Key words
yawning - depression - vigilance - sleepiness - antidepressants
Introduction
Yawning is an involuntary behavior, common in many species [1]. Several explanations for spontaneous yawning have been suggested, but debate about
biological functions continues [1]. In line with subjective experience, electroencephalography (EEG) and behavioral
studies provide convincing evidence that yawning preferentially occurs during states
of increased sleepiness [2]
[3].
Typical Depression: Exhaustion Rather than Sleepiness
Typical Depression: Exhaustion Rather than Sleepiness
Tiredness and feelings of fatigue or weariness are typically reported in MD. However,
whether unmedicated patients with MD experience more yawning than healthy controls
is unknown (see below). In contrast, personal experience with patients suffering from
MD even suggests a reduction of yawning in MD; a speculative hypothesis which awaits
further investigation in future studies. This points to the problem that terms, such
as tiredness and fatigue, are used for 2 completely different states: (i) tiredness/fatigue
in the sense of sleepiness, i. e., increased tendency to get drowsy or fall asleep
and (ii) tiredness/fatigue in the sense of exhaustion with a tonically high inner
tension and physiological arousal [4]. It is the latter syndrome which is typically found in patients with unipolar depression.
These patients have long sleep onset latencies [5]
[6]
[7], difficulties relaxing and often show signs of higher noradrenergic and hypothalamic-pituitary-adrenal
activity [8]
[9]. Tonically high EEG-assessed CNS-arousal is a replicated finding in unmedicated
patients with MD [10]
[11]
[12]. According to the recently proposed vigilance regulation model of affective disorders,
the withdrawal and sensation avoidance in depression is interpreted as an autoregulatory
reaction to this tonically increased CNS arousal [13].
Review on Yawning in Depression: Only Reported under Antidepressants
Review on Yawning in Depression: Only Reported under Antidepressants
A Pubmed Medline search entering yawning and depression as search terms, complemented
by a search of the respective reference lists, was performed. No studies comparing
yawning in unmedicated patients to that in healthy controls were identified. Concerning
associations with depression scores in normal populations, one small, unpublished
study [14] (N=31) associated scores from a yawning questionnaire with a self-rated depression
scale in a sample of friends and colleagues. However, as this study did not control
for major confounders such as age, sex, pathological sleepiness and drugs, these findings
remain somewhat ambiguous. For example, as in this particular study age was negatively
correlated with yawning and with depression, the reported positive association between
yawning and depression might be artificial. Furthermore, as will be discussed below,
antidepressants can cause yawning, which could have resulted in an artificial positive
correlation between yawning and depression.
The only studies the Medline search identified were those on depressed patients treated
with antidepressants. These were several case reports [15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29] and 2 clinical trials [30]
[31], in which yawning was reported as a side effect of antidepressants. Concerning the
clinical trials, yawning was assessed by means of side effect scales, not to assess
the frequency of spontaneously occurring yawning. Therefore, it is not surprising
that the vast majority of patients did not report any yawning before or during treatment.
Nonetheless, these clinical studies give evidence for increased occurrence of yawning
under antidepressants, especially the study by Nierenberg et al. [30] which included a placebo control and found that while no patient under placebo reported
yawning, 6 patients reported yawning under escitalopram (2.2%) and 15 (5.5%) under
duloxetine [30]. The same picture emerges in the randomized clinical trials, which are reviewed
in the Physicians’ Desk Reference [32] and which assessed yawning as side effect: Under paroxetine 4–5% of patients with
MD reported yawning, whereas 0% under placebo [32 (p. 1495, 1507, 2424)]. Depending
on dose, yawning was also reported in 1–4% of patients with MD taking desvenlafaxine
compared to <1% under placebo [32 (p. 3413)]. The case reports also suggested yawning
as a side effect of antidepressants, which occurred a few days to weeks after treatment
initiation and disappeared after dose reduction or withdrawal. In detail, yawning
has been associated with fluoxetine [15]
[19]
[26]
[27]
[28], paroxetine [16]
[23]
[28], sertraline [15]
[28], (es)citalopram [15]
[22]
[29], duloxetine [20], venlafaxine [18], Hypericum perforatum [16], imipramine [21] and clomipramine [16]
[17]
[25]. As experimental studies suggest a role of different neurotransmitters in yawning,
including serotonin and dopamine [33], this side effect may be caused by modulation of monoaminergic transmitter systems.
Most case reports did not report an association between yawning and drowsiness. However,
drowsiness or sleepiness was not systematically assessed. Thus, the increased yawning
might additionally also reflect the drug-induced decrease of arousal.
Sleepiness as Side Effect of Antidepressants
Sleepiness as Side Effect of Antidepressants
Drowsiness and somnolence are known frequent side effects of all common antidepressants
[34]
[35]
[36]
[37]. Indeed, most antidepressants, including those which are commonly labeled as “activating”
drugs, reduce the firing rate of neurons in the noradrenergic locus coeruleus (LC),
with LC activity playing a pivotal role in arousal. Preclinical studies found this
reduction for acute and for 2-week applications, applying different serotonin-, norepinephrine-,
serotonin-norepinephrine and norepinephrine-dopamine reuptake inhibitors, tricyclic
antidepressants and MAO inhibitors [38]. As also electroconvulsive therapy reduces the firing rate of neurons in the LC,
it was suggested that this reduction might be a common pathway of antidepressant action
[39]. According to the vigilance regulation model of affective disorders [13], this effect could normalize the tonically high CNS arousal found in patients with
MD.
Reports of Yawning in an Online Depression Forum
Reports of Yawning in an Online Depression Forum
As a first step to obtain more information about yawning in depression, we analyzed
all postings of users of an online discussion forum (www.diskussionsforum-depression.de)
for depressed patients, in which yawning was mentioned. The database of the online
forum contains about 450 000 postings written by 24 000 people during the last 11
years. This database was searched for the keyword “gähn*” (=“yawn*”) using the phpMyAdmin
tool (http://www.phpmyadmin.net/). The resulting selection of 373 postings was then
examined individually in order to remove mentions of yawning that were only metaphorical,
duplicates within one post, or not related to the posters themselves (such as “copy-paste”
citations of other posts). This resulted in 66 people writing about yawning and comprising
120 postings (0.027% of the content). 63 subjects reported increased yawning, where
all but one were treated with antidepressants. The only subject who reported yawning
without drug treatment was a woman with “anxiety, burnout and depression” in a posting
about “lack of energy”. Most of the treated subjects (56 of 62) reported their yawning
to occur during antidepressant treatment. Notably, from the remaining 6 participants
who did not attribute yawning to drug therapy but rather to their depressive symptomatology,
5 reported symptoms, which suggest atypical depression, a condition associated with
sleepiness and hypoarousal rather than hyperarousal [see 13]. These 5 patients reported symptoms which seem to fit well the diagnostic features
of atypical depression: hypersomnia (“permanently yawning, dead tired, can only go
to bed and then fall asleep immediately”, “I need about 9–10 h of sleep… I have no
problems sleeping so long…only concerned about [daytime] tiredness and exhaustion…
no energy… yawning due to lack of energy…”), hyperphagia (“eating from 5–7 bars of
chocolate…sugar addiction [patient reported no further chocolate consumption since
mood had improved]”) and leaden paralysis (“tired legs”, “body feels paralyzed, like
a stone”). Only 3 subjects reported a reduction of yawning which was accompanied with
increased wakefulness; 2 of the subjects during acute withdrawal of antidepressants,
and the third when starting with sulpiride treatment. Of the subjects reporting yawning
71% took a SSRI and 19% a SNRI. For further examination, 12 participants were excluded
who took more than one psychotropic drug or who did not specify their medication.
The remaining 51 patients, who reported yawning during monotherapy, comprised 29 patients
taking citalopram or escitalopram (57%), currently the most often prescribed antidepressant
in Germany [40]. The other compounds were venlafaxine (8 patients), sertraline (5 patients), fluoxetine
(3 patients), fluvoxamine, duloxetine and mirtazapine (each with 2 reports). With
exception of the latter, for all the mentioned SSRI and SNRI yawning is reported as
frequent side effect in the package inserts. From the 51 persons under monotherapy,
21 quantified their yawning as permanently, 5 as frequently; and most of the subjects
described yawning as an adverse reaction starting during the first weeks of medication.
Conclusion
In conclusion, yawning was hardly ever reported by unmedicated participants of an online depression forum. This is in line with the assumption of
a tonic hyperarousal in typical unipolar depression [13]. In contrast, yawning was spontaneously reported and recognized as an adverse reaction
by the forum’s patients taking antidepressants. Clinicians should be aware of this
possible side effect of antidepressants and that it might reflect the desired effect
of arousal-reduction in treatment of MD. It is a limitation that yawning variability
was not systematically assessed in the online forum. One can assume that only clearly
increased and bothersome yawning will spontaneously be reported in an online forum.
Therefore, a possible reduction in yawning and also a tolerable increase might only
be detected in studies systematically assessing yawning in MD and matched controls.
Whether yawning could be used clinically for the (differential) diagnosis of depression
or for the prediction of treatment outcome to antidepressants remains also to be addressed
in future clinical studies.
Acknowledgements
This study was conducted in cooperation with the Depression Research Centre of the
German Depression Foundation and with support from the Deutsche Bahn Stiftung.
