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
  • 1.1. Dysphoria
  • 1.2. Dysphoria / dysthymia with inactivity as ADHD symptom
  • 1.3. Dysphoria as a symptom of stress
  • 1.4. Treatment-resistant depression often masks undiagnosed ADHD
  • 1.5. Sequence of treatment: major depression before ADHD before dysphoria
  • 1.6. Depression in children with ADHD
• 2. Neurophysiological commonalities of depression and ADHD
  • 2.1. Dopamine in depression
  • 2.2. Low hedonic tone in ADHD and depression
• 3. Symptoms of depression
  • 3.1. Diagnostic manuals for depression
    • 3.1.1. Depression according to ICD 10
      • 3.1.1.1. Main symptoms
      • 3.1.1.2. Additional symptoms
    • 3.1.2. Depressive somatic syndrome according to ICD 10
    • 3.1.3. Major depression according to DSM 5
    • 3.1.4. Persistent depressive disorder (dysphoria, dysthymia) according to DSM 5
    • 3.1.5. Premenstrual dysphoric disorder (PMS, PMDS, BMDD)
      • 3.1.5.1. Representation according to Coryell
      • 3.1.5.2. Representation according to Pinkerton
  • 3.2. Total list of symptoms possible in depression
    • 3.2.1. Depressive perception
    • 3.2.2. Fatigue and sleep problems
    • 3.2.3. Self-esteem issues
    • 3.2.4. Fear
    • 3.2.5. Guilt
    • 3.2.6. Anhedonia
    • 3.2.7. Can no longer feel anything
    • 3.2.8. Drive reduced
    • 3.2.9. Inner restlessness / agitation
    • 3.2.10. Time perception disorder / Now is always
    • 3.2.11. Cognitive impairment
    • 3.2.12. Inner Void
    • 3.2.13. Decision problems
    • 3.2.14. Delusional thinking
    • 3.2.15. Suicidal thoughts
    • 3.2.16. Physical symptoms
• 4. Severity and forms of depression
  • 4.1. Severity of depression
  • 4.2. Subtypes of depression: melancholic and atypical depression
    • 4.2.1 Melancholic depression (formerly: “endogenous”, “neurotic” or “reactive” depression)
      • 4.2.1.1. Cortisol stress response in melancholic (internalizing) depression: increased
      • 4.2.1.2. Difference depression / ADHD in relation to corticoid receptors and DST
      • 4.2.1.3. Medication of melancholic (internalizing) depression
    • 4.2.2. Atypical depression
      • 4.2.2.1. Cortisol stress response in atypical depression: flattened
      • 4.2.2.2. Medication of atypical (externalizing) depression
  • 4.3. Seasonal affective disorder (SAD)
• 5. Hypotheses on the development of depression
  • 5.1. Hypothesis of depression as a consequence of chronic stress exposure
  • 5.2. Corticosteroid receptor hypothesis of depression
  • 5.3. CRH receptor hypothesis of depression
  • 5.4. Norepinephrine receptor hypothesis of depression
  • 5.5. Monoamine hypotheses of depression
    • 5.5.1. Serotonin deficiency hypothesis / norepinephrine deficiency hypothesis of depression
    • 5.5.2. Serotonin excess and norepinephrine excess and depression
    • 5.5.3. Dopamine and depression
  • 5.6. Immunological hypothesis of depression
    • 5.6.1. IFN-α can trigger depression
      • 5.6.1.1. Action pathways of IFN-α
      • 5.6.1.2. How IFN-α neurophysiologically triggers depression (kynurenine/glutamate hypothesis of depression)
      • 5.6.1.3. Effects of IFN-gamma
    • 5.6.2. IL-6
    • 5.6.3. Stress causes depression with correlating elevated inflammation levels
    • 5.6.4. NF-kB
  • 5.7. Kindling Hypothesis of Depression
  • 5.8. Neurotrophin hypothesis of depression
  • 5.9. Neurodegenerative hypothesis of depression
  • 5.10. Chronic nicotine use increases the risk of depression
  • 5.11. Chronic alcohol consumption increases the risk of depression
• 6. Neurophysiological correlates of depression symptoms
  • 6.1. Neurophysiological correlates of anhedonia
  • 6.2. Neurophysiological correlates of depression
• 7. Depression and stress
  • 7.1. Hypothalamic-pituitary axes affected
  • 7.2. Depression symptoms and cortisol diurnal rhythm
  • 7.3. Studies on cortisol in depression
    • 7.3.1. Depression and cortisol in women
    • 7.3.2. Depression and cortisol in children
    • 7.3.3. Cortisol stress response in asthma modulated by depressed mood
  • 7.4. Studies on other stress hormones in depression
  • 7.5. Depression and testosterone
• 8. Diagnosis of depression
  • 8.1. Diagnostic manuals
  • 8.2. Endocrine function tests
  • 8.3. Online self-tests
• 9. Differential diagnosis of depression and ADHD

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

3.1.1.1. 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.

3.1.1.2. 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

Annotation:
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)¶

3.1.5.1. 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.

3.1.5.2. 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
    e.g.
    • 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

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

4.2.1.1. 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

4.2.1.2. 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.

4.2.1.3. 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¶

4.2.2.1. 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 are^{4369 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.

4.2.2.2. 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

* 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

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

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

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

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.

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.

5.6.1.1. 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

5.6.1.2. How IFN-α neurophysiologically triggers depression (kynurenine/glutamate hypothesis of depression)¶

The depressive symptoms mediated by IFN-α (but not the other symptoms) are likely to be mediated by the reduction of tryptophan (TRP) due to its conversion to kynurenine (KYN) by the enzyme indoleamine 2,3-dioxygenase (IDO).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

5.6.1.3. 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-1β
• TNF-α
• 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.

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.

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¶

ADxS.org 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.:

• Beck Depression Inventory (BDI-II)
• Self-test for depression according to Goldberg

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

D = diagnostic symptime

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,