflow while sleeping (not a complete stop) that causes a drop in blood oxygen saturation and then arousal.
• 50% reduction in airflow with 3% blood oxygen desaturation OR
• 30% reduction in airflow with 4% blood oxygen desaturation

• Combined number of apneas, hypopneas, and RERAs per hour of sleep.
• The Apnea Hypopnea Index (AHI) and oxygen desaturation levels are used to indicate the severity of obstructive sleep apnea. (see later)

Sleep Stages: N1, N2, N3, REM

• The sleep test keeps track of which stage of sleep the patient occupies throughout the night. It will usually report how many times a patient entered a particular sleep stage and how long the patient spent in that stage.
• Humans typically experience around 3 sleep cycles per night of about 90 minutes in which they move through the stages in the given order.
• Adults usually spend about half their time in N2 sleep, about 20% in REM sleep, and about 30% in N1 and N3

N1:

• Lightest stage of sleep and starts when more than 50% of the alpha waves are replaced with low-amplitude mixed-frequency (LAMF) activity

N2:

• Represents deeper sleep as your heart rate and body temperate drop.
• Characterised by the presence of sleep spindles, K-complexes, or both.

N3:

• Deepest stage of sleep
• Characterised by a much slower frequency with high amplitude signals known as delta waves.
• Stage of sleep most difficult to awaken from (for some even with loud noises)

REM:

• This is the stage associated with dreaming. Interestingly, the EEG is similar to an awake individual, but the skeletal muscles are atonic and without movement.

Sleep Efficiency

• The patient’s total sleep time (TST) over the patient’s total time in bed (TIB) Should be over 90%

Oxygen Saturation (SaO2):

A measure of how much oxygen is in the blood, expressed as the percentage of oxygen capacity that is actually found in the blood

• Normal saturation is above or around 95% Between 95% and 90%:
• Mild desaturation Between 89% and 80%
• Moderate desaturation
• Severe Desaturation: Less than 80%: severe desaturation

Normal Sleep Study Result : 

SCORING CRITERIA

Polysomnography showing OSA

Note the green episodes of desaturation. These are respiratory events that will be scored.

HEALTH IMPACT OF OSA

• All-cause mortality – Severe OSA increases the risk of mortality compared to patients without OSA. [Marshall N et al., 2008], [Young T et al., 2008]
• Cardiac disease – OSA has been independently associated with metabolic syndrome and cardiovascular diseases. [Gottlieb DJ et al., 2010], [Redline S et al., 2010]
• Cognitive functioning – OSA causes excessive daytime sleepiness and fatigue, which impairs daily functioning. [Punjabi, 2008], [George, 2007]
• Motor vehicle crashes due to excessive daytime sleepiness.
• Patients with a combination of obesity, polycythemia, hypoventilation, hypersomnolence, and sleep apnoea have high in-hospital mortality from cardiorespiratory failure, pulmonary embolism, and renal failure.
• Patients with OSA have more significant perioperative complications from intubation difficulties and impaired arousal from sedatives.

OBSTRUCTIVE SLEEP APNEA (OSA) AND DEPRESSION

Major Depressive Disorder (MDD) and OSA exist in a bidirectional relationship with a significant overlap between symptoms. In clinical practice, differentiating symptoms such as fatigue, somnolence, poor concentration due to OSA or MDD can be challenging.

MDD has an 18% prevalence of associated OSA while OSA has a 17.6% prevalence of MDD.

People with depression have a higher prevalence of OSA although the pathophysiological relationship is unclear.

OSA shares many symptoms with depression including daytime sleepiness, fatigue, poor concentration, irritability, psychomotor retardation and weight gain. [American Psychiatric Association, 2000]

In a prospective study of 1,408 patients, it was shown that over the course of 4 years there was an odds ratio (OR) of 1.8 for OSA to develop or worsen when in the presence of depression. [Peppard P et al., 2006] This OR means that exposure to depression is associated with a relatively higher odds of outcome (i.e. the outcome is OSA). There have also been several retrospective cross-sectional studies that also support this observation of a relationship between OSA and depression:

• Out of 773 OSA patients studied in the general population, there was an OR of 1.4 for a history of depression. [Smith R et al., 2002] In addition, this study also showed that patients with OSA had an OR of 3.9, 2.6, and 2.5 for developing congestive heart failure, cardiovascular disease, and hypertension. This study highlights the significantly increased comorbid diagnoses in OSA patients.
• In a sleep-clinic, 93 patients exhibited a gender specific relationship between OSA, obesity and depression as measured with the Beck Depression Inventory. [Aloia MS et al., 2005] It was concluded that in men, OSA severity and somatic complaints contributed to depressive symptoms independent of obesity however in women there was a relationship between cognitive symptoms and obesity independent of OSA severity.
• A large study of >210,000 patient records showed that OSA was clinically associated with the prescription of antidepressants or antihypertensives. [Farney RJ et al., 2004] The highest prevalence was observed in patients who were young to middle-aged and were prescribed both antidepressants and antihypertensives.

PATHOPHYSIOLOGY OF DEPRESSION IN OSA

OSA is associated with oxygen desaturation, which causes repetitive periods of hypoxia and sleep fragmentation. New evidence suggests that the pathological mechanisms that underlie the association between OSA and depression involve impairments to several cerebral microvascular and neurovascular systems:

Sleep fragmentation and Hypoxaemia:

• Sleep fragmentation occurs due to recurrent neurophysiological arousals due to apneas and hypopneas
• Intermittent hypoxemia is a consequence of subsequent temporary drops of circulating oxygen, manifested by diminished oxyhemoglobin saturation.
• While both can affect daytime wakefulness, cognitive function, and mood, hypoxemia is postulated to play a more substantial role than sleep fragmentation in influencing depressive symptoms. [Ejaz et al., 2011]
• Even the most seemingly insignificant single component of OSA, snoring, can play a significant part in causing CVD, hypertension, and cerebral infarction due to hypoxic episodes [Jehan S et al., 2017]

Neuronal Injury

• Under normal conditions, cerebral perfusion is maintained even during blood pressure changes. During an apneic episode, however, blood pressure increases then falls rapidly, causing cerebral hypoperfusion. The prefrontal lobes, basal ganglia, and hippocampus are anatomically prone to hypoxic-ischemic damage caused by cerebral hypoperfusion. [Peng W et al., 2014], [Feng J et al., 2012]
• In animal models, hypoxemia is associated with dose-dependent cell loss in the areas rich in noradrenergic and dopaminergic pathways important for sleep/wake and mood regulation. More severe forms of depression, such as melancholic depression, are associated with dopaminergic and noradrenergic dysfunction. [Ejaz et al., 2011]
• Neuroimaging studies show evidence of hippocampus atrophy and white matter changes, particularly in the frontal lobes. [Zimmerman and Aloia, 2006]

Inflammation:

• The repetition of hypoxia and reoxygenation of the blood promotes oxidative stress in endothelial cells, increasing BBB permeability and the risk of cerebral small vessel disease (C-VSD). Furthermore, inflammatory processes at the BBB are associated with a loss of synaptic plasticity and neuronal dysfunction. [Lim and Pack, 2014]
• The activation of oxidative stress can trigger a cascade of inflammation by releasing tumour necrosis factor, interleukin-6 (IL-6) and IL-8 via transcription factor nuclear factor-κB (NF-κB), and activator protein. Interleukin 6 (IL-6) and tumour necrosis factor (TNF) are thought to be responsible for increased daytime sleepiness.
• Obesity associated with OSA is independently associated with a pro-inflammatory state via increased inflammatory mediators IL-6 and TNF-α and reduced adiponectin levels, which has an anti-inflammatory function. [Ellulu et al., 2017]
• This inflammatory cascade may mediate the relationship between OSA, CVD and Depression, all of which have inflammation as a factor in their pathogenesis.
• Insulin resistance may further contribute to the pathophysiology of depressive disorder and is proposed to underlie the association between depression and cardiovascular disease, similar to that with OSA. [Ejaz, 2011]

Read more about depression and cardiovascular disease. 

Endothelial Dysfunction:

• Intracranial blood pressure surges cause damage to the endothelial cells in arteries and arterioles. This damage causes a reduction in the production of nitric oxide—an important vasodilator that helps maintain the hemostatic environment. Therefore, endothelial dysfunction and hypoperfusion contribute to Cerebral small vessel disease (C-VSD), a known risk factor for the development of depression. [de Castro A et al., 2008] , [Direk N et al., 2012]
• Furthermore, this type of depression is known as vascular depression and involves the subcortical areas often presenting with melancholic features. This depression is also associated with greater white matter hyperintensities (WMH’s) and involves dopaminergic and noradrenergic pathways more than other forms of depression.

Antidepressant Resistance

• Interestingly, ischemic damage to the medial and prefrontal cortex is linked to poor response to antidepressant treatment independent of treatment non-adherence, which is also increased in this patient population. Therefore, OSA may contribute to the progression as well as the development of depression. [Harris M et al., 2009], [Waterman L et al., 2015]
• Depression, on the other hand, may exacerbate neuronal injury accompanying OSA and may affect regions controlling affect and cognition. [Cross RL et al., 2008]

The role of serotonin and noradrenaline in the neurobiology of depression and upper airway control in OSA: [Rukhadze & Fenik, 2018]

• Hypoglossal motoneurons innervate upper airway muscles including the genioglossus muscle, the main tongue protruder muscle, which plays the critical role in maintaining upper airway patency.
• The hypoglossal motoneurons have state-dependent activity, which is decreased during the transition from wakefulness to non-rapid eye movement sleep and is further suppressed during rapid eye movement sleep.
• Serotonin influences upper airway dilator motor neurons through the hypoglossal nucleus, further reduced in sleep states. Serotonin has an excitatory effect on hypoglossal motoneurons (excitatory serotonergic 5HT2A receptors are expressed in the hypoglossal nucleus).
• Serotonergic neurons are silent during REM sleep.
• Abnormalities in Serotonin transmission may affect genioglossus muscle activity via the hypoglossal nerve, compromising upper airway patency. [Canessa, 2011]
• Both Noradrenaline and serotonin lead to excitation of orofacial motoneurons including hypoglossal motoneurons, and reduce their activity during NREM (slow-wave) sleep and stop firing during REM sleep. The sleep-related withdrawal of 5-HT and NA aminergic excitation may cause decrements of motoneuronal activity, contributing to sleep-related upper airway hypotonia. [Hakim et al, 2012]
• Thus,  SSRIs and SNRIs may be helpful in the treatment of depression and OSA.

TREATMENT OF DEPRESSION IN OSA

CPAP 

• First-line therapy is continuous positive airway pressure (CPAP), which improves oxygenation and reduces sleep fragmentation. [Epstein L et al., 2009]
• Many randomised and controlled studies have shown that CPAP is associated with improvements in mood disturbances. [Waterman L et al., 2016], [El-Sherbini A et al., 2011], [Gagnadoux F et al., 2014], [Edwards C et al., 2015]
• Therefore, if oxygen supplementation by CPAP is associated with significant reductions in depressive symptoms, then this would suggest that hypoxia plays a vital role in influencing depressive symptoms.
• A more recent study by Canessa found improvement in memory, attention, and executive functions correlated with a grey matter volume increase in the hippocampus and frontal cortex volume in patients with OSA after treatment with CPAP. [Canessa N et al., 2010]

A systematic qualitative review examined all prospective studies in the literature that analysed changes in behavioural performance after CPAP therapy [McMahon J et al., 2003] :

• Improved subjective sleepiness
• Significant improvement in depressive outcomes
• Positive effects on fatigue and vigilance
• Improvements in general health-related quality of life
• Evidence of improved driving performance (i.e. vigilance, attentiveness, and cognition assessments)
• A general increase in perceived well-being. Significant reduction in depressive and cognitive symptoms [Hobzova M et al., 2017]
• Besides core symptoms of depression, patients also showed improvement in other areas, such as a sense of worthlessness, irritability, sadness, pessimism, disgust with themselves, and loss of pleasure. The patients also reported an improvement in partnership and sexual life and better performance in the job. [Iacono et al., 2016]
• Furthermore, early treatment and adherence to therapy are linked with an increased chance of functional and behavioural recovery and minimising residual neurological damage.

Medication:

• Antidepressants are indicated in the treatment of depression with comorbid OSA.
• A recent meta-analysis did not recommend any specific antidepressants in the treatment of OSA only. Mirtazapine and trazodone showed a statistically significant reduction in AHI in the treated groups but not in the sleepiness scale nor increased sleep efficiency. [AbdelFattah et al., 2020]
• Patients with comorbid OSA and depressive disorder were 1.5 times less likely to respond to antidepressant treatment (venlafaxine 300 mg/day) than those with a depressive disorder occurring alone. [Waterman L et al., 2015]
• Both tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants may decrease sleep efficiency in OSA patients. [Smith et al. 2002]
• Simultaneous use of antihypertensive medications and antidepressants increases the likelihood of a diagnosis of obstructive sleep apnea syndrome. [Farney et al. 2004]
• Treatment of comorbid insomnia and anxiety with a benzodiazepine and hypnotic may worsen OSA.
• In OSA patients, the severity of depression correlates with fatigue during the day and sleepiness.

Newer Medication Options:

• Armodafinil and Modafinil are FDA approved and evidence-based in the treatment of OSA. Both also have antidepressant effects and increase orexin levels. Low levels of orexin are found in OSA.
• Solriamfetol, a dopamine/norepinephrine reuptake inhibitor (DNRI), was approved in 2019 and is indicated to improve wakefulness in patients with excessive daytime sleepiness who have OSA. [Schweitzer P. K et al., 2019]
• Recently, a study looking at the combination of Reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. This study highlights the role of noradrenergic and muscarinic pathways on upper airway function. [Lim R et al., 2021]

SUMMARY

OSA is a chronic disorder associated with cardiovascular, metabolic, and neurocognitive diseases.

OSA-mediated episodes of hypoxia and arousal is associated with oxidative stress, inflammatory processes, and endothelial dysfunction, which contribute to the development of vascular depression.

Treatment with CPAP can resolve OSA-related symptoms and confer improvements in depressive symptoms and overall quality of life.

Specific antidepressants are useful in the treatment of comorbid OSA and depression.

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