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Depression and dysphoria in ADHD

Depression and dysphoria in ADHD

Depression is probably the disorder most often confused with ADHD and contributes the largest proportion of misdiagnoses in a real ADHD. ADHD has with the symptom of dysphoria with inactivity a very similar and in the snapshot of a diagnostic conversation of a few minutes hardly distinguishable appearance. However, this does not mean that every dysphoria is a compelling evidence for ADHD.
“True” depression is a disorder that exists independently (without ADHD) or comorbidly alongside ADHD. Dysphoria or dysthymia is a long-lasting chronic mood or dejection
Distinguished from dysphoria/dysthymia is moderate or severe depression, which shows a considerably more severe degree of depressive symptoms, but in contrast to dysthymia/dysphoria, it is much less likely to last as long as dysthymia/dysphoria, but rather occurs in phases lasting weeks to months.

1. Depression or ADHD - differential diagnosis and treatment

In distinction to dysphoria, depression is associated with a much more severe mood impairment, which, in distinction to the ADHD symptom of dysphoria (only) occurs not only during periods of inactivity But throughout.
To put it simply, dysphoria in inactivity is a long-lasting (already existing for years or always existing) gray, which, however, is regularly forgotten during exciting activities and is especially prominent on quiet evenings, weekends or during the first (activity-free) vacation days. Depression, on the other hand, is a deep black that occurs in phases over weeks or months and that can hardly be displaced even during or through activity.

True depression is not a symptom of ADHD, but it can be the result of persistent overwork due to ADHD.
In ADHD, basal cortisol levels are reduced. In contrast, basal cortisol levels are elevated in hospitalized depression (as well as, to a somewhat 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

1.1. Dysphoria

Almost every ADHD sufferer 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 an 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 ADHD symptom

The Wender-Utah criteria name the symptom of dysphoria with inactivity as an ADHD symptom. DSM and ICD, however, do not name this symptom. In our opinion, dysphoria during inactivity (only) is an original phenotypic ADHD symptom and must be distinguished from the disorders of depression or dysphoria.

1.3. Dysphoria as a symptom of stress

The stress benefit of dysphoria in inactivity is to keep the individual active in the face of an existing life-threatening stressor. Inactivity reduces the likelihood of coping with a life-threatening hazard. Emotional mood is a very powerful activity director. Living things try to achieve and maintain a positive, pleasant mood and avoid a negative mood.
This explains why, in cases of prolonged severe stress or ADHD, mood only drops during moments of passivity. It would not be beneficial for the survival of the individual if his mood were also reduced during the phases of actively combating the stressor.
Relaxation, enjoyment, recreation are not conducive to survival in times of relevant threat. This could explain the benefit of anhedonia associated with dysphoria and depression.

In this respect, dysphoria is a functional symptom of stress, whereas the symptoms of full-blown depression are more dysfunctional, as they no longer help to support the struggle against the stressor.

1.4. Treatment-resistant depression often masks undiagnosed ADHD

Among 160 adults with treatment-resistant depression, 34% were found to have previously undiagnosed ADHD in one study.3 This is consistent with data from other sources.4

Seemingly, therapy-resistant depression often has an undiagnosed ADHD disorder. The overload associated with untreated ADHD can cause (overload) depression. Separately, one study found 58% of psychiatric inpatients had ADHD (usually previously undiagnosed).

1.5. Sequence of treatment: major depression before ADHD before dysphoria

True moderate or severe depression (see melancholic/atypical depression below) 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 prioritized for treatment, since the elimination of ADHD-typical overload and ADHD-typical symptoms often reduces ADHD-related dysphoria as well.
In the treatment of dysphoric symptoms of ADHD, amphetamine medications (Elvanse) are usually superior to methylphenidate, according to reports available to us.
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) in ADHD in the article ⇒ Medications for ADHD - Overview

1.6. Depression in children with ADHD

Later depression was predicted in children with ADHD by the intensity of anhedonia in childhood.5 Depression also appears to be significantly gender-specific.

2. Neurophysiological commonalities of depression and ADHD

2.1. Dopamine in depression

The primary cause of depression is thought to be a disturbance in norepinephrine and serotonin metabolism in the brain.
In addition, studies suggest that dopamine deficiency (as is also typical of ADHD) may cause some depression symptoms. Much evidence points to the involvement of the reward system (especially the mesolimbic dopaminergic system) in anhedonia, dysthymia, and depression.678910

Medications that reduce dopamine turnover in the brain, such as neuroleptics or reserpine, can trigger depressive episodes.11
Conversely, the dopamine agonist bromocriptine has shown antidepressant properties in some studies.12
Similarly, a study of (but only 5) depressives showed a positive effect of augmenting (complementary to SSRI) administration of methylphenidate, which is known to raise dopamine and norepinephrine levels by reuptake inhibition.13

The fact that anhedonia is more similar to dysphoria than to the symptoms of moderate or severe depression could be understood as an indication that the ADHD-typical dysphoria (during inactivity) is originally caused by the ADHD-typical dopamine deficiency (primarily in the striatum). This would also explain why stimulant treatment (especially by amphetamine medication) can positively influence dysphoria. Moreover, anhedonia also occurs as an original ADHD symptom.
Chronic stress correlates with dopamine depletion in the brain and is treatable with dopaminergic substances. More on this at Alteration of the dopaminergic system by chronic stress In the article ADHD as a chronicized stress regulation disorder in the chapter Stress.

2.2. Low hedonic tone in ADHD and depression

In anhedonia, dopaminergic circuits associated with reward and motivation play a key role in maintaining hedonic tone, particularly bottom-up and top-down projections to the dopaminergic system of14

  • PFC
  • Lateral habenula
  • Ventral tegmentum.

Depression, ADHD, and addictive behaviors share a low hedonic tone.1415

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 of them that distinguish a disorder particularly well from others. Diagnostic manuals are therefore only useful for diagnosis, but not for treatment of a disorder.

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 2015.16 Main symptoms
  • Depressive, depressed mood
  • Loss of interest and joylessness
  • Decreased drive with increased fatigability (often even after small efforts) and activity limitation

At least two of them must last at least two weeks. Additional symptoms
  • Decreased concentration and attention
  • Decreased self-esteem and self-confidence
  • Guilt and feelings of worthlessness
  • Negative and pessimistic future prospects
  • Suicidal ideation, self-injury, or suicidal acts that have occurred
  • Sleep disorders
  • Reduced appetite

Mild episode: 2 additional symptoms.
Middle 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 enjoyment in normally pleasurable activities
  • Lack of ability to respond 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
  • Marked 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, instead of early morning awakening, persistent daytime fatigue is common, as well as an evening low instead of a morning low. However, this is not considered 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 them has to be depressed mood or loss of interest or joy.17

  • Depressed mood almost all day
  • Significantly decreased interest or enjoyment in all or almost all activities for most of the day
  • Significant (>5%) weight gain or loss, or decreased or increased appetite
  • Insomnia (difficulty falling asleep or staying asleep) or hypersomnia (sleep addiction)
  • Psychomotor agitation or retardation observed by others (not self-reported)
  • Fatigue or listlessness
  • Feelings of worthlessness or excessive or inappropriate guilt
  • Decreased ability to think or concentrate, or indecisiveness
  • Recurrent thoughts of death or suicide, suicide attempt, 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 for several days for most of the day

  • Depressed mood

and additionally at least 2 of the following symptoms:

  • Low appetite or overeating
  • Insomnia (difficulty falling asleep or staying asleep) or hypersomnia (sleep addiction)
  • Little energy or fatigue
  • Low self-confidence
  • Difficulty concentrating or making decisions
  • Feelings of hopelessness

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

At least 5 of the following symptoms17

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

At least 1 of the 5 symptoms from subgroup 1:

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

At least 2 of the 5 symptoms from subgroup 2:

  • Decreased interest in usual activities
  • Difficulty concentrating
  • Little energy or fatigue
  • Marked change in appetite, overeating, or specific cravings
  • Insomnia (difficulty falling asleep or staying asleep) or hypersomnia (sleep addiction)
  • Feeling overwhelmed or losing control
  • Physical symptoms such as breast tenderness or swelling, joint or muscle pain, feeling bloated, and weight gain

The likelihood of PMDS increases before menopause. Representation according to Pinkerton

At least 5 of the following symptoms18

  • Start 7 to 10 days before menstruation
  • End with the onset of menstruation, or subside no later than the following week

At least 1 of the 5 symptoms from subgroup 1:

  • Marked mood swings (e.g., sudden sadness)
  • Marked irritability or anger or increased interpersonal conflict
  • Pronounced depressed state, feeling of hopelessness or thoughts about lack of self-esteem
  • Marked anxiety, tension, or a nervous feeling

At least 2 of the 5 symptoms from subgroup 2:

  • Decreased interest in everyday activities, possibly leading to social withdrawal
  • Difficulty concentrating
  • Little energy or fatigue
  • Marked changes in appetite, overeating, or specific cravings
  • Insomnia (difficulty sleeping through the night) or hypersomnia (sleep addiction)
  • Feeling of being overwhelmed or loss of control
  • PMS accompanying physical complaints (e.g. breast tenderness, edema)

3.2. Total list of symptoms possible in depression

The following list covers most of the symptoms possible in depression. The presentation is largely based on Niklewski, Riecke-Niklewski.19 Not every depressive has all of the symptoms listed (just as with ADHD, not every sufferer has all of the possible symptoms).

3.2.1. Depressive perception

  • Prolonged
    • Weeks, months, years
    • Not only short-term negative affects such as
      • Anger
      • Trouble
  • See black
  • Depressed or depressive mood with daily rhythm
    • Low mood in the morning after getting up
      • Melancholic / psychotic depression
      • Rule case
      • Frequently excessive cortisol stress response
    • Mood low in first half of night
      • Atypical depression
      • Rarer
      • Frequently flattened cortisol stress response
  • Differences between feelings reduced
  • Frequent crying without cause
  • Sense of futility

3.2.2. Fatigue and sleep problems

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

Sleep problems are also elevated in ADHD.

For the risk of increase in sleep problems by veschid antidepressants, see Sleep-disrupting effects of medications In the article Sleep problems in ADHD in the section Nonpharmacological treatment and therapy of ADHD in the section Treatment and therapy.

3.2.3. Self-esteem issues

  • Feeling of worthlessness
  • Sense of insecurity
    • Be sure that nothing more succeeds to you
  • Devaluation of own achievements

Self-esteem problems are also very common in ADHD.

3.2.4. Fear

  • Fear of doing everything wrong
  • Fear of failure
    • Even with things that
      • Used to be mastered without any problems
      • Objectively continue to be mastered
  • Fear of separation and loss
  • Fear of loneliness
  • Fear to impoverish
  • Somatic anxiety
    • Panic attacks
    • Can no longer breathe
    • Tightness in the chest
    • Tightness in the throat
    • Difficulty swallowing
    • Pain in heart area

Anxiety is also very common in ADHD.

3.2.5. Guilt

  • Fear of the consequences of one’s own mistakes
  • Belief that punishment would be required

3.2.6. Anhedonia

  • Joylessness
  • Inability to feel joy
  • Long-lasting
    • Not only single days (everybody has that sometimes)
  • Leads to negative attitude to life and weariness of life

Anhedonia also occurs at an increased rate in ADHD.

3.2.7. Can no longer feel anything

  • Can no longer perceive even negative feelings
  • Feeling numbness
  • Emotions are flat
  • Emotional numbness
    • Joyless
    • Listless
    • Hopeless
    • Despondent
    • Low-energy
    • Listless
    • Indifferent
  • No hope to feel positive and strong again
  • Memory of former intense joy and sorrow is abstract and intellectual
  • Memories of past experiences remains without empathy for the emotions of that time

Emotional poverty also occurs at an increased rate in ADHD. More on this at Self-perception disorders as an ADHD symptom In the article Total list of ADHD symptoms according to manifestations in the chapter Symptoms.

3.2.8. Drive reduced

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

Drive problems are also very common in ADHD.

3.2.9. Inner restlessness / agitation

  • Agonizing restlessness impedes directed activity
  • Be driven
  • Inner tension
    • Jumpy
    • Overexcited
    • Stress-relieving behavior
      • Aimless running back and forth
  • Intense facial expressions and gestures
  • Easily confused with exaggerated whining or deliberate pitying

Inner restlessness is very common 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 often in ADHD, but usually in a different form (time perception 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 Overall 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 in ADHD.

3.2.12. Inner Void

Also occurs in ADHD.

3.2.13. Decision problems

  • Decision making disturbed
  • Overwhelm even small decisions
  • Fear of making mistakes, fear of failure, guilt, concentration problems, perfectionism exacerbate decision-making problems.

Decision-making problems are a common ADHD symptom and are more common in ADHD-I than in ADHD-HI and ADHD-C.
ADHD-I, according to our impression, correlates increased with melancholic depression, ADHD-HI (with hyperactivity / impulsivity), however, correlates more with atypical depression.

3.2.14. Delusional thinking

Hallmarks 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, the affected person is convinced of the truth of the delusional thoughts.

Fear for

  • Soulfulness (fear of going crazy)
  • 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 something unforgivable)
  • Self-worth (fear of being completely worthless/void)
  • Delusions of persecution

3.2.15. Suicidal thoughts

Mentally dealing with issues that gradually move toward death. Sequence can occur within hours or months.

  • Break up (usually not yet related to death at first)
  • First thoughts of suicide
  • Probing types of suicide
  • Collecting tablets, checking skyscrapers, bridges, etc.
  • Objects of life always receive the context of suicide
  • Attempt is often preceded by state of inner calm
    • Externally, the impression of improvement may occur immediately before trial

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

3.2.16. Physical symptoms

  • Somatic physical anxiety symptoms
  • Libido decreases / disappears
    • Rarely: increased libido; sometimes only at the beginning of a depression as a countermovement to still feel something
    • Often other sexual problems
      • Erection problems
      • Dry vagina
      • Pain during sexual intercourse
      • Orgasm Difficulties
  • Mood lows with typical daily rhythm (in the morning or at night)
  • Stomach problems
    • Burping
    • Upper abdominal pain
    • Pressure sensations
    • Nausea
    • Nausea
    • Constipation
    • Rather rarely diarrhea
  • Tension / pressure headaches
  • Tension feeling of the scalp (especially in women)
  • Severe itching of the head (especially in women)
  • Breathing problems
  • Pain in the heart area
    • Stitches
    • Burning
    • Pull
    • Tightness in the chest
    • Heart irregularities are perceived more intensively
      (cardiological confirmation nevertheless required)
  • Swallowing problems
  • General, not concrete pain
  • Hypochondria
    • Fear of incurable disease
  • Marked loss of appetite
  • Weight loss or weight gain (“kummerspeck”),

4. Severity and forms of depression

4.1. Severity of depression

  • Severe depression (major depression)
  • Dysphoria / dysthymia (mild chronic depression)
    Dysphoria and dysthymia will be referred to uniformly as dysphoria in the following.
    • Longer lasting to lifelong
      • Mostly weaker intensity
    • Differentiation from ADHD: there only in case of inactivity
  • Occasion-related depression
    • PMS/PMDS: depressive symptoms always in the 2 weeks before menstruation, not in the other 2 weeks
      • Reference to estrogens as a trigger
    • Pregnancy Depression
    • Breastfeeding Depression
    • Seasonal: in winter half year
      • Above-average occurrence of19
        • Hypersomnia (sleep addiction)
        • Carbohydrate cravings
      • Indication of D3 deficiency or melatonin deficiency as triggers
      • Regional appearance at19
        • 20% of the population in Alaska, 64th latitude
        • 12.5% of the population in New York, 41st latitude
        • 2.6% of Florida population, 28th latitude

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 may be an extreme form of melancholic depression) or bipolar depression, which is characterized by alternation of depressive and manic phases at different rhythms and intensities.

Depression, like ADHD, is not rigidly associated with a flattened or exaggerated endocrine stress response. Just as in ADHD the ADHD-I subtype often shows an exaggerated and ADHD-HI and ADHD-C tend to show a flattened endocrine stress response, depression also has (at least) two subtypes:20
1. melancholic depression (formerly “endogenous” depression), and even more so psychotic depression,21 which often show an exaggerated endocrine stress response (including hypercortisolism),22 occurs in 40 to 60% of adults2324 and
2. atypical or chronic depression, whose HPA axis response often corresponds to a (neutral or) flattened endocrine stress response (including hypocortisolism).252627282930

About 50% of all severely depressed patients show elevated basal daily cortisol levels. About 35 % are nonsuppressors on the dexamethasone test.313233

In burnout, on the other hand, the daytime cortisol level is significantly lower, the morning cortisol high (CAR) is absent, and the overall course of the day is flattened.34 This shows the breakdown of the cortisolergic system in the final stress phases. See more at Collapse of the cortisol system over the stress phases In the article The stress systems of humans-basics of stress in the chapter Stress.

The PVN of the hypothalamus of depressed patients has 4 times as many CRH and three times as many vasopressin neurons as that of unaffected individuals.35
The HPA axis reacts to acute stressors in a slowed manner and does not shut down cleanly. Affected individuals show faulty shutdown of the HPA axis in the hypothalamus and pituitary gland.36

The HPA axis is shut down by cortisol when enough cortisol is secreted to occupy the more cortisol-sensitive mineralocorticoid receptors enough to address the 1/10 as sensitive glucocorticoid receptors that trigger HPA axis shutdown
MR antagonists can improve depressive symptoms - induced by cortisol administration37 unless treatment-resistant depression is already present.38
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 multiple psychological problems, half from atypical depression. If the existing hypercortisolism was treated, the psychological problems were significantly reduced. However, the atypical depression persisted and even worsened. 39 Atypical depression correlates more with hypocortisolism than with hypercortisolism, making worsening of atypical depression with reduction in cortisol levels conclusive.

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. Moreover, the more severe the depression, the more pronounced this effect.40

That prolonged cortisolergic stress can induce depression is confirmed by the increased risk of depression with administration of artificial glucocorticoids.41

Men with elevated cortisol stress responses show a higher correlation of maltreatment as a child and depressive symptoms than men with moderate to lower cortisol responses.42

4.2.1 Melancholic depression (formerly: “endogenous”, “neurotic” or “reactive” depression)

  • Hyperactive stress response of the HPA axis43
    • Cortisol response to acute stressor is excessive
    • CRH system is activated
  • Patients are43
    • Anxious
    • Fear the future
    • Lose responsiveness to the environment
    • Suffer from insomnia
      • Especially to wake up several hours too early44
      • CRH impairs deep sleep.45
        In this respect, the sleep problems may be a direct consequence of the overactivated HPA axis.
    • Lose their appetite
    • Depression is worst in the morning46
    • Reduced activity of growth hormones
    • Reduced sexuality
    • Disturbed sense of time44
    • Feeling numb47
      • Not being able to be sad, which is perceived as tormenting47
      • Petrification, emptiness and solidification47
    • In extreme form (severe depressive episode with psychotic features) also47
      • Guilt
      • Impoverishment Delusion
      • Hypochondriac delusion
      • More delusions

Because of the often excessive cortisol response to acute stressors in melancholic depression, SSRIs that increase cortisol levels should be used judiciously in this form of depression.
Comments on serotonin reuptake inhibitors (SSRIs) in ADHD Cortisol stress response in melancholic (internalizing) depression: increased

Early on, depressed patients were found to have elevated cortisol levels in blood,4849 50 in CSF51 (which correlated with urinary cortisol and decreased with clomipramine treatment52 and which also correlated with elevated CRH levels)53 and in urine54 (hypercortisolism).
The elevated cortisol levels correlated with

  • CRH increased53
  • ACTH increased
  • Vasopressin increased
  • Imbalance between mineralocorticoid and / glucocorticoid receptors
  • HPA axis hyperfunction5556 Difference depression / ADHD in relation to corticoid receptors and DST

See here: Diagnosis and treatment of ADHD by cortisol / dexamethasone? In the chapter Cortisol and other stress hormones in ADHD. Medication of melancholic (internalizing) depression

The Handbook of Psychopharmacotherapy 57 points out that in severe (there: melancholic) depression, treatment with tricyclic antidepressants (mainly amitryptiline and clomipramine) or SSNRIs (there: duloxetine and venlafaxine) is superior to treatment with SSRIs.5859 Another meta-analysis (not available on this site) and another study, however, do not find any advantage of TCAs over SSRIs in severe (melancholic) depression.60
The less than optimal effect of SSRIs was further addressed in the presentation of the SSRI sertraline, which was said to work better than other SSRIs in severe melancholic depression.61 Likewise, Ritzmann was critical of SSRIs in melancholic depression in the Swiss Pharma Critique.62
Meanwhile, another source cites activating SSRIs or SNRIs as the agents of choice for internalizing depression, whereas externalizing forms of depression would be treated more with sedating antidepressants.63

In melancholic depression, a low probability of response to placebo and psychotherapy64 and a particularly good response to tricyclic antidepressants, lithium augmentation, and electroconvulsive therapy are reported.656667 Electroconvulsive therapy showed particularly good recovery of HPA axis function in combination with drug treatment.68
Drug treatment proved to be significantly superior to behavioral therapy.60

However, the evidence to date comes only from small studies and clinical empirical experience. There have been few systematic direct comparisons of different antidepressant classes in patients with different depression subtypes.6465

4.2.2. Atypical depression Cortisol stress response in atypical depression: flattened

It was not until long after the discovery of hypercortisolism in many depressed patients that it became apparent that in depression, 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 presented here.436920

Between 15%70 and 40% of all depression is said to be atypical depression.

  • Hypoactive stress response of the HPA axis4369
    • Reduced cortisol response to acute stressor
    • Decreased CRH levels
  • Patients are4369 69
    • Lethargic
    • Tired
    • Hyperphagic (eating disorder with increased food intake)
    • Hypersomniac (“sleep addiction”)
    • Reactive to environment
    • Diurnal variation of depression being least bad in the morning
    • Feeling of leaden heaviness in arms and legs (DSM IV)
    • Rejection Sensitivity (DSM IV)

Because of the flattened cortisol response to acute stressors in atypical depression, SSRIs are the first choice in treating this form of depression. The Depression League recommends SSRIs especially for atypical depression.71 In addition, MAOA inhibitors may be helpful.
Nevertheless, it should be noted that SSRIs increase the number of DAT in the striatum, which could exacerbate ADHD symptoms.
Comments on serotonin reuptake inhibitors (SSRIs) in 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 difference is only that the hypocortisolism existing here causes an upregulation of the receptors.

One publication posits a flattened cortisol stress response in (melancholic) depression as a consequence of prolonged chronic existence of depression.72 That prolonged stress causes downregulation of stress systems (the autonomic nervous system and the HPA axis) is well known.7374 It is open whether the differences between chronic melancholic depression and atypical depression align only with respect to the cortisol stress response. This might suggest that cortisol stress responses would not play a causal role in the etiology of depression. Further, it would have to follow that, contrary to previous general belief, the cortisol stress response should not play a crucial role in distinguishing depression subtypes. Medication of atypical (externalizing) depression

In atypical depression, SSRIs (selective serotonin reuptake inhibitors) and TCAs (tricyclic antidepressants) are thought to work poorly. Irreversible MAO inhibitors are said to be effective, but these should generally only be taken under a strict diet.75

4.3. Seasonal affective disorder (SAD)

Seasonal depression or winter depression regularly develops in the fall / winter season and ends in early summer, when the days are bright again and sunlight has become strong again.

Seasonal depression was found in 27% of awakened ADHD sufferers. Adult ADHD sufferers have 10 times the risk of developing seasonal depression.7677

For seasonal depression, we see two pathways of development, both of which are well compatible with the increased frequency in ADHD sufferers.

a. Reduced exposure to sunlight decreases vitamin D formation. ADHD sufferers often suffer from vitamin D deficiency. For explanation, see Vitamin D3 In the article Vitamins, minerals, dietary supplements in ADHD in the section Medications for ADHD in the section Treatment and therapy.

b. In addition, a disturbance of melatonin formation due to insufficient light exposure is likely to affect the corresponding ipRGC cells of the retina of the eye, which are responsible for the perception of the measure of brightness. If these cells are hypersensitive, the decreasing differences in brightness in late autumn/winter cause a deficient control of the circadian rhythm. This can be a common cause of seasonal depression.

Sufferers of seasonal depression showed an aberrant function of ipRGC cells. They responded with reduced pupil dilation to blue light but not to red light.7879 This leads to the hypothesis of reduced photosensitivity to blue light, resulting in weaker control of the nucleus suprachiasmaticus by natural daylight.

The function of ipRGCs is also thought to be suboptimal in ADHD. See Dopamine and melatonin: waking/sleeping behavior, circadian rhythm In the article Dopamine in the section Neurotransmitters in ADHD in the section Neurological aspects.

sixty-nine percent of adults with ADHD reported increased visual sensitivity to light, compared with 24% of those not affected. In addition, ADHD sufferers wore sunglasses more frequently than did nonaffected individuals. It is possible that increased visual light sensitivity in ADHD sufferers reflects aberrant retinal development or function.80

5. Hypotheses on the development of depression

Most hypotheses map to a disruption of the HPA axis.
Other causes of depression can be found at Corvell.81

5.1. Hypothesis of depression as a consequence of chronic stress exposure

This hypothesis suggests that chronic stress exposure causes prolonged excessive cortisol exposure and excessive ACTH exposure, which then cause damage to the HPA axis and limbic system. Cortisol has neurotoxic effects on hippocampus and PFC, which are impaired in depression. Depression sufferers often show enlarged pituitary and hypothalamus. Prolonged cortisol exposure often causes insulin resistance and abdominal fat deposition, which are typical in depression.20

Depression often shows dysregulation of the HPA axis:82838485

  • Cortisol:
    • Elevated cortisol levels in blood and urine86
    • Increased number of secretion periods of cortisol86
    • Lower sensitivity of GR to cortisol
      Thus reduced negative feedback in the HPA axis (shutdown disturbed). Thereby during stress:
      • Overproduction of CRH and vasopressin
        and resulting
        • Overproduction of cortisol87
        • Overproduction of IL-1-beta88 IL-1-beta levels and post-DST cortisol levels correlated in healthy individuals as in depressed individuals.89 See immune hypothesis of depression below.
  • CRH
    • Increased number of CRH-producing neurons in hypothalamus90 and frontal brain,91 thereby:
    • Elevated CRH levels in cerebrospinal fluid92
    • Downregulation of CRH receptor binding93
    • Decreased CRH receptor expression91 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 (these were resilient). Expression changes in microRNA and mRNA were measured:94 * Expression changes in microRNA and mRNA correlated with depressive response:

* Downregulation of serotonergic/dopaminergic synapses in the nucleus accumbens
* Downregulation of MAPK/calcium signaling pathways in the nucleus accumbens
* Downregulation of RNA associated with morphine dependence
* Upregulation of cAMP/PI3K-Akt signaling pathways in the nucleus accumbens
* Upregulation of amino acid metabolism
  • Expression changes in microRNA and mRNA correlated with resilient response:
    • Upregulation of serotonergic/dopaminergic synapses in the nucleus accumbens
    • Upregulation of 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 tyrosine metabolism

Another study in mice found correlations of chronic stress and decreased reward-oriented behavior with:95

  • 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 encoding enzymes of the kynurenine pathway
  • In the ventral tegmentum
    • Higher concentrations of kynurenine and the microglial 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, by means of a. Alteration of synthesis and release and b. Alteration of the receptors of serotonin, norepinephrine and dopamine9697 in limbic and neocortical brain structures trigger the changes in mood and behavior typical of depression.8396

Chronic stress reduces GABA levels. GABA and stress
GABA is an inhibitory neurotransmitter and interacts with glutamate, an exitory neurotransmitter. GABA and glutamate inhibit each other. Thus, a prolonged decreased GABA level leads to an excessive glutamate level. Decreased GABA and increased glutamate levels are considered a cause of depression.98

While GABA inhibits ACTH release from the HPA axis (by directly addressing the nucleus paraventricularis (PVN) in the hypothalamus, glutamate promotes ACTH release via projections from the hypothalamus and brainstem.99

Treatment of depression by glutamate antagonists is a new drug approach to depression treatment. In March 2019, the FDA approved the glutamate antagonist ketamine as a nasal spray for the treatment of depression for the first time in the United States (esketamine). Approval is pending in Europe. In Germany, esketamine is currently used off-label as a nasal spray or infusion for the treatment of depression. Intravenous administration is done on an outpatient basis in a day ward. Experience has been positive.100

The 2017 APA dosage recommendation for esketamine is 0.5 mg/kg body weight, two doses per week for 4 to 6 weeks. The effect occurs (unlike all other known antidepressants) within hours to a few days.

The mechanism of action of ketamine is as yet unknown. It seems to release growth hormones, which are reduced in depression. In addition, communication between brain regions responsible for mood regulation seems to be improved.
In rats, the short-term response involves robust and load-independent topological changes in cognitive, sensory, emotional, and reward circuits associated with depressive behavior. The medium-term response within 48 hours in depressed rats included normalization of connectivity in the habenular nuclei, middle thalamus, and hippocampus.101

The long-term effects are unknown so far. Possible side effects are known to be blood pressure increase, pulse increase, eye pressure and intracranial pressure increases. During ingestion, an effect similar to that caused by light alcohol consumption is reported. More rarely, positively perceived experiences of dissociation, anxiety or panic states, illusions, hallucinations, or horror trips occur.100

In an individual case known to us, a woman with melancholic depression showed a significant improvement in the previously existing sleep disturbance 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 results from a disruption of negative feedback on cortisol (cortisol, as the last hormone of the HPA axis, has, among other functions, the task of shutting down the HPA axis again; this function is disrupted) which is accompanied by an alteration of mineralocorticoid (MR) and glucocorticoid (GR) receptors.55102

Prolonged hypercortisolism (too much cortisol) may cause downregulation of the amount and sensitivity of MR and GR receptors103 or genetic alteration of receptor structure or function.104

Change in GR due to early childhood stress

In adult rats separated from the mother once for 24 hours at 6, 9, or 12 days of age, GR-mediated cortisol feedback (HP axis deactivation with subsequent cortisol decline) was deficient and impaired.103 In addition to a concomitant increase in MR and decrease in GR in the hippocampus, increased activation of the adrenal gland also occurred as a result of increased ACTH levels.105 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 because ACTH levels decreased at a slower rate despite elevated cortisol levels.106

Maternal experiences of violence in pregnancy107 or maltreatment in early childhood108 cause increased methylation of promoter regions of the gene for glucocorticoid receptors (GR) and thus decreased GR density in the hippocampus.109 The hippocampus is responsible for storing information in long-term memory and inhibiting the HPA axis.

One study failed to find a correlation between GR gene methylation and cortisol stress response in trauma, schizophrenia, or bipolar sufferers.110

Similarly, disruption of glucocorticoid receptor chaperone regulation, e.g. via FKBP5, may affect GR activation, translocation of the activated hormone-receptor complex into the nucleus, transcription of the GR, and its reprovision in the cell.20

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 time. Intracerebroventricular administration of GR antagonists decreased the cortisol stress response somewhat but did not shorten it.111 In the CA1 area of the hippocampus, MR regulate the maintenance of excitability, whereas GR suppress excitability. Blockade of MR increases basal cortisol levels as well as the HPA axis cortisol response to acute stressors.112 MR regulate salt starvation in addition.

Limbic MR appear to primarily regulate cortisolergic effects on the treatment of information and the organization of behavioral strategies. GR, on the other hand, mediate the effects of cortisol on fear, hunger, and the storage of information. Behaviors mediated by GRs can persist for weeks in adulthood and be permanent during adolescence. High cortisol levels decrease the number of GR and increase the number of MR in the hippocampus. Mineralocorticoids (such as activating aldosterone and deactivating deoxycorticosterone) downregulate MR like GR.112

If the relative number of MRs increases compared to GRs in the limbic system, this causes in animals

  • Reduced emotional reactivity112
  • Reduced adrenocortical reactivity112
  • Reduced ability to organize behavior with the help of external stimuli112

5.3. CRH receptor hypothesis of depression

The CRH receptor hypothesis assumes that prolonged high CRH release from the hypothalamus results in downregulation of pituitary CRH receptors. This results in reduced ACTH release, which causes reduced cortisol release in the adrenal cortex, so that the shutdown of the HPA axis actually mediated by cortisol is omitted. Due to the lack of shutdown of the HPA axis, CRH secretion remains unchecked, which thus proves to be both a cause and a consequence.

Untreated depressed individuals show increased CRH concentrations in cerebrospinal fluid. Depressed individuals show increased CRH concentrations as well as increased expression of the CRH gene in the PVN of the hypothalamus, the locus coeruleus, and the PFC.20

5.4. Norepinephrine receptor hypothesis of depression

The corticosteroid hypothesis is not the only mechanism describing changes due to permanent stress. The various mechanisms are likely to coexist and operate as general stress consequence mechanisms in disorders other than depression. One example is the norepinephrine receptor hypothesis of depression, which is presented below based on the description by Fuchs, Flügge (2004):113

  1. Stress increases the concentration of norepinephrine.
  2. When norepinephrine levels are permanently elevated, the number of alpha2-adrenoceptors in the target regions of noradrenergic neurons is initially reduced (downregulation).
    Downregulation occurs presynaptically (at noradrenergic terminals) as well as postsynaptically (e.g., at glutamatergic neurons).
  3. Presynaptic downregulation impairs negative feedback inhibition of norepinephrine release. Therefore, noradrenergic neurons remain permanently activated during stress activation after downregulation of noradrenaline receptors.
  4. Sustained activation leads to depletion of the norepinephrine neurons, so that the amount of norepinephrine now decreases.
  5. In response, postsynaptic (noradrenergic) alpha2-adrenoceptors may upregulate.

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 disturbances, listlessness or loss of appetite are caused by malfunctions of monoaminergic neurotransmitter systems.20

Monoamines are e.g. serotonin and noradrenaline, but also dopamine, adrenaline and several others.

5.5.1. Serotonin deficiency hypothesis / norepinephrine deficiency hypothesis of depression

Previously, the monoamine hypothesis was primarily related to the monoamines serotonin and norepinephrine.

It is true that the main antidepressants are serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, or serotonin/norepinephrine reuptake inhibitors. Nevertheless, about one-third of sufferers do not respond to these antidepressants.

5.5.2. Serotonin excess and norepinephrine excess and depression

Meanwhile, a deficiency of serotonin or norepinephrine is considered only one of several possible causes of depression
Elevated as well as decreased noradrenaline levels were found in depressives.20
Similarly, evidence of decreased as well as increased serotonin levels has been found in depressed individuals.20

The active ingredient tianeptine acts, among other things, as a serotonin reuptake enhancer. However, tianeptine has several other effects, e.g. it increases dopamine in the nucleus accumbens, so that it is unclear which neurophysiological effects mediate the antidepressant effect of tianeptine.

The findings on norepinephrine 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 they are taken, whereas SSRIs take effect at the earliest after 2 to 4 weeks.

Treatment with monoaminergic drugs (e.g., serotonin or norepinephrine reuptake inhibitors) also causes remission of symptoms in only about 30% of depression sufferers.20 Other sources speak of even lower rates.114 Data according to which antidepressants had no effect in 30% of those affected115 may also include only a slight improvement in symptoms with regard to the remaining 70%.

5.5.3. Dopamine and depression

Norepinephrine deficiency, dopamine deficiency, and serotonin deficiency can trigger a symptom pattern typical of depression. For example, reserpine triggers psychomotor slowing, fatigue, and anhedonia through these mechanisms of action, which is why reserpine was initially thought to trigger depression. However, the cognitive symptoms of depression such as hopelessness or guilt are not induced. It is now known that the symptoms caused by reserpine result from a depletion of monoaminergic salivary vesicles20 due to the consequent deficiency of norepinephrine (and dopamine), but not due to a deficiency of serotonin.116 The depression symptoms caused by reserpine can be abolished by tricyclic antidepressants.117 This is similar to the description of the neurochemical causes of dysthymia.118 The symptoms induced by reserpine strongly resemble the description of SCT (sluggish cognitive tempo).
Deprivation of tryptophan, which is essential for serotonin synthesis, can induce a serotonin deficiency. With this, a relapse can be caused in formerly depressed patients.20

Majore depression, especially in recurrent episodes, shows decreased expression of DAT in the striatum. This could be a consequence of compensatory downregulation due to low dopamine signaling within the mesolimbic pathways.119

Dopamine deficiency in the PFC and striatum is a known neurophysiological correlate of ADHD. Approximately 1/3 of all treatment-resistant depressions are found to have previously unidentified ADHD. Such dopamine deficiency may be due to genetic causes or stress-related (epigenetic). Various environmental influences alter dopaminergic transmission through epigenetic changes,120 including PAR-4 and DRD-2 expression in the striatum.

Details of PAR-4 and DRD-2 expression in the striatum

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 temporal cortex; knockout of the Par-4 gene resulted in depression-like behavior in mice.121120 One study shows that Par-4 interacts with a specific isoform of the D2 receptor (D2i3). This very interaction is essential for Gαio-mediated inhibition of cAMP activity. The Par-4 interacting region of the D2 receptor contains a calmodulin-binding domain. Ca2+-activated calmodulin competes with Par-4 for this site. This study shows that Gαio-dependent (and transcription factor CREB-determined) D2 regulation of gene expression depends on the balance between binding of Par-4, on the one hand, and 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.122 Further correlations to PAR-4 and DRD-2 expression reduction in mild chronic stress are reported by Moriam, Sobhani (2013).120

5.6. Immunological hypothesis of depression

Various inflammatory markers are often altered in depression.

Depressives have elevated levels of

  • IL-1β,123 especially in melancholic depression.88 Dexamethasone decreased IL-1β in healthy, not depressed, subjects.88 IL-1β levels and cortisol levels after DST correlated in healthy subjects (both low) as in depressed subjects (both high).89 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-2123
  • IL-6123
  • IL-10123
  • IFN-7123
  • IFN-γ124
  • SIL-2R123
  • C-reactive protein (CRP)123
  • Haptoglobin (Hp)123
  • Α2-Macroglobulin (α2 M)123
  • Neopterin124 which correlated with decreased L-tryptophan levels.

Antidepressants cause the production of pro-inflammatory cytokines (such as IFN-α) to be decreased and the production of anti-inflammatory cytokines to be increased.125

5.6.1. IFN-α can trigger depression

Interferon α, as a drug against hepatitis C or malignant melanoma, induces severe depression in 40 to 50% of affected individuals and fatigue, loss of energy, and motor slowing in up to 80% in a dose-dependent manner.126 Anorexia, fatigue, and pain do not occur immediately but within 14 days of IFN-α treatment initiation. In contrast, depressed mood, anxiety, and cognitive impairment occurred later and mainly in patients who met DSM-IV criteria for major depression. Action pathways of IFN-α

IFN-α has two pathways of action127

  • Rapid consequence: neurovegetative syndrome
    • Psychomotor slowdown
    • Fatigue
    • Alterations in dopamine metabolism in 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).128 90% of the degradation of tryptophan occurs via the kynurenine pathway.129
Plasma levels of IFN-α correlate highly with depression features according to the MADRS and fatigue scores according to the MFI.130

IDO converts tryptophan to kynurenine, this (by kynurenine aminotransferase) to kynurenic acid and quinolinic acid.131 As a consequence of the increased degradation of tryptophan to kynurenine by IDO (promoted by IFN-alpha and IFN-gamma) and simultaneous promotion of the conversion of kynurenine to kynurenic acid by kynurenine aminotransferase, which is also promoted by IFN-gamma,115 there is further hyperactivation of the glutamate system,132 which may be responsible for the repeatedly observed downregulation of glutamate receptors in depression.115

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 neurotoxin133, which are in equilibrium with each other in a healthy state
Another metabolite of kynurenine is 3-hydroxykynurenine, which promotes oxidative stress.134

Interestingly, administration of the glutamate antagonist kynurenic acid to the medial PVN decreased the cortisol stress response by 24%, whereas administration to the dorsal PVN increased the cortisol stress response by 31%.135 However, this response appears to vary from stressor to stressor.136

The antidepressant effect of glutamate antagonists has long been known.137 As such, ketamine,138139 amantadine and cyloserine in particular (but memantine to a lesser extent) show antidepressant effects in humans.115 Glutamate antagonists increase dopamine, norepinephrine, and serotonin levels in the brain.140 Serotonin elevation in PFC and hippocampus was higher than with additional citalopram administration.141
IFN-α-induced depression and “naturally” occurring depression show142

  • Identical symptom severity of
    • Anxiety
    • Depressed mood
    • Impaired work activity
  • Deviant in IFN-α induced depression
    • Greater psychomotor slowdown
    • Higher weight loss
    • Lower feelings of guilt

Parameters that make depression more likely after antiviral treatment with interferon are:143

  • High initial levels of IL-6
  • Female sex
  • Previous depressions
  • Subthreshold depression symptoms
  • Low educational level 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 with115

  • Prolonged reaction times in humans144145
  • Cognitive deficits (e.g. learning disabilities) in people146145
  • Fear in animals147

5.6.2. IL-6

Individuals with major depression and early stress experiences responded to psychological stress (TSST) with an exaggerated IL-6 stress response and increased DNA binding of NF-kB in peripheral blood mononuclear cells.148
Elevated IL-6 levels in adolescents with early stressful experiences predicted the development of depression 6 months later.149 Childhood stress experiences appear to promote the formation of a neuroimmune pipeline that enhances inflammatory signaling between the brain and 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 elevated 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 blood

The glutamate antagonist ketamine reduces these levels.150

5.6.4. NF-kB

Individuals with major depression and early stress experiences respond to psychological stress (TSST) with an exaggerated IL-6 stress response and increased DNA binding of NFkB in peripheral blood mononuclear cells.148

5.7. Kindling Hypothesis of Depression

Kindling is the term for an ongoing increase in neuronal responses to rather infrequent and weak stimulation of brain areas due to learning processes in the context of neuronal plasticity. The mechanism is associated with the learning capacity of the immune system, which, after initial training of responses to an antigen, reacts faster and stronger upon renewed contact with it.151
The same patterns are thought to be evident in the release of IL-6, which is released more rapidly and more strongly when the IL-6 response has already been established prenatally (e.g., by maternal stress during pregnancy).151 This model is transferable to other cytokines.152
This picture could at the same time explain the two-hit model, that in case of existing early childhood stress, an added renewed stress (mainly in adolescence) can lead to a more intense inflammatory response, which in turn can trigger a disturbance of dopaminergic, serotonergic, noradrenergic and glutamatergic neurotransmission.153 Therefore, in old age, the immune response is increased.154 Moderate and severe maltreatment in childhood correlates positively with the overall change in the cytokine IL-6 stress response and the maximum IL-6 concentration during TSST.155

The Kindling hypothesis was proven for epilepsy in animal models. Epilepsy could initially be induced by electrical stimulation; thereafter, seizure propensity continued to increase on its own until the full-blown epileptic seizures occurred. In humans, there is no evidence for this, but there are indications.

It is 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
(mainly BDNF) which leads to damage of neurons (especially in the hippocampus).
Short-term damage can be eliminated by antidepressants. Untreated depression can cause long-lasting damage resulting in irreversible hippocampal atrophy.132

5.9. Neurodegenerative hypothesis of depression

An imbalance between neuroprotective and neurodegenerative breakdown products of tryptophan metabolism (TRYCATs) may cause morphological effects in brain regions involved in affective disorders.132

5.10. Chronic nicotine use increases the risk of depression

Nicotine dependence increases the risk of depression.156
Depressed smokers who consumed lower-nicotine cigarettes for 6 weeks157 or who quit smoking showed reduced depression symptoms.158

In mice exposed to chronic mild stress, single doses of nicotine alleviated stress-induced depression symptoms and memory difficulties. This effect appears to be due to an antagonistic action of nicotine on CB1 and CB2 cannabinoid receptors.159 Thus, a distinction must be made between single and chronic nicotine use.160

5.11. Chronic alcohol consumption increases the risk of depression

Meta-studies show a high correlation between alcohol dependence and depression. They point to a causal causation of depression by alcohol, less to a reverse causality.161 Depression caused by (chronic) alcohol consumption disappears after cessation of alcohol consumption.162
Short-term alcohol consumption increases serotonin levels, while chronic alcohol consumption decreases serotonin levels in cerebrospinal fluid. Alcohol thereby addresses the serotonin receptors 5-HT3, 5-HT1B and 5-HT1A as well as the serotonin transporter.163
Alcohol further increases dopamine levels in the brain by moderating dopamine levels through serotonin. Serotonin thus forms a kind of lever for dopamine levels in the dorsal striatum, the brain’s reward center.163

Alcoholics of the more common Type A / Type 1 (types according to Cloninger, 1987) have a later onset, alcoholism is more likely to have occurred environmentally, novelty seeking is lower, and dopaminergic deficits are more common. Be are more likely to use alcohol for its anxiety-relieving effects. Alcoholics of the rarer type B / type 2 have an earlier onset, alcoholism is more often hereditary, addiction problems are greater, novelty seeking is higher, more men are affected, and serotonergic problems are more common.163164

SSRIs and other antidepressants have been used successfully to treat alcohol dependence.163

In rats, chronic stress that triggered depressive responses increased alcohol consumption. Guanfacine, which is also used as an ADHD drug, reduced the stress-induced depressive effect and the likelihood of alcohol relapse.165

6. Neurophysiological correlates of depression symptoms

6.1. Neurophysiological correlates of anhedonia

Anhedonia in healthy people is associated with

  • An enlargement
    • Of the left pallidum166
    • Of the superior frontal gyrus166
    • Of the postcentral parietal gyrus166
    • Of the inferior parietal gyrus166
    • The activity of the ventromedial PFC during the processing of positive information167
  • A reduction
    • The size of the anterior caudate nucleus167
    • The activity of the nucleus accumbens168169
    • The activity of the basal forebrain169
    • The activity of the hypothalamus169
  • 7 to 8 days of immobilization stress (3 to 4 hours/day) decreased the strength of excitatory synapses at D1-MSNs but not at D2-MSNs of the nucleus accumbens nucleus in mice.170 This may suggest that a D1-MSN-specific change in excitatory transmission is responsible for the induction of anhedonia.171

6.2. Neurophysiological correlates of depression

Depression is associated in response to positive stimuli with172

  • A reduction in the activity of
    • PFC
      • Ventral173
      • Corpus callosum173
      • Medial
    • Ventral striatum (incl. nucleus accumbens)174
  • An increase in the activity of
    • Thalamus
    • Putamen
    • Insula
    • Inferior frontal cortex
    • Anterior cingulate cortex (ACC)
      • Esp. subgenual ACC, which processes negative affects175
      • ACC is reduced, with increased metabolic activity173
      • In the rostral ACC weaker activation for positive information and stronger activation for negative information176
      • In the dorsal ACC weaker activation by musical stimuli, stronger activation by nonmusical stimuli in depressives. Greatest response to negative nonmusical stimuli.176
      • Different: notorious underactivation of the ACC in depression177; we could not find any evidence for this so far
      • Teens with depression show175
        • 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 distribution stress (CSDS): relileient or depression-prone. In depression-prone mice, the frequency of excitatory synaptic inputs is decreased in D1 MSNs and increased in D2 MSNs.178 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.179
    • After 10 days of CSDS showed180
      • An increase in β-catenin signaling in D2-MSNs in resilient mice
      • In depression-prone animals, a decrease in β-catenin signaling
    • 7 to 9 weeks of chronic unpredictable mild stress (CUMS), such as that used as a depression model in animals, was treatable with the dopamine D2 agonist pramipexole (SND-919).181

7. Depression and stress

7.1. Hypothalamic-pituitary axes affected

In depression, multiple hypothalamic-pituitary axes are affected.182

  • HPA axis

    • Hypothalamus:
      • CRH (corticotropin-releasing hormone).
    • Pituitary gland:
      • ACTH (corticotropin)
      • MSH (melanotropin, produced from POMC during ACTH synthesis)
    • 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)otropin (TSH)
    • Thyroid gland:
      • Thyroxine
    • Depression is associated with reduced triiodothyroxine (T3) levels in approximately 6% of those affected, which is treated with augmenting (= accompanying) T3 administration.183
  • 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 inhibition of the HHS axis.20
      GHRH promotes deep sleep. However, since in atypical depression, which is characterized by a strongly increased need for sleep, there is rather an underactivation of the HPA axis and thus of the hypothalamus, and in melancholic depression, which is characterized by disturbances of deep sleep, there is mostly an overactivation of the HPA axis and thus of the hypothalamus, the connection to GHRH is not directly comprehensible.
      Nevertheless, the literature suspects an imbalance between the HHS and HHG axes.184
  • Hypothalamic-pituitary-gonadal axis (HHG axis)
    The HHG system is likely to play a role primarily in pregnancy and maternity bed depression

    • Pituitary gland:
      • FSH (follicle stimulating hormone)
      • LH (Luteinizing Hormone)
    • Testis / ovary:
      • Sex hormones
      • Ovulation
      • Spermatogenesis
    • Elevated CRH levels contribute to inhibition of the HHG axis.20

In this paper, only the relationship between HPA axis and depression will be further described.

7.2. Depression symptoms and cortisol diurnal rhythm

In melancholic depression, depression symptoms are strongest in the morning,4344 46 in contrast to atypical depression, where they are weakest in the morning and tend to increase in the evening.43
We hypothesize that depression symptoms in melancholic depression are strongest when daytime cortisol levels are highest, i.e., in the morning and forenoon, whereas in atypical depression they are worst when daytime cortisol levels are lowest, i.e., in the afternoon through the first half of the night.
It is also striking that the sleep problems typical of melancholic depression coincide in the second half of the night with the cortisol level, which typically rises again at that time. Sleep is also disturbed in adrenal hyperfunction, in which too much cortisol is produced.
Atypical depression is equally characterized by a flattened cortisol stress response and an overall increased need for sleep - a relationship also known to occur with adrenal hypofunction.

7.3. Studies on cortisol in depression

Unfortunately, most studies of the cortisol response in depression do not distinguish between the subtypes of melancholic (usually exaggerated endocrine stress response) and atypical (often flattened endocrine stress response) depression, so the results should be viewed with caution.
For example, DSM IV does not differentiate the criteria of melancholic and atypical depression.

7.3.1. Depression and cortisol in women

Surprisingly, quite a few studies reveal that women have an increased likelihood of atypical depression.70185
This is not consistent with experience from the field of ADHD research, according to which women more often show an internalizing stress response, which is usually accompanied by an exaggerated cortisol response to acute stressors. Meanwhile, atypical depression often correlates with a flattened cortisol response to acute stressors.

7.3.2. Depression and cortisol in children

About half of all depressed adults have an excessive cortisol stress response.186
Children and adolescents with depression, on the other hand, hardly have an exaggerated cortisol response, consequently respond inconspicuously to the dexamethasone/CRH test187186 and do not respond at all to tricyclic antidepressants.188186189

This is consistent with the experience presented below that tricyclic antidepressants are superior for melancholic depression, if melancholic (endogenous) depression is understood to be characterized by an exaggerated cortisol stress response.

Individual studies on cortisol in depression:

  • 115 adolescents (9-16 years) with depressive symptoms underwent the Socially Evaluated Cold Pressor Test (SE-CPT) in the afternoon.
    Among those with stress-induced elevated cortisol levels, only in boys did the degree of depressive symptoms correlate with the intensity of cortisol elevation, but not with elevated baseline cortisol or recovery cortisol levels.
    Among those without stress-induced cortisol elevation, measures of depression symptoms correlated with overall elevated cortisol levels 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 correspondence in the fact that the sex ratio of boys to girls in ADHD is 1.6 to 1, and boys are more often diagnosed with hyperactive subtypes of ADHD, which (unlike ADHD-I) are associated with 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 requiring a greater amount of cortisol to activate the feedback inhibitory system of the HPA axis.190
  • A meta-analysis of 1129 acutely severely depressed adults showed an increased cortisol response to acute stress in men, but a decreased cortisol response in women. The changes largely regressed in women and completely regressed in men as the disorder subsided.191
    The result is unexpected for us, because women are supposed to develop internalizing disorders more than men. Therefore, we would have expected that rather men should be depicted with a reduced cortisol response on average and women with an increased cortisol response on average. However, the study does not distinguish between melancholic and atypical depression
    Furthermore, the difference in depression could arise more from the duration of the depression. As shown above, in new-onset depression the cortisol stress response should possibly be increased and in chronic long-lasting depression the cortisol stress response should be flattened (breakdown of the cortisolergic system).
  • Depression without traumatic childhood experiences correlates with increased cortisol response to stress.192
  • 30 Severely depressed adults showed a higher and more prolonged cortisol response to the TSST than did nondepressed 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.193; n = 55))
  • A study of 406 average 50-year-old women found a reduction in basal (non-stress-induced) cortisol levels over the day as depression symptoms increased.194
  • Elevated morning cortisol levels at 13 years predicted increased depression rates at 16 years.195
  • Depression or depressive personality traits196197 198 correlated with elevated morning (CAR) or serum cortisol levels.
  • Cortisol response to a combined dexamethasone/CRH test was significantly increased in depression.199
  • Age and severity of depression influenced cortisol release.200
  • When age and severity of depression were taken into account, the dexamethasone/CRH test achieved a sensitivity of more than 90% for recurrent depressive disorders201

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. A common consequence of too much cortisol is allergies. Interestingly, the basically flattened cortisol stress response of asthmatics seems to change to a clearly noticeable cortisol response with increasing depressed mood.202

7.4. Studies on other stress hormones in depression

Most studies of 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 abused in childhood showed an increased ACTH response to an acute psychosocial stressor.203
  • If the abused women suffered from current depression at the same time, the ACTH response to an acute psychosocial stressor was further increased; likewise, the cortisolresponse and the heart rate response were now also increased.203
  • Women with previous trauma without current depression also showed an exaggerated ACTH response to pituitary CRH stimulation with medication.204
  • In contrast, early abused women with current depression showed a reduced ACTH response to pituitary CRH stimulation with medication. This suggests underactive CRH receptors in the pituitary.204
  • Early-maltreated women with depression and without current depression, like non-maltreated women with depression, showed a greatly reduced cortisolresponse to adrenal cortex stimulation with medication ACTH.204
  • Early abused men with and without depression showed an enhanced ACTH- and cortisolresponse to the dexamethasone test. This suggests an exaggerated sensitivity of the HPA axis and impaired feedback inhibition of the HPA axis.205 In contrast, depressed men without early maltreatment did not show enhanced ACTH and cortisol responses.
  • In acutely depressed males with early childhood stress experience and a comparison group of unaffected individuals, not depression but only the description of early childhood stress intensity correlated with the elevation of basal CRH levels in CSF.206

7.5. Depression and testosterone

Increasing testosterone levels may help (to a small extent) to alleviate depression. This also applies to patients with normal testosterone levels.207 In individuals with increased aggression, it should be taken into account 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 existing symptoms.

8.2. Endocrine function tests

Further, endocrine function tests can aid in diagnosis
For more, see 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 distinguish a possible depression from a possible ADHD disorder.

Online differential test depression (85 questions)

On the Internet you can find further e.g.:

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 activity and interest in activity and is present throughout, this speaks more for depression in our opinion. This does not mean the mood-lifting effect of exercise, which occurs independently of the disorder.

Differential diagnosis 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 agitation D (for ADHD-HI, ADHD-C) D (for agitated depression)
Impulsivity D (for ADHD-HI, ADHD-C)
Persistent depressed 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
Decreased appetite n D, n
Chattiness D (in ADHD-HI, ADHD-C)
Low energy/psychomotor retardation n D, n
Low self-esteem b D
Worthlessness/excessive 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

About 50% of all severely depressed patients show elevated basal daily cortisol levels (overactive HPA axis). About 35 % are nonsuppressors in the dexamethasone test.313233

In burnout, on the other hand, the daytime cortisol level is significantly lower, the morning cortisol high (CAR) is absent, and the overall course of the day is flattened.34. This shows the breakdown of the cortisolergic system in the final stages of stress. See more at Collapse of the cortisol system over the stress phases In the article The stress systems of humans-basics of stress in the chapter Stress,

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