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Depression and attention-deficit/hyperactivity disorder (ADHD) are two different mental disorders, but they can have similarities. Depression is characterized by a more severe impairment of mood that occurs consistently and regardless of activity or inactivity - especially when doing things that the person actually likes. In contrast, dysphoria during inactivity is a typical ADHD symptom in which mood is only impaired during inactive phases.
A “real” depression is an independent disorder that exists independently (without ADHD) or comorbidly alongside ADHD (usually as a result of ADHD-related permanent overload). Approximately one in three treatment-resistant depressions is due to unrecognized / untreated ADHD. Dysphoria or dysthymia is the term used to describe a long-lasting, chronic mood or depression Dysphoria/dysthymia must be distinguished from moderate or severe depression, which has a considerably more severe level of depressive symptoms but, in contrast to dysthymia/dysphoria, lasts much less as long as dysthymia/dysphoria, but rather occurs in phases lasting weeks to months.
Neurophysiologically, there are similarities between depression and ADHD, particularly in the dopamine system, which can be disrupted in both disorders. In anhedonia, dopaminergic circuits associated with reward and motivation play an important role.
The symptoms of depression include depressed mood, loss of interest, reduced drive, reduced concentration and attention, self-esteem problems, feelings of guilt, negative future prospects, suicidal thoughts, sleep disorders and reduced appetite. Physical symptoms such as stomach problems, headaches and breathing problems can also occur.
The degrees of severity and forms of depression include severe depression, mild chronic depression (dysphoria/dysthymia) and occasion-related depression such as PMS/PMDS, pregnancy depression and seasonal depression in the winter months.
As with ADHD, there are also different subtypes of depression, such as melancholic and atypical depression. Melancholic depression is characterized by an excessive endocrine stress response, while atypical depression is characterized by a flattened endocrine stress response. Around half of severely depressed patients have an elevated cortisol level. Burnout patients have a lower cortisol level.
In melancholic depression, the CRH and vasopressin neurons in the hypothalamus of depressed patients are elevated. MR antagonists are a possible treatment method. In contrast, there is a correlation between hypocortisolism and atypical depression.
Chronic nicotine and alcohol consumption increase the risk of depression, with alcohol consumption also affecting serotonin levels in the brain.
Overall, there are still many unanswered questions and a need for further research into the neurophysiological correlates of anhedonia and depression as well as their diagnosis and differential diagnosis.
1. Depression or ADHD - differential diagnosis and treatment¶
In contrast to dysphoria, depression is associated with a much stronger mood impairment, which, in contrast to the ADHD symptom of dysphoria (only) occurs during periods of inactivity Not only during periods of inactivity, but throughout.
In simple terms, dysphoria is a long-lasting gray (which has existed for years or always existed) that is regularly forgotten during exciting activities and is particularly noticeable on quiet evenings, weekends or during the first (activity-free) days of vacation. Depression, on the other hand, is a deep black that occurs in phases over weeks or months and can hardly be displaced even during or through activity.
Genuine depression is not a symptom of ADHD, but can be the result of permanent overload due to ADHD.
The basal cortisol levels are reduced in ADHD. In contrast, basal cortisol levels are elevated in hospitalized depression (as well as, to a lesser extent, in hospitalized anxiety disorders and obsessive-compulsive disorders).1
Emotional dysregulation, irritability, anger and agitation in ADHD correlate with ADHD-specific genes and not with genes specifically associated with affective disorders (depression).2
People with depression alone also exhibit a clinically relevant level of ADHD symptoms, such as:3
executive dysfunction
reduced cognitive attention performance.
A discriminant function analysis based on self-reported symptoms of MDD, ADHD and executive dysfunction correctly identified all healthy individuals and identified MDD and ADHD sufferers relatively well (85% and 82%, respectively). Comorbid MDD + ADHD was indistinguishable from single MDD or ADHD using the usual self-assessment questionnaires of MDD and ADHD symptoms (0% correct), which improved significantly with the inclusion of executive dysfunction questions (42% correct predictions).3
Almost everyone with ADHD suffers from dysphoric symptoms. Conversely, dysphoria can also be found without ADHD. In this respect, dysphoria is not proof of ADHD, but a constant companion of existing ADHD.
Characteristics of dysphoria
Little energy and drive
Low self-esteem
Low capacity for joy in daily life (anhedonia)
Duration of 2 years and more
1.2. Dysphoria / dysthymia with inactivity as an ADHD symptom¶
The Wender-Utah criteria list the symptom of dysphoria during inactivity as an ADHD symptom. DSM and ICD, however, do not mention this symptom. In our opinion, dysphoria (only) with inactivity is an original phenotypic ADHD symptom and should be distinguished from the disorder of depression or dysphoria.
The stress benefit of dysphoria during inactivity is to keep the person active in the face of an existing life-threatening stressor. Inactivity reduces the likelihood of coping with a life-threatening danger. Emotional mood is a very strong driver of activity. Living beings try to achieve and maintain a positive, pleasant mood and avoid a negative mood.
This explains why the mood only drops in moments of passivity during prolonged severe stress or ADHD. It would not be conducive to the individual’s survival if their mood was also reduced in the phases of actively combating the stressor.
Relaxation, pleasure and recreation are not conducive to survival in times of a relevant threat. This could explain the benefits of the anhedonia associated with dysphoria and depression.
In this respect, dysphoria is a functional stress symptom, whereas the symptoms of full-blown depression are rather dysfunctional, as they no longer contribute to supporting the fight against the stressor.
1.4. Treatment-resistant depression often hides unrecognized ADHD¶
In a study of 160 adults with treatment-resistant depression, 34% were found to have previously undiagnosed ADHD.5 This is consistent with data from other sources.6
Apparently, therapy-resistant depression is often accompanied by an unrecognized ADHD disorder. The overload associated with untreated ADHD can cause (overload) depression. Irrespective of this, a study found that 58% of psychiatric inpatients had ADHD (usually undiagnosed).
There is evidence that ADHD has a causal effect for an increased risk of:7
severe clinical depression
post-traumatic stress disorder
Suicide attempts
Anorexia nervosa
There was no evidence of a causal relationship between ADHD and7
bipolar disorder
Fear
Schizophrenia
1.5. Treatment sequence: Severe depression before ADHD before dysphoria¶
True moderate or severe depression (see below under melancholic / atypical depression) should be prioritized for treatment.
In the case of mild depression in the sense of dysphoria / dysthymia, on the other hand, comorbid ADHD should be treated as a priority, as the elimination of the ADHD-typical overload and ADHD-typical symptoms often reduces the ADHD’s own dysphoria.
According to the reports available to us, amphetamine medication (Elvanse) is usually superior to methylphenidate in the treatment of dysphoric symptoms of ADHD.
Serotonin reuptake inhibitors are generally contraindicated in ADHD-I (without hyperactivity), but may be indicated in ADHD-HI (with hyperactivity).
⇒ Comments on serotonin reuptake inhibitors (SSRIs) for ADHD in the article ⇒ Medication for ADHD - overview
Later depression in children with ADHD was predicted by the intensity of anhedonia in childhood.8 Depression also appears to be significantly gender-specific.
2. Neurophysiological similarities between depression and ADHD¶
Depression is primarily thought to be caused by a disruption of the noradrenaline and serotonin metabolism in the brain.
More and more studies indicate that disorders of the dopamine system (which also exist in ADHD) can also cause symptoms of depression.
In anhedonia, dopaminergic circuitry associated with reward and motivation plays a key role in maintaining hedonic tone, particularly bottom-up and top-down projections into the dopaminergic system of9
PFC
Lateral habenula
Ventral tegmentum.
In depression, ADHD and addictive behavior, the ability to feel pleasure is reduced (“low hedonic tone”).910
Diagnostic manuals (DSM, ICD) do not contain the totality of all symptoms that can occur in a disorder, but only those that distinguish one disorder particularly well from others. Diagnostic manuals are therefore only useful for diagnosing a disorder, but not for treating it.
Mild episode: 2 additional symptoms.
Medium episode: 3 to 4 additional symptoms.
Severe episode: 5 or more additional symptoms.
3.1.2. Depressive somatic syndrome according to ICD 10¶
Loss of interest or pleasure in normally enjoyable activities
Lack of ability to react emotionally to a friendly environment or joyful events
Early morning awakening, two or more hours before the (usual) time
Morning low
The objective finding of psychomotor inhibition or agitation
Significant loss of appetite
Weight loss, often more than 5% of body weight in the past month
Significant loss of libido
Remark:
In the rather rarer atypical depression, persistent daytime tiredness is common instead of early morning awakening and an evening low instead of a morning low. However, this is not taken into account by ICD 10.
End with the onset of menstruation, or decrease in the following week at the latest
At least 1 of the 5 symptoms from subgroup 1:
Significant mood swings (e.g. sudden sadness)
Pronounced irritability or anger or increased interpersonal conflicts
Pronounced depressive state, feeling of hopelessness or thoughts about lack of self-esteem
Significant anxiety, tension or a nervous feeling
At least 2 of the 5 symptoms from subgroup 2:
Reduced interest in everyday activities, possibly leading to social withdrawal
Concentration difficulties
Low energy or tiredness
Significant changes in appetite, overeating or specific cravings
Insomnia (difficulty sleeping through the night) or hypersomnia (sleep addiction)
Feeling of being overwhelmed or losing control
Physical complaints accompanying PMS (e.g. breast tenderness, edema)
3.2. Complete list of possible symptoms of depression¶
The following list includes most of the possible symptoms of depression. The presentation is largely based on Niklewski, Riecke-Niklewski.14 Not everyone with depression has all of the symptoms listed (just as not everyone with ADHD has all of the possible symptoms).
Fear of making mistakes, fear of failure, feelings of guilt, concentration problems and perfectionism exacerbate decision-making problems.
Decision-making problems are a common ADHD symptom and occur more frequently in ADHD-I than in ADHD-HI and ADHD-C.
In our impression, ADHD-I correlates more with melancholic depression, while ADHD-HI (with hyperactivity / impulsivity) correlates more with atypical depression.
Characteristics of psychotic depression
Delusion is an objectively false belief caused by an illness that is not shared by other people. Delusional thoughts usually concern primal fears. In extreme cases, those affected are convinced that the delusional thoughts are true.
Fear for
Salvation (fear of going mad)
Health (fear of incurable diseases)
Life (fear of near death)
Impoverishment (fear of losing everything)
Sin (fear of having sinned)
Guilt (fear of having done unforgivable things)
Self-worth (fear of being completely worthless/void)
12.5 % of the population in New York, 41st parallel
2.6 % of the population in Florida, 28th parallel
4.2. Subtypes of depression: melancholic and atypical depression¶
In addition to the subtypes of melancholic and atypical depression discussed here, there are other subtypes, such as psychotic depression (which could be an extreme form of melancholic depression) or bipolar depression, which is characterized by alternating depressive and manic phases in different rhythms and intensities.
Like ADHD, depression is not rigidly linked to a flattened or excessive endocrine stress response. Just as in ADHD the ADHD-I subtype often shows an excessive endocrine stress response and ADHD-HI and ADHD-C tend to show a flattened endocrine stress response, there are also (at least) two subtypes in depression:15
1. melancholic depression (formerly “endogenous” depression), and even more so psychotic depression,16 which often show an excessive endocrine stress response (including hypercortisolism),17 occurs in 40 to 60 % of adults1819 and
2. atypical or chronic depression, whose HPA axis response often corresponds to a (neutral or) flattened endocrine stress response (e.g. hypocortisolism).202122232425
Around 50 % of all severely depressed patients show an elevated basal daily cortisol level. Around 35 % are non-suppressors in the dexamethasone test.262728
The PVN of the hypothalamus of depressed patients has 4 times as many CRH neurons and 3 times as many vasopressin neurons as that of unaffected patients.30
The HPA axis reacts more slowly to acute stressors and does not switch off properly. Those affected show a faulty shutdown of the HPA axis in the hypothalamus and pituitary gland.31
The HPA axis is shut down by cortisol when enough cortisol is released to occupy the more cortisol-sensitive mineralocorticoid receptors to the point that the 1/10 as sensitive glucocorticoid receptors that trigger HPA axis shutdown are addressed
MR antagonists can improve depressive symptoms induced by the administration of cortisol32 unless the depression is already resistant to treatment.33
We hypothesize that such use of MR antagonists may be indicated in atypical depression (which correlates with a flattened cortisol stress response) and may be less helpful in melancholic (and psychotic) depression (which is characterized by exaggerated cortisol stress responses).
Two thirds of all Cushing’s patients suffer from various psychological problems, half of them from atypical depression. If the existing hypercortisolism was treated, the psychological problems were significantly reduced. However, the atypical depression persisted and even worsened. 34 Atypical depression is more likely to correlate with hypocortisolism than with hypercortisolism, which suggests a worsening of atypical depression when cortisol levels are reduced.
A meta-study shows (in contrast to most other studies) that the cortisol response of depressed patients to an acute psychological stressor does not differ from that of healthy people, but that the recovery-related return to the cortisol level before the stressor is significantly slower in depressed patients. This effect is also all the more pronounced the more severe the depression is.35
The fact that prolonged cortisol stress can trigger depression is confirmed by the increased risk of depression when artificial glucocorticoids are administered.36
Men with elevated cortisol stress responses show a higher correlation of childhood maltreatment and depressive symptoms than men with moderate to lower cortisol responses.37
4.2.1 Melancholic depression (formerly: “endogenous”, “neurotic” or “reactive” depression)¶
In extreme form (severe depressive episode with psychotic features) also42
Feelings of guilt
Impoverishment mania
Hypochondriacal delusion
Further delusions
Due to the often excessive cortisol response to acute stressors in melancholic depression, SSRIs that increase cortisol levels should only be used with caution in this form of depression. ⇒ Notes on serotonin reuptake inhibitors (SSRIs) for ADHD
4.2.1.1. Cortisol stress response in melancholic (internalizing) depression: increased¶
Elevated cortisol levels in the blood,434445 in the cerebrospinal fluid46 (which correlated with urinary cortisol and was reduced by clomipramine47 and which also correlated with elevated CRH levels)48 and in the urine49 (hypercortisolism) were detected early on in depressive patients.
The elevated cortisol levels correlated with
4.2.1.3. Medication for melancholic (internalizing) depression¶
The Handbuch der Psychopharmakotherapie 52 points out that treatment with tricyclic antidepressants (primarily amitryptiline and clomipramine) or SSNRIs (there: duloxetine and venlafaxine) is superior to treatment with SSRIs in severe (melancholic) depression.5354 In contrast, another meta-analysis (which cannot be found on this site) and a further study do not find any advantage of TCAs over SSRIs in severe (melancholic) depression.55
The suboptimal effect of SSRIs was also discussed when the SSRI sertraline was presented, which is said to work better than other SSRIs in severe melancholic depression.56 Ritzmann was also critical of SSRIs for melancholic depression in the Swiss pharmaceutical review.57
Another source, however, mentions activating SSRIs or SNRIs as the drugs of choice for internalizing depression, while externalizing forms of depression are more likely to be treated with sedating antidepressants.58
In melancholic depression, a low probability of response to placebo and psychotherapy is reported59 and a particularly good response to tricyclic antidepressants, lithium augmentation and electroconvulsive therapy.606162 Electroconvulsive therapy in combination with drug treatment showed a particularly good recovery of HPA axis function.63
Drug treatment proved to be clearly superior to behavioral therapy.55
However, the findings to date only stem from small studies and clinical empirical experience. There are hardly any systematic direct comparisons of the various antidepressant classes in patients with different subtypes of depression.5960
4.2.2.1. Cortisol stress response in atypical depression: flattened¶
It was not until long after the discovery of hypercortisolism in many depressive patients that it became apparent that, in addition to the known variant with hypercortisolism (excessive cortisol stress response), there is also a variant with hypocortisolism (reduced cortisol stress response, reduced CRH levels) - the atypical depression described here.386415
Between 15 %65 and 40 % of all depressions are said to be atypical depressions.
Hyperphagic (eating disorder with increased food intake)
Hypersomnic (“sleep addiction”)
Reactive to the environment
Diurnal variation of depression, which is least severe in the morning
Feeling of leaden heaviness in arms and legs (DSM IV)
Rejection Sensitivity (DSM IV)
Due to the flattened cortisol response to acute stressors in atypical depression, SSRIs are the first choice for treating this form of depression. The Depression League recommends SSRIs especially for atypical depression.66 MAOA inhibitors can also be helpful.
Nevertheless, it should be noted that SSRIs increase the number of DAT in the striatum, which could exacerbate ADHD symptoms. ⇒ Notes on serotonin reuptake inhibitors (SSRIs) for ADHD
The existence of depression with a flattened cortisol response does not necessarily argue against the corticosteroid hypothesis of the development of depression explained above. The only difference is that the hypocortisolism present here causes upregulation of the receptors.
One publication presents a flattened cortisol stress response in (melancholic) depression as a consequence of the prolonged chronic existence of depression.67 It is known that prolonged stress causes a downregulation of the stress systems (the autonomic nervous system and the HPA axis).6869 It remains to be seen whether the differences between chronic melancholic depression and atypical depression are only similar in terms of the cortisol stress response. This could indicate that the cortisol stress responses do not play a causal role in the etiology of depression. It should also follow that the cortisol stress response should not play a decisive role in the differentiation of depression subtypes, contrary to the general opinion to date.
4.2.2.2. Medication for atypical (externalizing) depression¶
SSRIs (selective serotonin reuptake inhibitors) and TCAs (tricyclic antidepressants) are said to have a poor effect in atypical depression. Irreversible MAO inhibitors are said to be effective, but these should generally only be taken under a strict diet.70
Seasonal depression or winter depression regularly occurs in the fall/winter and ends in early summer when the days are light again and the sunlight has become strong again.
Seasonal depression was found in 27% of adults with ADHD. Adults with ADHD have a 10-fold risk of developing seasonal depression.7172
We see two pathways for seasonal depression, both of which are well compatible with the increased frequency in ADHD sufferers.
b. In addition, a disruption in melatonin production due to insufficient exposure to light on the corresponding ipRGC cells of the retina of the eye, which are responsible for the perception of the degree of brightness. If these cells are hypersensitive, the diminishing differences in brightness in late fall/winter result in inadequate control of the circadian rhythm. This can be a common cause of seasonal depression.
People affected by seasonal depression showed a deviating function of the ipRGC cells. They reacted with reduced pupil dilation to blue light, but not to red light.7374 This leads to the hypothesis of a reduced sensitivity to blue light, which causes a weaker control of the suprachiasmatic nucleus by means of natural daylight.
69% of adults with ADHD reported an increased visual sensitivity to light, compared to 24% of those not affected. In addition, those with ADHD wore sunglasses more frequently than those without. It is possible that increased visual light sensitivity in ADHD sufferers reflects abnormal retinal development or function.75
There are various hypotheses (or pathways) for depression.
Hypothesis of chronic stress that leads to damage to the HPA axis and the limbic system. GABA and glutamate play a role in this. A new treatment method is the use of glutamate antagonists such as ketamine.
Corticosteroid receptor hypothesis. According to this hypothesis, the hyperfunction of the HPA axis in depression is associated with a disruption of the negative feedback to cortisol and changes in the MR and GR receptors. Early childhood stress and genetic changes can influence the receptors.
CRH receptor hypothesis, according to which a long-lasting high CRH release leads to a downregulation of the CRH receptors and thus the HPA axis remains activated.
Noradrenaline receptor hypothesis, which describes how stress reduces the number of noradrenaline receptors and thereby impairs the negative feedback inhibition of noradrenaline release.
Monoamine hypothesis. This states that a deficit of monoaminergic neurotransmitters or a reduced sensitivity of the receptors in the brain can trigger depression.
The immunological hypothesis shows that various inflammatory markers are altered in depression, which indicates an impaired immune response.
The Kindling hypothesis describes how repeated stimulation of the brain can lead to stronger and faster reactions.
The neurotrophin hypothesis states that glucocorticoids can cause a deficiency of neurotrophic factors and thus trigger damage to nerve cells, particularly in the hippocampus.
The neurodegenerative hypothesis assumes that an imbalance between neuroprotective and neurodegenerative degradation products in the brain leads to morphological changes.
The NRF2 hypothesis states that reduced NRF2 activity is associated with depression and is increased by antidepressant treatment.
Most hypotheses depict a disruption of the HPA axis.
Other causes of depression can be found at Corvell.76
5.1. Hypothesis of depression as a consequence of chronic stress exposure¶
This hypothesis assumes that chronic stress exposure causes prolonged excessive cortisol exposure and excessive ACTH exposure, which then cause damage to the HPA axis and the limbic system. Cortisol has neurotoxic effects on the hippocampus and PFC, which are impaired in depression. Depression sufferers often show an enlarged pituitary gland and hypothalamus. Prolonged cortisol exposure often causes insulin resistance and abdominal fat deposits, which are typical in depression.15
Depression often shows a dysregulation of the HPA axis:77787980
Overproduction of IL-1-beta83 The IL-1-beta values and the cortisol values after the DST correlated in healthy people as well as in depressed people.84 See the immune hypothesis of depression below.
CRH
Increased number of CRH-producing neurons in the hypothalamus85 and frontal brain,86 as a result:
Reduced CRH receptor expression86 in the frontal brain
Individual findings on chronic stress and depression
4 weeks of chronic unpredictable stress triggered depression in some mice but not in others (which were resilient). Expression changes in microRNA and mRNA were measured89
For depressive reactions:
Downregulation of serotonergic/dopaminergic synapses in the nucleus accumbens
Downregulation of the MAPK/calcium signaling pathways in the nucleus accumbens
Downregulation of RNA associated with morphine dependence
Upregulation of the cAMP/PI3K-Akt signaling pathways in the nucleus accumbens
Upregulation of the amino acid metabolism
With a resilient response:
Upregulation of serotonergic/dopaminergic synapses in the nucleus accumbens
Upregulation of the MAPK/calcium signaling pathways in the nucleus accumbens
Downregulation of the chemokine signaling pathway
Downregulation of the synaptic vesicle cycle
Upregulation of RNA associated with nicotine dependence
Upregulation of the calcium signaling pathway
Upregulation of the tyrosine metabolism
Another study in mice found correlations of chronic stress and reduced reward-seeking behavior with:90
In the spleen
Higher levels of granulocytes, inflammatory monocytes and T helper 17 cells
In plasma
Higher levels of inducible nitric oxide synthase
In the liver
Higher expression of genes that encode enzymes of the kynurenine pathway
In the ventral tegmentum
Higher concentrations of kynurenine and the microglia markers Iba1 and Cd11b
Higher binding activity of the DA D1 receptor
In the nucleus accumbens
Higher kynurenine level
Lower dopamine turnover
Lower c-fos expression
Cortisol and CRH can cause the changes typical of depression by a. Changes in the synthesis and release and b. Changes in the receptors of serotonin, noradrenaline and dopamine9192 in limbic and neocortical brain structures can trigger the changes in mood and behavior typical of depression.7891
Chronic stress reduces the GABA level. ⇒GABA and stress GABA is an inhibitory neurotransmitter and interacts with glutamate, an excitatory neurotransmitter. GABA and glutamate inhibit each other. A persistently reduced GABA level thus leads to an excessive glutamate level. Decreased GABA and increased glutamate levels are considered to be a cause of depression.93
While GABA inhibits ACTH release from the HPA axis (by directly addressing the paraventricular nucleus (PVN) in the hypothalamus), glutamate promotes ACTH release via projections from the hypothalamus and brainstem.94
The treatment of depression with glutamate antagonists is a new drug approach to treating depression. In March 2019, the FDA approved the glutamate antagonist ketamine as a nasal spray for the treatment of depression (esketamine) for the first time in the USA. Approval has been applied for in Europe. In Germany, esketamine is currently used off-label as a nasal spray or infusion for the treatment of depression. Intravenous administration takes place on an outpatient basis in a day ward. Experience has been positive.95
The APA’s 2017 dosage recommendation for esketamine is 0.5 mg / kg body weight, two doses per week over 4 to 6 weeks. The effect occurs (unlike with all other known antidepressants) within hours to a few days.
The mechanism of action of ketamine is still unknown. It appears to release growth hormones, which are reduced in depression. It also appears to improve communication between brain regions that are responsible for mood regulation.
In rats, the short-term response involved robust and load-independent topological changes in cognitive, sensory, emotional and reward-related circuits associated with depressive behavior. The medium-term response within 48 hours in depressed rats included normalization of connectivity in the nuclei habenulares, middle thalamus and hippocampus.96
Ketamine modulates the disruption of dopamine-dependent synaptic plasticity in the prefrontal cortex, which mediates the expression of depressive behavior.97
The long-term effects are still unknown. Possible side effects known include an increase in blood pressure, pulse rate, eye pressure and intracranial pressure. While taking the drug, an effect similar to that of light alcohol consumption has been reported. Rarely do positively perceived experiences of dissolution of boundaries, anxiety or panic states, illusions, hallucinations or horror trips occur.95
In an individual case known to us, a woman with melancholic depression showed a clear improvement in the previously existing sleep-through disorder by taking glycine (like GABA, an inhibitory neurotransmitter) in the evening.
5.2. Corticosteroid receptor hypothesis of depression¶
The “corticosteroid receptor hypothesis of depression” states that the HPA axis hyperfunction of melancholic depression is caused by a disturbance of the negative feedback to cortisol (cortisol as the last hormone of the HPA axis has, among other things, the task of switching the HPA axis off again; this function is disturbed), which is associated with a change in the mineralocorticoid (MR) and glucocorticoid (GR) receptors.5098
Prolonged hypercortisolism (too much cortisol) can trigger downregulation of the amount and sensitivity of MR and GR receptors99 or cause a genetic change in the structure or function of the receptors.100
Changes in GR due to early childhood stress
In adult rats that were separated from their mother once for 24 hours at the age of 6, 9 or 12 days, the cortisol feedback mediated by the GR (HP axis deactivation with subsequent cortisol decrease) was deficient and impaired.99 In addition to a simultaneous increase in MR and decrease in GR in the hippocampus, there was also increased activation of the adrenal gland as a result of increased ACTH levels.101 Separation from the mother did not alter the proactive feedback mediated by MR, but caused a more prolonged increase in ACTH levels. Reactive feedback was impaired, as ACTH levels decreased at a slower rate despite increased cortisol levels.102
Experiences of violence by the mother during pregnancy103 or maltreatment in early childhood104 cause increased methylation of promoter regions of the gene for glucocorticoid receptors (GR) and thus a reduced GR density in the hippocampus.105 The hippocampus is responsible for storing information in long-term memory and inhibiting the HPA axis.
One study found no correlation between methylation of the GR gene and the cortisol stress response in trauma, schizophrenia or bipolar patients.106
Similarly, a disruption of the regulation of the chaperones of the glucocorticoid receptor, e.g. via FKBP5, can impair the activation of the GR, the translocation of the activated hormone-receptor complex into the cell nucleus, the transcription of the GR and its recycling in the cell.15
Blockade of MR in the hippocampus by intracerebroventricular administration (but not by administration into the blood) of an MR antagonist increases basal cortisol levels within 60 minutes as well as the cortisol response to acute stressors and maintains it for a longer period of time. Intracerebroventricular administration of GR antagonists slightly reduced the cortisol stress response, but did not shorten it.107 In the CA1 area of the hippocampus, MR regulate the maintenance of excitability, while GR suppress excitability. Blockade of MR increases basal cortisol levels and the cortisol response of the HPA axis to acute stressors.108 MR also regulate salt appetite.
Limbic MR appear to primarily regulate cortisolergic effects on information processing and the organization of behavioral strategies. GR, on the other hand, mediate the effects of cortisol on anxiety, hunger and information storage. Behaviors mediated by GR can persist for weeks in adulthood and be permanent during adolescence. High cortisol levels reduce the number of GRs and increase the number of MRs in the hippocampus. Mineralocorticoids (such as activating aldosterone and deactivating deoxycorticosterone) downregulate both MR and GR.108
If the relative number of MR increases compared to the GR in the limbic system, this has the following effects in animals
The CRH receptor hypothesis assumes that prolonged high CRH release from the hypothalamus leads to downregulation of the CRH receptors of the pituitary gland. This results in a reduced release of ACTH, which causes a reduced release of cortisol in the adrenal cortex, so that the shutdown of the HPA axis actually mediated by cortisol does not occur. Due to the failure to switch off the HPA axis, the release of CRH remains unchecked, which thus proves to be both a cause and a consequence.
Untreated depressives show increased CRH concentrations in the cerebrospinal fluid. Depressives show increased CRH concentrations as well as increased expression of the CRH gene in the PVN of the hypothalamus, in the locus coeruleus and in the PFC.15
5.4. Noradrenaline receptor hypothesis of depression¶
The corticosteroid hypothesis is not the only mechanism that describes changes caused by long-term stress. The various mechanisms are likely to exist alongside each other and, as general stress response mechanisms, also apply to disorders other than depression. One example is the noradrenaline receptor hypothesis of depression, which is described below by Fuchs, Flügge (2004):109
Stress increases the concentration of noradrenaline.
If the noradrenaline level is permanently elevated, the number of alpha2-adrenoceptors in the target regions of the noradrenergic nerve cells is initially reduced (downregulation).
Downregulation occurs presynaptically (at the noradrenergic terminals) and postsynaptically (e.g. at glutamatergic neurons).
Presynaptic downregulation impairs the negative feedback inhibition of noradrenaline release. Therefore, the noradrenergic nerve cells remain permanently activated during stress activation after downregulation of the noradrenaline receptors.
The permanent activation leads to a depletion of the noradrenaline nerve cells, so that the amount of noradrenaline now decreases.
In response to this, the postsynaptic (noradrenergic) alpha2-adrenoceptors can upregulate again.
Uptake-2 transporter involvement could be seen as a further indication of norardenergic involvement in depression.
Antidepressants (tricyclic ADs, noradrenaline reuptake inhibitors, serotonin reuptake inhibitors) take 2 weeks or more to take effect. It has been discussed that uptake-2 transporters (which take up low affinity but high throughput noradrenaline and serotonin) prevent an increase in extracellular noradrenaline to therapeutically relevant levels. Normetanephrine, a norepinephrine metabolite and potent OCT3 blocker, accelerated the extracellular norepinephrine increase in the frontal cortex induced by a NET/SERT blocker and its antidepressant effect. However, other studies could not reproduce this.110
According to the monoamine hypothesis, depression is triggered by a deficit of monoaminergic neurotransmitters or by a reduced sensitivity of the receptors responsible for this in the central nervous system (brain). Many depressive symptoms, e.g. sleep disorders, listlessness or loss of appetite, are caused by malfunctions of monoaminergic neurotransmitter systems.15
Monoamines are, for example, serotonin and noradrenaline, but also dopamine, adrenaline and many others.
5.5.1. Serotonin deficiency hypothesis / noradrenaline deficiency hypothesis of depression¶
In the past, the monoamine hypothesis was primarily related to the monoamines serotonin and noradrenaline.
It is true that the most important antidepressants are serotonin reuptake inhibitors, noradrenaline reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors. Nevertheless, around a third of those affected do not respond to these antidepressants.
5.5.2. Excess serotonin and excess noradrenaline and depression¶
A lack of serotonin or noradrenaline is now considered to be just one of several possible causes of depression
Both increased and decreased noradrenaline levels were found in depressive patients.15
Evidence of both reduced and increased serotonin levels was also found in depressive patients.15
The active ingredient tianeptine acts as a serotonin reuptake promoter, among other things. However, tianeptine has a number of other effects, e.g. it increases dopamine in the nucleus accumbens, so it is unclear which neurophysiological effects mediate the antidepressant effect of tianeptine.
The findings on noradrenaline and serotonin correspond to the different findings on the cortisol stress response and could indicate different phenotypes of depression.
The assumption that depression is directly caused by a monoamine deficiency (e.g. serotonin deficiency) itself is contradicted by the fact that SSRIs raise serotonin levels immediately after ingestion, whereas SSRIs take effect after 2 to 4 weeks at the earliest.
Treatment with monoaminergic medication (e.g. serotonin or noradrenaline reuptake inhibitors) also causes a remission of symptoms in only around 30% of depression sufferers.15 Other sources speak of even lower rates.111 Information according to which antidepressants had no effect on 30% of those affected,112 may also include only a slight improvement in symptoms for the remaining 70%.
Noradrenaline deficiency, dopamine deficiency and serotonin deficiency can trigger a symptom pattern typical of depression. For example, reserpine triggers psychomotor slowness, fatigue and anhedonia through these mechanisms of action, which is why it was initially assumed that reserpine would trigger depression. However, the cognitive symptoms of depression such as hopelessness or feelings of guilt are not induced. It is now known that the symptoms caused by reserpine result from a depletion of monoaminergic salivary vesicles15 due to the resulting lack of noradrenaline (and dopamine), but not due to a lack of serotonin.113 The depression symptoms caused by reserpine can be eliminated by tricyclic antidepressants.114 This is similar to the description of the neurochemical causes of dysthymia.115 The symptoms caused by reserpine are strongly reminiscent of the description of SCT (sluggish cognitive tempo).
Withdrawal of tryptophan, which is essential for serotonin synthesis, can induce a serotonin deficiency. This can cause a relapse in previously depressed patients.15
Major depression, especially in recurrent episodes, shows reduced expression of DAT in the striatum. This could be a consequence of compensatory downregulation due to low dopamine signaling within the mesolimbic pathways.116
Dopamine deficiency in the PFC and striatum is a known neurophysiological correlate of ADHD. In around 1/3 of all treatment-resistant depressions, a previously unidentified ADHD is detected. Such a dopamine deficiency can be caused by genetic causes or stress-related (epigenetic). Various environmental influences alter dopaminergic transmission through epigenetic changes,117 including PAR-4 and DRD-2 expression in the striatum.
Details of PAR-4 and DRD-2 expression in the striatum
The prostate apoptosis response 4 (Par-4) protein is co-expressed with DRD2 in striatal neurons and interacts with DRD2 in neuronal cells. Par-4 normally increases DRD2 signaling and thereby inhibits DRD2-mediated dopamine neurotransmission. A postmortem autopsy study in patients with major depression found a 67% decrease in Par-4 expression in the temporal cortex; knockout of the Par-4 gene resulted in depression-like behavior in mice.118117 A study shows that Par-4 interacts with a specific isoform of the D2 receptor (D2i3). This interaction is essential for Gαio-mediated inhibition of cAMP activity. The region of the D2 receptor that interacts with Par-4 contains a calmodulin-binding domain. Ca2+-activated calmodulin competes with Par-4 for this site. The study demonstrates that Gαio-dependent (and transcription factor CREB-determined) D2 regulation of gene expression depends on the balance between the binding of Par-4 on the one hand and the binding of calmodulin to the D2 receptor on the other. Increases in intracellular Ca2+ concentration, possibly in response to D2 receptor activation, could lead to repression of Par-4 and uncoupling of the D2 receptor from Gαio, thus providing negative feedback on D2-mediated cAMP attenuation.119 Further links to PAR-4 and DRD-2 expression reduction in mild chronic stress are reported by Moriam, Sobhani (2013).117
Various inflammatory markers are often altered in depression.
Depressed people have increased levels of
IL-1β,120 especially in melancholic depression.83 Dexamethasone reduced IL-1β in healthy subjects, not in depressed subjects.83IL-1β levels and cortisol levels after DST correlated in healthy (both low) and depressed (both high) subjects.84 This suggests that a hyperactivated HPA axis or insufficiently reactive glucocorticoid receptors cause increased IL-1β levels. This would link the glucocorticoid hypothesis and the immune hypothesis of depression.
Neopterin121 which correlated with reduced L-tryptophan levels.
Antidepressants have the effect of reducing the production of pro-inflammatory cytokines (such as IFN-α) and increasing the production of anti-inflammatory cytokines.122
Interferon α as a drug against hepatitis C or malignant melanoma triggers severe depression in 40 to 50 % of those affected depending on the dose and fatigue, loss of energy and motor slowdown in up to 80 %.123 Anorexia, fatigue and pain do not occur immediately, but only within 14 days of starting IFN-α treatment. Depressed mood, anxiety and cognitive impairment, on the other hand, occurred later and mainly in patients who met the DSM-IV criteria for major depression.
Changes in the dopamine metabolism of the basal ganglia
Does not respond to antidepressants
Late-onset consequence: depressive syndrome
Depressive symptoms
Activation of neuroendocrine pathways
Altered serotonin metabolism
Responds to antidepressants
5.6.1.2. How IFN-α neurophysiologically triggers depression (kynurenine/glutamate hypothesis of depression)¶
The depressive symptoms mediated by IFN-α (but not the other symptoms) are likely to be mediated by the reduction of tryptophan (TRP) due to its conversion to kynurenine (KYN) by the enzyme indoleamine 2,3-dioxygenase (IDO).125 90% of the degradation of tryptophan occurs via the kynurenine pathway.126
Plasma levels of IFN-α correlate highly with depression characteristics according to the MADRS and fatigue values according to the MFI.127
IDO converts tryptophan to kynurenine, which is converted (by kynurenine aminotransferase) to kynurenic acid and quinolinic acid.128 As a result of the increased breakdown of tryptophan to kynurenine by means of IDO (promoted by IFN-alpha and IFN-gamma) and simultaneous promotion of the conversion of kynurenine to kynurenic acid by means of kynurenine aminotransferase, which is also promoted by IFN-gamma,112 there is further hyperactivation of the glutamate system,129 which may be responsible for the repeatedly observed downregulation of glutamate receptors in depression.112
Tryptophan is a precursor of kynurenic acid (a (glutamate) NMDA receptor antagonist), which is a precursor of quinolinic acid (a (glutamate) NMDA receptor agonist and neurotoxin130, which are in balance with each other in a healthy state
Another metabolite of kynurenine is 3-hydroxykynurenine, which promotes oxidative stress.131
Interestingly, administration of the glutamate antagonist kynurenic acid in the medial PVN reduced the cortisol stress response by 24%, while administration in the dorsal PVN increased the cortisol stress response by 31%.132 However, this response appears to vary from stressor to stressor.133
The antidepressant effect of glutamate antagonists has been known for a long time.134 As such, ketamine,135136 amantadine and cyloserine (less so memantine) in particular have antidepressant effects in humans.112Glutamate antagonists increase the levels of dopamine, noradrenaline and serotonin in the brain.137 The serotonin increase in PFC and hippocampus was higher than with additional citalopram administration.138 IFN-α-induced depression and “naturally” occurring depression show139
Identical symptom severity of
States of anxiety
Depressive mood
Impaired work activity
Deviating in IFN-α-induced depression
Stronger psychomotor deceleration
Higher weight loss
Feeling less guilty
Parameters that make depression more likely after antiviral treatment with interferon are:140
IFN-gamma increases the enzyme kynurenine monoxygenase, which converts kynurenic acid to quinolinic acid.
Quinolinic acid and a high quinolinic acid / kynurenine ratio correlate with112
Individuals with severe depression and early stress experiences responded to psychological stress (TSST) with an elevated IL-6 stress response and increased DNA binding of NF-kB in peripheral blood mononuclear cells.145
Elevated IL-6 levels in adolescents with early stress experiences predicted the development of depression 6 months later.146 Childhood stress experiences appear to promote the formation of a neuroimmune pipeline that enhances inflammatory signaling between the brain and the periphery. Once established, this pipeline leads to a coupling of depression and inflammation that can later lead to affective difficulties and biomedical complications.
5.6.3. Stress causes depression with correlating increased inflammation levels¶
Stress triggers depressive behavior in mice. This correlates with increased levels of
IL-1β
TNF-α
IL-6
Reactive microglia in the hippocampus
TLR4p38 receptors in the hippocampus
P2X7 receptors in the hippocampus
Corticosterone in the blood
The glutamate antagonist ketamine reduces these values.147
Individuals with severe depression and early stress experiences respond to psychological stress (TSST) with an elevated IL-6 stress response and increased DNA binding of NFkB in peripheral blood mononuclear cells.145
Kindling is the term for a continuous increase in neuronal responses to rather rare and weak stimulation of brain areas due to learning processes in the context of neuronal plasticity. The mechanism is associated with the immune system’s ability to learn, which reacts faster and more strongly upon renewed contact with an antigen after the initial formation of reactions to it.148
The same patterns should be seen in the release of IL-6, which is released faster and more strongly if the IL-6 response has already been established prenatally (e.g. due to maternal stress during pregnancy).148 This model can be transferred to other cytokines.149
This picture could also explain the two-hit model, according to which existing early childhood stress can lead to a renewed stress (primarily in adolescence) resulting in a more intense inflammatory reaction, which in turn can trigger a disruption of dopaminergic, serotonergic, noradrenergic and glutamatergic neurotransmission.150 The immune response is therefore increased in old age.151 Moderate and severe maltreatment in childhood correlates positively with the overall change in the stress response of the cytokine IL-6 as well as the maximum IL-6 concentration during TSST.152
The Kindling hypothesis has been proven for epilepsy in animal models. Epilepsy could initially be induced by electrical stimulation; the readiness to have a seizure then increased on its own until the full-blown epileptic seizure occurred. There is no proof of this in humans, but there are indications.
It is being discussed whether this mechanism could also be responsible for affective disorders (depression, bipolar disorder, mania).
According to the neurotrophin hypothesis, glucocorticoids cause a deficiency of neurotrophic factors
(primarily BDNF), which leads to damage to nerve cells (especially in the hippocampus).
Short-term damage can be remedied by antidepressants. Untreated depression can cause long-lasting damage resulting in irreversible hippocampal atrophy.129
An imbalance between neuroprotective and neurodegenerative degradation products of tryptophan metabolism (TRYCATs) can cause morphological effects in brain regions involved in affective disorders.129
A meta-analysis of 84 studies found that NRF2 appears to be decreased in depression and that NRF2 is increased by antidepressant treatment (medication or other methods). Antioxidant systems and plasticity-promoting molecules, such as those in the Nrf2-HO-1, BDNF-TrkB, and cyclic AMP-CREB signaling pathways, may protect against depression, while glycogen synthase kinase-3β and nuclear factor κB counteract these actions, increasing depression-like behaviors. Since Nrf2 also has tumorigenic and atherogenic potential, the balance between benefit and harm will need to be considered when developing new drugs aimed at increasing intracellular Nrf2 levels.153
5.11. Chronic nicotine consumption increases the risk of depression¶
Nicotine dependence increases the risk of depression.154
Depressed smokers who consumed lower-nicotine cigarettes for 6 weeks155 or who gave up smoking showed reduced symptoms of depression.156
In mice exposed to chronic mild stress, a single dose of nicotine alleviated stress-induced depression symptoms and memory difficulties. This effect appears to be due to an antagonistic effect of nicotine on the CB1 and CB2 cannabinoid receptors.157 A distinction must therefore be made between single and chronic nicotine consumption.158
5.12. Chronic alcohol consumption increases the risk of depression¶
Meta-analyses show a high correlation between alcohol dependence and depression. They indicate a causal causation of depression by alcohol, rather than a reverse causality.159 Depression caused by (chronic) alcohol consumption disappears after cessation of alcohol consumption.160
Short-term alcohol consumption increases the serotonin level, while chronic alcohol consumption reduces the serotonin level in the cerebrospinal fluid. Alcohol addresses the serotonin receptors 5-HT3, 5-HT1B and 5-HT1A as well as the serotonin transporter.161
Alcohol also increases the dopamine level in the brain by moderating the dopamine level through serotonin. Serotonin thus forms a kind of lever for the dopamine level in the dorsal striatum, the brain’s reward center.161
Alcoholics of the more common type A / type 1 (types according to Cloninger, 1987) have a later onset, alcoholism is more likely to be environmentally induced, novelty seeking is lower and there are more frequent dopaminergic deficits. They tend to use alcohol for its anxiolytic effects. Alcoholics of the rarer type B / type 2 have an earlier onset, the alcoholism is more often hereditary, the addiction problems are greater, novelty seeking is higher, more men are affected and there are more serotonergic problems.161162
SSRIs and other antidepressants are successfully used to treat alcohol dependence.161
In rats, chronic stress that triggered depressive reactions increased alcohol consumption. Guanfacine, which is also used as an ADHD medication, reduced the stress-induced depressive effect and the likelihood of alcohol relapse.163
6. Neurophysiological correlates of depression symptoms¶
7 to 8 days of immobilization stress (3 to 4 hours/day) reduced the strength of excitatory synapses at D1-MSNs but not at D2-MSNs of the nucleus accumbens core in mice.168 This may indicate that a D1-MSN-specific change in excitatory transmission is responsible for the induction of anhedonia.169
Especially subgenual ACC, which processes negative affects173
ACC is reduced, with increased metabolic activity171
In the rostral ACC, weaker activation for positive information and stronger activation for negative information174
In the dorsal ACC weaker activation by musical stimuli, stronger activation by non-musical stimuli in depressives. Greatest response to negative non-musical stimuli.174
Different: notorious underactivation of the ACC in depression175; we have not yet been able to find any evidence for this
Greater functional connectivity between sgACC and amygdala
Reduced functional connectivity between sgACC and PFC
Increased functional connectivity between dACC and insula during affective processing
Imbalance between D1 and D2 receptor activity
Mice respond differently to chronic social defense stress (CSDS): resilient or depression-prone. In depression-prone mice, the frequency of excitatory synaptic inputs is decreased in D1 MSNs and increased in D2 MSNs.176 Animals resilient to CSDS show an increase in synaptic strength at the large mushroom spines of D1-MSNs and a concomitant decrease in synaptic strength at those of D2-MSNs. However, in one study, susceptible mice showed no significant change in synaptic strength at D1 MSNs or D2 MSNs.177
An increase in β-catenin signaling in D2-MSNs increases in resilient mice
A decrease in β-catenin signaling in animals prone to depression
7 to 9 weeks of chronic unpredictable mild stress (CUMS), such as that used as a model of depression in animals, was treatable with the dopamine D2 agonist pramipexole (SND-919).179
In depression, several hypothalamic-pituitary axes are affected.180
HPA axis
Hypothalamus:
CRH (corticotropin-releasing hormone).
Pituitary gland:
ACTH (corticotropin)
MSH (melanotropin, produced during ACTH synthesis from POMC)
Adrenal cortex:
Glucocorticoids (e.g. cortisol)
Mineralocorticoids
Sex hormones (e.g. DHEA)
Skin:
Melanin
Hypothalamic-pituitary-thyroid axis (HHT axis)
Hypothalamus:
TRH (thyrotropin-releasing hormone)
Pituitary gland:
Thyr(e)otropine (TSH)
Thyroid gland:
Thyroxine
Depression is associated with reduced triiodothyroxine (T3) levels in around 6% of those affected, which is treated with augmentative (= concomitant) T3 administration.181
Hypothalamic-pituitary-liver axis (HHS axis)
Hypothalamus:
GHRH (growth hormone releasing hormone)
Pituitary gland:
STH (somatotropin)
GH (Growth Hormone)
Liver:
IGF-1
Elevated CRH levels contribute to the inhibition of the HHS axis.15 GHRH promotes deep sleep. However, since atypical depression, which is characterized by a greatly increased need for sleep, is more likely to involve underactivation of the HPA axis and thus the hypothalamus, and melancholic depression, which is characterized by deep sleep disorders, usually involves overactivation of the HPA axis and thus the hypothalamus, the connection to GHRH is not directly comprehensible.
The specialist literature nevertheless suspects an imbalance between the HHS and HHG axis.182
Hypothalamic-pituitary-gonadal axis (HHG axis)
The HHG system is likely to play a role primarily in pregnancy and maternity depression
Pituitary gland:
FSH (follicle stimulating hormone)
LH (luteinizing hormone)
Testicles / ovary:
Sex hormones
Ovulation
Spermatogenesis
Elevated CRH levels contribute to the inhibition of the HHG axis.15
In this article, only the connection between the HPA axis and depression is described further.
7.2. Depression symptoms and cortisol diurnal rhythm¶
In melancholic depression, the symptoms of depression are strongest in the morning,383941 in contrast to atypical depression, where they are weakest in the morning and tend to be stronger in the evening.38
We suspect that the symptoms of depression in melancholic depression are strongest when daytime cortisol levels are highest, i.e. in the morning and in the morning, whereas in atypical depression they are worst when daytime cortisol levels are lowest, i.e. in the afternoon until the first half of the night.
It is also noticeable that the sleep problems typical of melancholic depression in the second half of the night coincide with the typical rise in cortisol levels. Sleep is also disturbed in the case of adrenal hyperfunction, where too much cortisol is produced.
Atypical depression is equally characterized by a flattened cortisol stress response and an overall increased need for sleep - a connection that is also known to exist in the case of adrenal insufficiency.
Unfortunately, most studies on the cortisol response in depression do not distinguish between the subtypes of melancholic (usually excessive endocrine stress response) and atypical (often flattened endocrine stress response) depression, which is why the results should be viewed with caution.
For example, DSM IV does not differentiate the criteria for melancholic and atypical depression.
Surprisingly, a number of studies have shown that women are more likely to suffer from atypical depression.65183
This is not consistent with experience from the field of ADHD research, according to which women more frequently show an internalizing stress response, which is usually accompanied by an excessive cortisol response to acute stressors. Atypical depression, however, often correlates with a flattened cortisol response to acute stressors.
Around half of all depressed adults have an excessive cortisol stress response.184
Children and adolescents with depression, on the other hand, hardly have an excessive cortisol response, consequently react inconspicuously to the dexamethasone/CRH test185184 and do not respond at all to tricyclic antidepressants.186184187
This is consistent with the experience presented below that tricyclic antidepressants are superior in melancholic depression if melancholic (endogenous) depression is understood to be characterized by an excessive cortisol stress response.
Individual studies on cortisol in depression:
115 adolescents (aged 9-16) with depressive symptoms were given the Socially Evaluated Cold Pressor Test (SE-CPT) in the afternoon.
Among those with stress-induced elevated cortisol levels, only in boys did the level of depressive symptoms correlate with the intensity of the cortisol elevation, but not with elevated baseline cortisol or recovery cortisol levels.
Among those without stress-induced cortisol elevation, the level of depression symptoms correlated with an overall elevated cortisol level in both boys and girls.
The authors conclude that depression symptoms are associated with prolonged activation of the HPA axis and that recovery from psychosocial stressors is impaired, especially in boys. (The latter may find a correspondence in the fact that the sex ratio of boys to girls in ADHD is 1.6 to 1 and boys are more frequently diagnosed with hyperactive subtypes of ADHD, which (unlike ADHD-I) are associated with an inability to recover) .
The impaired recovery from psychosocial stressors in boys could be caused by a shift in input from excitatory input to greater inhibitory input or by a greater amount of cortisol being required to activate the feedback inhibitory system of the HPA axis.188
A meta-analysis of 1129 acutely severely depressed adults showed an increased cortisol response to acute stress in men, but a reduced cortisol response in women. The changes largely disappeared in women and completely disappeared in men when the disorder subsided.189
The result is unexpected for us, as women are more likely to develop internalizing disorders than men. We would therefore have expected to see men with a reduced cortisol response on average and women with an increased cortisol response on average. However, the study does not differentiate between melancholic and atypical depression
Furthermore, the difference in depression could result more from the duration of the depression. As described above, the cortisol stress response may be increased in newly occurring depression and the cortisol stress response may be flattened in chronic long-term depression (collapse of the cortisolergic system).
Depression without traumatic childhood experiences correlates with an increased cortisol response to stress.190
30 severely depressed adults showed a higher and more persistent cortisol response to the TSST than unaffected adults. The combination of early childhood stress experience and high chronic stress during adolescence was the strongest predictor of increased cortisol release on the TSST.191; n = 55))
A study of 406 women aged 50 on average found a reduction in (non-stress-induced) basal cortisol levels throughout the day as symptoms of depression increased.192
Elevated morning cortisol levels at age 13 predicted an increased rate of depression at age 16.193
Depression or depressive personality traits194195196 correlated with increased morning (CAR) or serum cortisol levels.
The cortisol response to a combined dexamethasone/CRH test was significantly increased in depression.197
Age and severity of depression influenced the release of cortisol.198
When age and severity of depression were taken into account, the dexamethasone/CRH test achieved a sensitivity of more than 90% for recurrent depressive disorders199
7.3.3. Cortisol stress response in asthma modulated by depressed mood¶
Asthmatics often show a reduced cortisol stress response. Cortisol inhibits inflammation and switches the immune system to fighting external disruptive factors. Allergies are a common consequence of too much cortisol. Interestingly, the generally flattened cortisol stress response of asthmatics seems to change to a clearly noticeable cortisol response with increasing depressive mood.200
7.4. Studies on other stress hormones in depression¶
Most studies on other stress hormones in depression also do not distinguish between the basic types of melancholic (internalizing) and atypical (externalizing) depression. Therefore, these results should also be viewed with caution.
Other stress hormones in depression:
Adult women who were sexually abused or physically maltreated in childhood showed an increased ACTH response to an acute psychosocial stressor.201
If the abused women were also suffering from current depression, the ACTH response to an acute psychosocial stressor was further increased; the cortisolresponse and the heart rate response were also increased.201
Women with previous trauma without current depression also showed an excessive ACTH response to drug-induced CRH stimulation of the pituitary gland.202
In contrast, early maltreated women with current depression showed a reduced ACTH response to drug-induced CRH stimulation of the pituitary gland. This indicates underactive CRH receptors in the pituitary gland.202
Early maltreated women with depression and without current depression showed a greatly reduced cortisolresponse to drug ACTH stimulation of the adrenal cortex, as did non-maltreated women with depression.202
Early maltreated men with and without depression showed an increased ACTHand cortisolresponse to the dexamethasone test. This suggests an excessive sensitivity of the HPA axis and a disturbed feedback inhibition of the HPA axis.203 In contrast, depressed men without early maltreatment did not show an increased ACTH and cortisol response.
In acutely depressed men with early childhood stress experience and a comparison group of unaffected men, it was not the depression, but only the description of the early childhood stress intensity that correlated with the increase in basalCRH values in the cerebrospinal fluid.204
An increase in testosterone levels can (to a small extent) help to alleviate depression. This also applies to patients with a normal testosterone level.205 In people with increased aggression, it should be borne in mind that aggression is associated with an increased testosterone-cortisol ratio. ⇒ The neurophysiological correlates of aggression
ADxS.org offers an online depression test for differential diagnosis. This takes a good 10 minutes. It serves to provide initial indications to differentiate a possible depression from a possible ADHD disorder.
Dysphoria during inactivity is an original symptom of ADHD. If dysphoria does not occur during activity or if dysphoria is strongly interest-driven, these are clear signs against depression and for ADHD. If, on the other hand, the dysphoria is independent of the activity and the interest in the activity and is present throughout, we believe this is more likely to indicate depression. This does not refer to the mood-enhancing effect of exercise, which occurs regardless of the disorder.
n = possible side effect of disorder-specific medication
Around 50 % of all severely depressed patients show an elevated basal daily cortisol level (overactive HPA axis). Around 35 % are non-suppressors in the dexamethasone test.262728
