The effect of Cortisol Awakening Response (CAR) on mood
Glucocorticoids (Drug)

Author: Simona Scalabrin
Date: 03/02/2012


Perchè al risveglio sono di cattivo umore?

E’ esperienza comune svegliarsi al mattino abbattuti da emozioni “crepuscolari”: tristezza, svogliatezza, negatività… Insomma di pessimo umore!
Quali sono le basi biochimiche di tale fenomeno?
La chiave di tutto è il cortisolo, il cui picco secretivo avviene proprio di prima mattina, al momento del risveglio.


The cortisol awakening response (CAR) is an increase of about 50% in cortisol levels occurring 20–30 minutes after awakening in the morning in most people.

It is thought to be linked to the hippocampus' preparation of the hypothalamic-pituitary-adrenal axis (HPA) to face anticipated stress.

The average level of cortisol upon waking is roughly 15 nmol/l; 30 minutes later it may be 23 nmol/l, though there are wide variations.
The cortisol awakening response reaches a maximum approximately 30 minutes after awakening though it may still be heightened by 34% an hour after waking.
The pattern of this response to waking is relatively stable for any individual.

Following this, cortisol levels decline throughout the day with lowest levels during the first half of the night.

Cortisol awakening response is larger for those:
- Waking up to a working day compared to work-free weekend day.
- Experiencing chronic stress and worry.
- Overloaded with work.
- In acute stress. People taking part in a competitive ballroom dance tournament had an increased cortisol awakening response on the morning of their competition day but not their non-competition one.

PubMed1 CAR during the course of an exam stress period

PubMed2 Day-to-day differences in cortisol levels

The function of cortisol awakening response has been suggested to link with a stress-related preparation in regard to the upcoming day by the hippocampus.

Short-term stressors and even cyclical daily variations cause elevated cortisol levels that are normal and healthy to provide energy for different activities.


Release of the hormone cortisol is normally tightly regulated. However, when regulation fails and cortisol is hypersecreted, significant emotional changes occur, including depression, raising the question of whether cortisol effects on the brain could be generating depressive symptoms.
Dysregulation leading to cortisol hypersecretion is also observed in depression, where emotion changes compose the core symptoms.
However, cortisol as a causative agent in generating emotional changes in depression has rarely been investigated despite evidence that cortisol impacts emotional states and the neurophysiology of brain regions that process emotion.


 Hypothalamus-Pituitary-Adrenal (HPA) axis dysregulation is often seen in major depression, and is thought to represent a trait vulnerability, rather than merely an illness marker, for depressive disorder and possibly anxiety disorder.
Vulnerability traits associated with stress-related disorders might reflect increased sensitivity for the development of psychopathology through an association with HPA axis activity.

PubMed3 Parental history of depression or anxiety and the cortisol awakening response

PubMed4 Prospective prediction of major depressive disorder from CAR

Cortisol, serotonin and depression: all stressed out?

BJPsych Cortisol, serotonin and depression

The fact that patients with major depression exhibit decreased brain serotonin (5-hydroxytryptamine, 5-HT) function and elevated cortisol secretion has reached the status of textbook truism.

More recent formulations have suggested that elevated cortisol levels, probably caused by stressful life events, may themselves lower brain 5-HT function and this in turn leads to the manifestation of the depressive state.
This elegant proposal neatly ties abnormalities of cortisol secretion and 5-HT function into a causal chain in which cortisol is the key biological mediator through which life stress lowers brain 5-HT function, thereby causing depression in vulnerable individuals.

- People with depression in the community exhibit abnormal brain 5-HT function, although the cause of this abnormality requires further study. Decreased tryptophan availability is one possibility,
- The synthesis of 5-HT in the brain is dependent on the availability of its amino acid precursor tryptophan from plasma.
- Tryptophan competes with branched-chain amino acids (BCAA) for transport across the blood-brain barrier and therefore the ratio of tryptophan to BCAA in plasma is a critical determinant of the availability of tryptophan for brain 5-HT synthesis.
- Patients with depression have been reported to have low plasma levels of tryptophan, and so a lower plasma tryptophan:BCAA ratio.
Why should tryptophan availability be decreased?
- Increased cortisol secretion may play a role by inducing tryptophan 2,3-dioxygenase, the main metabolising enzyme of tryptophan. Elevated cortisol levels could therefore explain lowered plasma tryptophan levels.

Il Flipper e la Nuvola SIDS

Perhaps some subjects may respond to “stress levels” of cortisol by developing depression, but in these cases cortisol hypersecretion must interact with other predisposing factors.
Although tryptophan availability to the brain might be compromised to some extent in any of us who experience life events and difficulties, this might lead to clinical depression only in the presence of other predisposing factors.


I. During the Cortisol Awakening Response, cortisol levels reach a peak.
II. Cortisol is the key biological mediator through which life stress lowers brain 5-HT function.
III. Serotonin is the molecule responsible for our happiness… But during CAR its levels are lower!

Symptoms of low levels of serotonin
• Chronic fatigue: One feels extremely exhausted all the time, and even after sleeping, one doesn't feel refreshed.
• Disturbance in appetite: Usually one loses appetite for eating.
• Loss in sexual interest.
• Feeling of low self-esteem, low self-confidence: Pessimism starts to set in, one starts feeling worthless, overtly critical of one's own life; anger, irritation and even aggression becomes very common.
• Disorganization of mind: The thoughts become disorganized, one loses concentration and attention and the body refuses to be in harmony with the mind.

Oh! In other words, bad mood after awakening is normal, and caused by the lower lever of the “molecule of happiness”, due to CAR.

Obviously, it is not real clinical depression… The bad mood doesn’t last too long, but for half an hour we don’t feel well at all!

Moreover, few studies have examined the association between psychological trait factors and the cortisol awakening response.

PubMed5 Psychological traits and the cortisol awakening response

A very interesting study examined the relationship between multiple psychological trait factors and the cortisol awakening curve, in a sample of persons without psychopathology, hypothesizing that persons scoring high on vulnerability traits demonstrate an elevated cortisol awakening curve.
RESULTS: In adjusted analyses, high scores of hopelessness reactivity were consistently associated with a higher cortisol awakening response.
In addition persons scoring higher on extraversion, control/perfectionism reactivity, and mastery tended to show a slightly flatter CAR.
The CONCLUSION is important: hopelessness reactivity is consistently associated with HPA axis dysregulation. Hopelessness reactivity may represent a predisposing vulnerability for the development of a depressive or anxiety disorder, possibly in part mediated by HPA axis activity.

In conclusione, abbiamo scoperto che il cattivo umore mattutino e la Cortisol Awakening Response sono strettamente collegate: l'effetto chiave del cortisolo sul tono dell'umore si esplica attraverso l'attivazione dell'enzima triptofano-ossigenasi, che comporta una riduzione della quantità di triptofano. Dal momento che il livello di serotonina nel cervello è dipendente dalla quantità di triptofano, il cortisolo riduce drammaticamente i livelli di serotonina, causando cattivo umore.

Buon risveglio!

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