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Depression and dysphoria in ADHD

Depression and dysphoria in ADHD

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

Depression and ADHD are differentiated by:3

  • cognitive flexibility
  • Initiation
  • Inhibition
  • Metacognition

While ADHD is characterized in particular by problems with cognitive control, depression is characterized by a low desire for reward.4

1.1. Dysphoria

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.

1.3. Dysphoria as a stress symptom

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

1.6. Depression in children with ADHD

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

2.1. Dopamine for depression

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.

More on this at Depression as a dopaminergic disorder

2.2. Low hedonic tone in ADHD and 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

3. Symptoms of depression

3.1. Diagnostic manuals for depression

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.

3.1.1. Depression according to ICD 10

The presentation of symptoms for the diagnosis of depression according to ICD-10 is taken from the S-3 guidelines 2015.11 Main symptoms
  • Depressive, depressed mood
  • Loss of interest and joylessness
  • Reduced drive with increased fatigue (often even after minor exertion) and restricted activity

At least two of these must last at least two weeks. Additional symptoms
  • Reduced concentration and attention
  • Reduced self-esteem and self-confidence
  • Feelings of guilt and worthlessness
  • Negative and pessimistic future prospects
  • Suicidal thoughts, self-harm or suicidal acts
  • Sleep disorders
  • Reduced appetite

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

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.

3.1.3. Major depression according to DSM 5

Within 2 weeks, 5 or more of the following symptoms must occur almost every day.
One of these must be depressed mood or loss of interest or joy.12

  • Depressed mood almost the whole day
  • Significantly reduced interest or enjoyment in all or almost all activities for most of the day
  • Significant (> 5 %) weight gain or loss or reduced or increased appetite
  • Insomnia (difficulty falling asleep or sleeping through the night) or hypersomnia (sleep addiction)
  • Psychomotor agitation or retardation observed by others (not self-reported)
  • Tiredness or listlessness
  • Feelings of worthlessness or excessive or inappropriate guilt
  • Reduced ability to think or concentrate or indecision
  • Recurrent thoughts of death or suicide, attempted suicide or a specific plan to commit suicide

3.1.4. Persistent depressive disorder (dysphoria, dysthymia) according to DSM 5

For 2 years or more, there is a risk of death for most of the day for several days

  • Depressive mood

as well as at least 2 of the following symptoms:

  • Poor appetite or overeating
  • Insomnia (difficulty falling asleep or sleeping through the night) or hypersomnia (sleep addiction)
  • Low energy or tiredness
  • Low self-confidence
  • Difficulty concentrating or making decisions
  • Feelings of hopelessness

3.1.5. Premenstrual dysphoric disorder (PMS, PMDS, BMDD) Illustration according to Coryell

At least 5 of the following symptoms12

  • Occur in the week before menstruation and
  • Subside within a few days after the onset of menstruation and
  • Disappear completely or almost completely in the week after menstruation

At least 1 of the 5 symptoms from subgroup 1:

  • Significant mood swings (e.g. suddenly sad or tearful)
  • Pronounced irritability or anger or increased interpersonal conflicts
  • Pronounced depressive mood, hopelessness or lack of self-esteem
  • Significant anxiety, tension or a nervous feeling

At least 2 of the 5 symptoms from subgroup 2:

  • Reduced interest in usual activities
  • Concentration difficulties
  • Low energy or tiredness
  • Significant change in appetite, overeating or specific cravings
  • Insomnia (difficulty falling asleep or sleeping through the night) or hypersomnia (sleep addiction)
  • Feeling of being overwhelmed or losing control
  • Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a feeling of bloating and weight gain

The probability of PMDS increases before the menopause. Illustration according to Pinkerton

At least 5 of the following symptoms13

  • Start 7 to 10 days before menstruation
  • 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).

3.2.1. Depressive perception

  • Longer lasting
    • Weeks, months, years
    • Not only short-term negative affects such as
      • Anger
      • Trouble
  • See black
  • Depressed or depressed mood with daily rhythm
    • Low mood in the morning after getting up
      • Melancholic / psychotic depression
      • Standard case
      • Often excessive cortisol stress response
    • Low mood in the first half of the night
      • Atypical depression
      • Rarer
      • Frequently flattened cortisol stress response
  • Differences between feelings reduced
  • Frequent unprovoked crying
  • Feeling of futility

3.2.2. Tiredness and sleep problems

  • Atypical depression:
    • Constant daytime tiredness
  • Melancholic / psychotic depression:
    • Short sleep
    • Awakening in the 2nd half of the night (with the onset of the rise in basal cortisol levels)

Sleep problems are also increased with ADHD.

For the risk of an increase in sleep problems due to various antidepressants, see Sleep-disrupting effect of medication In the article Sleep problems with ADHD in the section Non-drug treatment and therapy of ADHD in the chapter Treatment and therapy.

3.2.3. Self-esteem problems

  • Feeling of worthlessness
  • Feeling of insecurity
    • Be sure that you won’t succeed at anything
  • Devaluation of own achievements

Self-esteem problems are also very common with ADHD.

3.2.4. Fear

  • Fear of doing everything wrong
  • Fear of failure
    • Even for things that
      • Were previously mastered without any problems
      • Objectively continue to be mastered
  • Fear of separation and loss
  • Fear of loneliness
  • Fear of impoverishment
  • Somatic anxiety
    • Panic attacks
    • Get no more air
    • Tightness in the chest
    • Tightness in the throat
    • Difficulty swallowing
    • Pain in the heart area

Anxiety is also very common in ADHD.

3.2.5. Feelings of guilt

  • Fear of the consequences of your own mistakes
  • Belief that punishment would be necessary

3.2.6. Anhedonia

  • Cheerlessness
  • Inability to feel joy
  • Long lasting
    • Not just individual days (everyone has them)
  • Leads to a negative attitude towards life and weariness with life

Anhedonia is also more common in ADHD.

3.2.7. No longer being able to feel anything

  • Can also no longer perceive negative feelings
  • Feeling of numbness
  • Emotions are flat
  • Emotional numbness
    • Joyless
    • Listless
    • Hopeless
    • Despondent
    • Without energy
    • Listless
    • Indifferent
  • No hope of feeling positive and strong again
  • Memory of past intense joy and sadness is abstract and intellectual
  • Memories of past experiences remain without empathy for the emotions of that time

Emotional poverty is also more common in ADHD. More on this at Self-perception disorders as an ADHD symptom In the article Complete list of ADHD symptoms according to manifestations in the chapter Symptoms.

3.2.8. Drive reduced

  • Life energy missing
  • Every movement is too much
  • Lack of strength for simple everyday activities
  • As if you had to walk through water
  • Inhibition affects
    • Physical activities
    • Mental activities

Drive problems are also very common with ADHD.

3.2.9. Inner restlessness / agitation

  • Agonizing restlessness makes directed activity difficult
  • Be driven
  • Inner tension
    • Jumpy
    • Overexcited
    • Tension-relieving behavior
      • Aimless running back and forth
  • Intensive facial expressions and gestures
  • Easily confused with exaggerated whining or deliberate pity-seeking

Inner restlessness occurs very frequently in ADHD in a confusable form.

3.2.10. Time perception disorder / Now is always

  • Time estimation is more difficult
    • Time does not pass/stands still
    • Also occurs very frequently in ADHD, but usually in a different form (perception of time has a different focus)
  • Momentary perceptions are perceived as final (now is always)

Time perception problems are also very common in ADHD in an identical form, see Time perception problems in ADHD (chronasthenia) In the article Complete list of ADHD symptoms according to manifestations in the chapter Symptoms.

3.2.11. Cognitive impairment

  • Attention impaired
  • Concentration impaired
  • Memory impaired

Attention problems are central symptoms of ADHD.

3.2.12. Inner emptiness

Also occurs with ADHD.

3.2.13. Decision problems

  • Decision-making disturbed
  • Even small decisions are overwhelming
  • 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.

3.2.14. Delusional thinking

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)
  • Delusions of persecution

3.2.15. Suicidal thoughts

Mentally dealing with topics that gradually move towards death. The process can take place within hours or months.

  • Breaking up (usually not related to death at first)
  • First thoughts of suicide
  • Probing types of suicide
  • Collecting tablets, checking high-rise buildings, bridges, etc.
  • Objects of life are always given the context of suicide
  • The attempt is often preceded by a state of inner peace
    • Externally, the impression of improvement can arise immediately before the attempt

10 to 15 % of all untreated sufferers of severe depression kill themselves.

3.2.16. Physical symptoms

  • Somatic physical anxiety symptoms
  • Libido decreases / disappears
    • Rare: increased libido; sometimes only at the beginning of a depression as a counter-movement to still feel something
    • Often other sexual problems
      • Erection problems
      • Dry vagina
      • Pain during sexual intercourse
      • Orgasm difficulties
  • Mood lows with typical daily rhythm (morning or night)
  • Stomach problems
    • Burp
    • Upper abdominal pain
    • Feelings of pressure
    • Nausea
    • Nausea
    • Constipation
    • Rarely diarrhea
  • Tension / pressure headaches
  • Feeling of tension in the scalp (especially in women)
  • Severe itching on the head (especially in women)
  • Breathing problems
  • Pain in the heart area
    • Stitches
    • Burning
    • Pull
    • Tightness in the chest
    • Heart irregularities are perceived more intensely
      (cardiologic confirmation nevertheless required)
  • Swallowing problems
  • General, not specific pain
  • Hypochondria
    • Fear of incurable disease
  • Significant loss of appetite
  • Weight loss or weight gain (“love handles”),

4. Degrees of severity and forms of depression

4.1. Severity of the depression

  • Severe depression (major depression)
  • Dysphoria / dysthymia (mild chronic depression)
    Dysphoria and dysthymia are referred to collectively below as dysphoria.
    • Longer lasting to lifelong
      • Usually weaker intensity
    • Differentiation from ADHD: there only with inactivity
  • Occasion-related depression
    • PMS/PMDS: depressive symptoms always in the 2 weeks before menstruation, not in the other 2 weeks
      • Indication of estrogens as a trigger
    • Pregnancy depression
    • Breastfeeding depression
    • Seasonal: in the winter months
      • Above-average frequency of occurrence of14
        • Hypersomnia (sleep addiction)
        • Carbohydrate cravings
      • Indication of D3 deficiency or melatonin deficiency as a trigger
      • Regional appearance at14
        • 20 % of the population in Alaska, 64th parallel
        • 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

In burnout, on the other hand, the daily cortisol level is significantly lower, the morning cortisol peak (CAR) is absent and the course of the day is flattened overall.29 This shows the breakdown of the cortisolergic system in the last phases of stress. More on this at Collapse of the cortisol system over the stress phases In the article The human stress system - the basics of stress in the chapter Stress.

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)

  • Hyperactive stress response of the HPA axis38
    • Cortisol response to acute stressor is excessive
    • CRH system is activated
  • Patients are38
    • Anxious
    • Fear the future
    • Lose the ability to react to the environment
    • Suffer from insomnia
      • Waking up several hours too early, in particular39
      • CRH impairs deep sleep.40
        The sleep problems can therefore be a direct consequence of the overactivated HPA axis.
    • Lose their appetite
    • Depression is worst in the morning41
    • Reduced activity of the growth hormones
    • Reduced sexuality
    • Disturbed sense of time39
    • Feeling of numbness42
      • Not being able to be sad, which is perceived as agonizing42
      • Petrification, emptiness and numbness42
    • 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 Cortisol stress response in melancholic (internalizing) depression: increased

Elevated cortisol levels in the blood,4344 45 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

  • CRH increased48
  • ACTH increased
  • Vasopressin increased
  • Imbalance between mineralocorticoid and / glucocorticoid receptors
  • HPA axis hyperfunction5051 Difference between depression / ADHD in relation to corticoid receptors and DST

See also Diagnosis and treatment of ADHD with cortisol / dexamethasone? In the chapter Cortisol and other stress hormones in ADHD. 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. Atypical depression 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.

  • Hypoactive stress response of the HPA axis3864
    • Reduced cortisol response to acute stressor
    • Reduced CRH levels
  • Patients are3864 64
    • Lethargic
    • Tired
    • 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. 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

4.3. Seasonal affective disorder (SAD)

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.

a. Reduced exposure to sunlight reduces vitamin D production. People with ADHD often suffer from a vitamin D deficiency. For an explanation, see Vitamin D3 In the article Vitamins, minerals, dietary supplements for ADHD in the section Medication for ADHD in the chapter Treatment and therapy.

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.

The function of the ipRGCs is also assumed to be suboptimal in ADHD. For more information, see Dopamine and melatonin: waking/sleeping behavior, circadian rhythm In the article Dopamine in the section Neurotransmitters in ADHD in the chapter Neurological aspects.

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

5. Hypotheses on the development of depression

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

  • Cortisol:
    • Elevated cortisol levels in blood and urine81
    • Increased number of secretion periods of cortisol81
    • Reduced sensitivity of the GR to cortisol
      This reduces negative feedback in the HPA axis (deactivation disrupted). Thus during stress:
      • Overproduction of CRH and vasopressin
        and as a result
        • Overproduction of cortisol82
        • 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:
    • Increased CRH levels in the cerebrospinal fluid87
    • Downregulation of CRH receptor binding88
    • 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

  • Reduced emotional reactivity108
  • Reduced adrenocortical reactivity108
  • Reduced ability to organize behaviour with the help of external stimuli108

5.3. CRH receptor hypothesis of depression

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

  1. Stress increases the concentration of noradrenaline.
  2. 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).
  3. 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.
  4. The permanent activation leads to a depletion of the noradrenaline nerve cells, so that the amount of noradrenaline now decreases.
  5. 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

5.5. Monoamine hypotheses of depression

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%.

5.5.3. Dopamine and depression

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

5.6. Immunological hypothesis of depression

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.83 IL-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.
  • IL-2120
  • IL-6120
  • IL-10120
  • IFN-7120
  • IFN-γ121
  • SIL-2R120
  • C-reactive protein (CRP)120
  • Haptoglobin (Hp)120
  • Α2-Macroglobulin (α2 M)120
  • 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

5.6.1. IFN-α can trigger depression

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. Pathways of action of IFN-α

IFN-α has two pathways of action124

  • Rapidly occurring consequence: neurovegetative syndrome
    • Psychomotor deceleration
    • Tiredness
    • 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 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.112 Glutamate 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

  • High baseline levels of IL-6
  • Female gender
  • Previous depression
  • Subliminal symptoms of depression
  • Low level of education Effects of IFN-gamma

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

  • Prolonged reaction times in humans141142
  • Cognitive deficits (e.g. learning difficulties) in people with143142
  • Anxiety in animals144

5.6.2. IL-6

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-
  • TNF
  • 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

5.6.4. NF-kB

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

5.7. Kindling hypothesis of depression

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).

5.8. Neurotrophin hypothesis of depression

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

5.9. Neurodegenerative hypothesis of depression

An imbalance between neuroprotective and neurodegenerative degradation products of tryptophan metabolism (TRYCATs) can cause morphological effects in brain regions involved in affective disorders.129

5.10. NRF2 hypothesis of depression

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

6.1. Neurophysiological correlates of anhedonia

In healthy people, anhedonia is associated with

  • An enlargement
    • Of the left pallidum164
    • Of the superior frontal gyrus164
    • Of the postcentral parietal gyrus164
    • Of the inferior parietal gyrus164
    • The activity of the ventromedial PFC during the processing of positive information165
  • A reduction
    • The size of the anterior caudate nucleus165
    • The activity of the nucleus accumbens166167
    • The activity of the basal forebrain167
    • The activity of the hypothalamus167
  • 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

6.2. Neurophysiological correlates of depression

Depression as a reaction to positive stimuli is associated with170

  • A reduction in the activity of
    • PFC
      • Ventral171
      • Corpus callosum171
      • Medial
    • Ventral striatum (incl. nucleus accumbens)172
  • An increase in the activity of
    • Thalamus
    • Putamen
    • Insula
    • Inferior frontal cortex
    • Anterior cingulate cortex (ACC)
      • 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
      • Young people with depression show173
        • 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
    • After 10 days of CSDS178
      • 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

7. Depression and stress

7.1. Affected hypothalamic-pituitary axes

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,3839 41 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.

7.3. Studies on cortisol in depression

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.

7.3.1. Depression and cortisol in women

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.

7.3.2. Depression and cortisol in children

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 traits194195 196 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 basal CRH values in the cerebrospinal fluid.204

7.5. Depression and testosterone

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

8. Diagnosis of depression

8.1. Diagnostic manuals

Depression is diagnosed by taking a history of the existing symptoms.

8.2. Endocrine function tests

Endocrine function tests can also support the diagnosis
More on this in the article *⇒ Pharmacological endocrine function tests*in the chapter Diagnostics.

8.3. Online self-tests 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.

Online Differential Test Depression (85 questions)

Further information can be found on the Internet:

9. Differential diagnosis of depression and ADHD

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.

Differential diagnosis of ADHD/depression

Table (modified) according to Burleson Daviss (2018) Moodiness in ADHD - A Clinicians Guide, S. 95

Symptom ADHD Depression
Attention problems D D
Hyperactivity / motor restlessness D (for ADHD-HI, ADHD-C) D (for agitated depression)
Impulsivity D (for ADHD-HI, ADHD-C)
Persistent depressive mood not persistent, only with inactivity D
Mood swings b, n b, n
Irritability b, n D, n
Boredom b (rather rare in our opinion) D
Anhedonia b D
Hypersomnia n D, n
Insomnia b, n D, n
Reduced appetite n D, n
Chattiness D (for ADHD-HI, ADHD-C)
Low energy / psychomotor retardation n D, n
Low self-esteem b D
Worthlessness / Excessive feelings of guilt D
Hopelessness D
Suicidal thoughts or behavior D
Overestimation of own abilities b D
Psychotic symptoms b
Psychosocial impairment D D

D = diagnostic symptoms

b = symptoms relevant to treatment

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

In burnout, on the other hand, the daily cortisol level is significantly lower, the morning cortisol peak (CAR) is absent and the course of the day is flattened overall.29. This shows the collapse of the cortisolergic system in the last phases of stress. More on this at Breakdown of the cortisol system over the stress phases In the article The human stress system - the basics of stress in the chapter Stress,

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