Pathogenesis (development of disease)
Depression is a mental illness, but it is often unrecognized or misrecognized. The cause has not yet been identified with certainty, but there are probably several causes that influence each other. It is assumed that depression has a genetic component as well as a psychosocial burden. Furthermore, it is assumed that there are imbalances in the neurotransmitters (messenger substances), especially serotonin (biogenic amine; regulates the tone (tension) of the blood vessels and affects gastrointestinal activity and signal transmission in the central nervous system) and norepinephrine (hormone related to adrenaline that stimulates the cardiovascular system). Thus, there is primarily altered noradrenergic and serotoninergic activity. In addition, there is a dysregulation (misregulation) between the pituitary gland and the adrenal cortex, which is manifested by changes in CRH (corticotropin-releasing hormone) and cortisol (steroid hormone/stress hormone that is released after stressful situations and activates catabolic (“degrading”) metabolic processes). Furthermore, it has been demonstrated that approximately 80% of depressed patients have altered glucocorticoid receptor (GR) functionality. This confirms that depression is primarily a stress disorder. It is also possible that herpes viruses play a role in the pathogenesis of depression: In patients with bipolar and major depressive disorders, a high rate of infection with the human herpes virus HHV-6 was found in Purkinje neurons. With the aid of high-resolution magnetic resonance imaging, it was possible to demonstrate that the more severe the disorder, the larger the hypothalamus. In patients with a so-called affective disorder, the left hypothalamus was on average 5% larger than in healthy individuals. This may be explained by the fact that the so-called hypothalamic-pituitary-adrenal axis (HPA axis) is ramped up when stressful situations are present. In people with depression, this feedback mechanism is out of function, meaning that they suffer from a hyperactive stress system, even when there are no obvious stressful situations.
Etiology (causes)
The following are causes that are associated with an increased likelihood of depression occurring:
Biographical causes
- Genetic stress
- Family history of bipolar or depressive disorders
- Suicide attempts in the family history
- Genetic risk dependent on gene polymorphisms:
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Genes: FKBP5
- SNP: rs1545843 in an intergenic region.
- Allele constellation: AA (1.4-fold).
- SNP: rs1360780 in the FKBP5 gene.
- Allele constellation: CT (1.3-fold).
- Allele constellation: TT (1.3-fold)
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Infections of the mother during pregnancy – pathogens of the TORCH complex (Toxoplasma, “Other”, rubella virus, cytomegalovirus and herpes simplex virus) (risk of the child to depression increased by 24%).
- Birth weight < 1,000 grams
- Gender – while circa 25% of adult women experience depression, only circa 10% of all adult men are affected – these differences narrow in middle and older age; suicide attempts (attempted suicides) are more common in women than in men; completed suicides are 2 to 3 times more common in men, as they choose more violent methods
- Age – clustered occurrence in old age (first occurrence > 60 yrs = old-age depression).
- Hormonal factors – postpartum (after childbirth; in the puerperium), menopause, andropause (menopause in women / men).
- Physicians in continuing education
- Followers of the Gothic culture
Behavioral causes
- Nutrition
- Trans fatty acids – significantly increase the risk of developing depression.
- Malnutrition and undernutrition
- Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
- Consumption of stimulants
- Alcohol (woman: > 40 g/day; man: > 60 g/day).
- Drug use
- Amphetamines (indirect sympathomimetic) and metamphetamines (“crystal meth”).
- Cannabis (hashish and marijuana)
- Psycho-social situation
- Current stressful life events
- Stress – Acute stress and life crises (chronic stress/continuous stress).
- Bullying: teens who reported being regularly bullied by classmates were more likely to develop depression in early adulthood.
- Lack of social support
- Loneliness (in old age) – People over 50 who frequently felt lonely (without necessarily being so) were subsequently more likely to develop depression in a long-term study.
- Low light at night while sleeping – brightness ≥ 5 lux during nighttime bedtime almost doubles the likelihood of developing depressive symptoms (hazard ratio [HR]: 1.89; 95% confidence interval between 1.13 and 3.14)
- Disruption of circadian rhythm (disturbance of the day-night rhythm), i.e., increased activity during nocturnal rest periods and inactivity during the daytime
- Overweight (BMI ≥ 25; obesity) – at a BMI body mass index/body mass index) > 30, the prevalence (disease frequency) of anxiety disorders and depression is twice as high
- Underweight (BMI < 18.5) – U-shaped association between BMI and depressive symptoms has been demonstrated: most depressive symptoms were found in underweight adults, followed by obese and severely obese patients
Disease-related causes
- Alcohol abuse (alcohol dependence)
- Anxiety disorders in pregnancy (risk factor for postpartum depression, PPD).
- Apoplexy (stroke)
- Burnout syndrome
- Chronic inflammatory bowel disease (CED; ulcerative colitis, Crohn’s disease).
- Chronic obstructive pulmonary disease (COPD) – every third patient with COPD has depression!
- Diabetes mellitus
- Hypothyroidism (hypothyroidism) or hyperthyroidism (hyperthyroidism).
- Hormonal imbalances – gestational diabetes (gestational diabetes), childbirth (→ postpartum depression, PPD), premenstrual syndrome (PMS), menopause, andropause.
- (Among depressed men, men with lowered levels of free testosterone were three times more likely to be depressed than those with normal testosterone levels)
- Comorbid somatic diseases/concomitant physical diseases (e.g., tumor diseases, musculoskeletal, endocrine, cardiovascular, and pulmonary diseases, metabolic disorders, allergies, brain diseases, infectious diseases)
- Premenstrual dysphoric disorder (PMDS / PMDD; mood swings in the days before menstruation) (risk factor for postpartum depression, PPD).
Medications
- 5-alpha-reductase type II – finasteride
- Antiarrhythmics
- Class Ic antiarrhythmics (flecainide).
- Mexiletine
- Antibiotics
- Aminoglycosides (amikacin, gentamicin, netilmicin, sisomicin, tobramycin).
- Quinolones (ciprofloxacin, enoxacin, fleroxacin, grepafloxacin, levofloxacin, lomefloxacin, ofloxacin, rosoxacin, sparfloxacin, temafloxacin).
- Antidepressants – SSRI and SSNRI: odds ratio 1.88 (1.34-2.64); tricyclic antidepressants: odds ratio 2.66 (1.45-4.36); collective: children aged 5 to 20 years.
- Antiepileptic drugs (felbamate, gabapentin, lamotrigine, tiagabine, topiramate, valproic acid/valproate).
- Antihypertensives-beta blockers and calcium antagonists: hazard ratio 2.11 (95% confidence interval (CI) 1.12-3.98) and 2.28 (95% CI 1.13-4.58), respectively; inpatient admission for affective disorders (84% major depression; 15% bipolar disorder)
- ACE inhibitors
- Beta-blockers (propranolol, rare!)
- Indole coloid (reserpine)
- Antimalarials (atovaquone, mefloquine, proguanil).
- Antiparkinsonian drugs
- Anticholinergic (benzatropine, biperidine, bornaprine, metixene, orphenadrine, pridinol, procyclidine, trihexyphenidyl).
- Dopaminergic (amantadine, cabergoline, dihydroergocryptine mesilate, levodopa, pergolide).
- Antipsychotics (neuroleptics) – benperidol, bromperidol, butyrophenones, chlorpromazine, chlorprothixene, clopenthixol, clozapine, dixyrazine, decanoate, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol/decanoate, levomepromazine, melperone, metofenazate, olanzapine, Oxypertin, perazine, periciacin, perphenazine/enantate, phenothiazines, pimozide, pipamperone, promazine, promethazine, prothipendyl, reserpine, risperidone, sulforidazine, thioridazine, tiotixene, trifluoperazine, trifluperidol, triflupromazine, zotepine, zuclopenthixol/acetate/ decanoate.
- Antiviralia (amantadine).
- Barbiturates
- Drugs
- Finasteride
- Hormones
- Antiandrogens (bicalutamide, cyproterone acetate, flutamide).
- Antiestrogens (tamoxifen)
- Aromatase inhibitors (anastrozole)
- Progestogens (levonorgestrel, lynestrenol, medroxyprogesterone acetate, norethisterone).
- GnRH analogues (goserelin).
- Glucocorticoids (cortisone, prednisolone).
- Estrogens
- Hormonal contraceptives (contraception using hormone-containing preparations) led to more frequent subsequent prescription of antidepressants in the following cases:
- Progestin-containing contraceptives: 34 percent more frequent (incidence rate IRR 1.34; 95 percent confidence interval 1.27-1.40),
- Intrauterine system with levonorgestrel: 40 percent more common (IRR 1.4; 1.31-1.42).
- Vaginal ring with etonogestrel: 60% more common (IRR 1.6; 1.55-1.69).
- Hormone patch with norelgestromin: 100% more common (IRR 2.0; 1.76-2.18).
- H2 antihistamines (cimetidine, ranitidine).
- Immunomodulators (interferon α2, interferon 2β).
- Local anesthetics (lidocaine, mepivacaine, procaine).
- Multi-tyrosine kinase inhibitor (vandetanib).
- Neuroleptics (tetrabenazine).
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (efavirenz, nevirapine).
- Nucleoside analogues (abacavir, didanosine, lamivudine, stavudine, zidovudine).
- Opioids (oxycodone)
- Phosphodiesterase-4 inhibitor/PDE-4 inhibitor/tsDMARDs (target synthetic DMARDs) (apremilast).
- Proton pump inhibitors (PPIs) – esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.
- Psychotropic substances/psychostimulants (amphetamines, modafinil).
- Retinoids (acitretin, isotretinoin).
- Tyrosine kinase inhibitors (TKi) – vandetanib
- Antivirals
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – efavirenz, nevirapine, rilpivirine.
- Nucleoside analogues (abacavir, foscarnet, ganciclovir,ribavirin).
- Nucleotide analogues (tenofovir)Nucleoside reverse transcriptase inhibitors (NRTI) – didanosine, lamivudine, stavudine, zalcitabine, zidovudine.
- Protease inhibitors (PI; protease inhibitors) – lopinavir. Ritonavir
- Cytokines (interferon ß-1a, interferon ß-1b, glatiramer acetate).
- Cytostatic drugs (pentostatin)
Environmental pollution – intoxications (poisonings).
- Regions with particularly poor air quality
Further
- Baby blues (risk factor for postpartum depression, PPD).
- Suicide attempts
- Negative emotionality (high propensity to show disstress) in early childhood is a possible risk factor
- Condition after treatment in an intensive care unit (every third patient shows depressive symptoms; still existing one year later)