DEPRESSION

Nota:

• A long-term disease with high chances of relapse

1. TYPES
   1. Major depression (MD)

      Nota:

      •    May begin suddenly-possibly triggered by loss (major life event)-continue months or years-single episode/multiple episode (more common) (more women)   
      1. Melancholic depression

         Nota:

         • severe variant of MDD as patients’ loss of pleasure more closely approaches absolute anhedonia and neurovegetative symptoms take on greater intensity
         1. melancholic vs non-melancholic

            Nota:

            • A twin study of melancholic depression concluded that melancholic and non-melancholic depression demonstrated quantitative (e.g., higher concordance rates of MDD in melancholic co-twins compared to non-melancholic co-twins) but not qualitative differences, suggesting shared rather than disparate etiologic mechanisms The
   2. Dysthymia

      Nota:

      • mild depression for years
   3. Bipolar Disorder

      Nota:

      •    Depression with periods of mania (less need for sleep, reckless behaviour, racing thoughts)   (men and women)   
      1. Manic Episode
         1. A distinct period of abnormally and persistently elevated, expansive or irritable mood

            Nota:

            •    •Three of the following symptoms persist (four if the mood is only irritable) and have been persistent to a significant degree –Inflated self esteem or grandiosity –Decreased need for sleep –More talkative than usual or pressure to keep talking –Flight of ideas or subjective experience that thoughts are racing    –Distractability,   –Increase in goal-directed activity –Excessive involvement in pleasurable activities which are likely to have unwanted consequences, e.g. shopping sprees, hyper sexuality, ‘gambling’   
         2. Mood disturbance

            Nota:

            •    •causing impairment in ability to carry out normal work and to interact with others, or to necessitate hospitalization to prevent harm to self or others •At no time during the disturbance have there been delusions or hallucinations for as long as two weeks in the absence of prominent mood symptoms   
         3. Not superimposed on schizophrenia

            Nota:

            • different symptoms to schizo?
         4. Not due to the physiologic effects of a substance
   4. Seasonal Affective Disorder (SAD)

      Nota:

      • depression due to decrease in sunlight
   5. Atypical depression

      Nota:

      • characterized by hypersomnia, hyperphagia, and mood reactivity (e.g., brightening in response to positive events). Atypical criteria also include ‘leaden paralysis’ in the limbs and long-standing patterns of ‘interpersonal rejection sensitivity’—symptoms which are inherently more difficult to standardize or objectively measure. Despite the possible presence of mood reactivity, it is not necessarily the case that atypical depression represents a ‘milder’ form of MDD
      1. earlier age of onset
      2. females
   6. Postpartum depression,
2. HISTORY
   1. Reserpine
      1. First used for insomia/ Schizo
         1. calmed patients
      2. depletes monoamines

         Nota:

         • deplete all monoamines by preventing reuptake into vesicles (so depletes).  Inhibits storage of monoamine neurotransm-itters   
      3. treats major depression
      4. Carlsson (2002)

         Nota:

         • chlorpromazine reduced dopaminergic neurotransmission
   2. 1950s -Chlorpromazine
      1. was shown to be a sedative
      2. Used in Schizo- reduced + symptoms
      3. Carlsson (2002)

         Nota:

         • reserpine and chlorpromazine reduced dopaminergic neurotransmission
      4. Da receptor antagonist
   3. 1950s- Iproniazid
      1. antibacterial for tuberculosis
         1. reported to be mood elevating
      2. antidepressant
         1. inhibits monoamine oxidase

            Nota:

            • (an enzyme that inactivates Na, Da and 5HT) 
   4. 1957- Imipramine
      1. Developed for Schizophrenia
         1. not very effective
      2. anti-depressant
         1. monoamine reuptake inhibitor
3. Epidemiology

   Nota:

   •    Point prevalence         •  6 – 8% in women  •  3 – 4% in men    Lifetime prevalence •  20% in women  •  10% in men   
   1. X2 more in women
4. SYMPTOMS
   1. have to be present for 2 weeks
   2. Emotional

      Nota:

      •    Loss of interest-sadness-irritability  Feeling empty Enjoyment gone Hopelessness  Loss of sexual desire  Loss of feelings for family or friends  Guilt Loss of self esteem Crying spells, sadness or irritability Poor memory Self neglect Suicidal thoughts  Difficult to make decisions
   3. Physical

      Nota:

      •    Sleep disturbances (such as early morning waking,   sleeping too much or insomnia) Lack of energy  Loss of appetite  Weight loss or gain  Unexplained headaches or backaches  Indigestion or changes in bowel habits   
5. ANIMAL MODELS
6. RISKS

   Nota:

   • Depression is a highly prevalent psychiatric disorder with a lifetime risk close to 20% and is associated with high levels of morbidity and mortality.2Depressed patients are at higher risk of serious physical health problems such as coronary artery disease and diabetes3 and worsening of the prognosis of other medical conditions
   1. coronary artery disease
   2. Diabetes
   3. worsening of ongoing conditions

Nota:

• see The neurobiology of depression

1. GENETICS

   Nota:

   • See The genetics of major depression: Moving beyond the monoamine hypothesis
2. CHEMICAL IMBALANCE

   Nota:

   • These forebrain networks are significantly modulated by monoamine projections from midbrain and brainstem nuclei >>In addition to controlling alertness and awareness, these neurotransmitters modulate the salience of emotional stimuli
   1. MONOAMINE HYPOTHESIS- 1974
      1. DA
         1. Evidence
            1. antidepressant drugs

               Nota:

               • produced a calming affect by altering monoamine levels- >> increase monoamine levles
               2. Monoamine oxidase inhibitors

                  Nota:

                  • produce immediate increases in monoamine transmission, whereas their mood-enhancing properties require weeks of treatment
      2. NA

         Nota:

         • increased
      3. 5-HT

         Nota:

         • increased
         1. Evidence
            1. rodent stress models

               Nota:

               • shown that enhancements in dopamine and noradrenaline transmission can have maladaptive roles in stress-related disorders by strengthening memories of aversive life events
               1. Hu et al (2007)
      4. Mechanism

         Nota:

         • acute increases in the amount of synaptic monoamines induced by antidepressants produce secondary neuroplastic- by transcriptional or translational changes
         1. 5-HT receptors
            1. p11

               Nota:

               • serotonin 5-HT1B receptor interacts with a calcium-binding protein named p11, which was upregulated in cerebral cortex on chronic treatment with SSRIs and was also found to be downregulated in post-mortem cingulate cortex samples from depressed individuals
               1. overexpression of p11

                  Nota:

                  • produced an antidepressant phenotype, implicating this SSRI-mediated upregulation of p11 as an important mechanism downstream of serotonin receptor activation
                  1. led to depression
            2. CREB

               Nota:

               • transcription factor CREB (cyclic-AMP-response-element-binding protein), which is downstream of several serotonin and other stimulatory G-protein-coupled receptors, in the hippocampus; this effect has been validated in human post-mortem tissue and directly linked to antidepressant-like responses in animal models2
               1. animal models
               2. (-) region specific effect

                  Nota:

                  • stress activation of CREB in NAc triggers depression-like responses, which underscores crucial region-specific actions of neurotransmitters and their downstream effectors that have not been incorporated into simplistic deficiency models
   2. NEUROENDOCRINE
      1. Cortisol/ CRF

         Nota:

         • increased
         1. Rodents

            Nota:

            • depressive-like symptoms following administration of glucocorticoids
            1. Gourley et al (2007)
         2. Excessive glucocorticoids- HPC

            Nota:

            • Excess glucocorticoids, through the activation of glucocorticoid receptors, can reduce SGZ proliferation rates and produce atrophic changes in hippocampal subregions61. This could contribute to the hippocampal volume reductions seen in depression. 
            1. e.g. cushing's
            2. explains HPC volume reduction
         3. corticotropin-releasing factor receptor antagonists- currently in clinical trials
      2. BDNF

         Nota:

         • decreased
         1. Rodents
            1. inconsistent evidence
               1. knockouts

                  Nota:

                  • antidepressant effects were observed on direct infusion of BDNF into the hippocampus and were blocked on the conditional or inducible knockout of the gene encoding BDNF from forebrain regions
                  1. Monteggia et al (2007)
               2. preclinical

                  Nota:

                  • either have failed to show these patterns of changes induced by stress and by antidepressants, or have shown the opposite effects
                  1. Martinowich et al (2007)
               3. VTA-NAc

                  Nota:

                  • ventral tegmental area, nucleus accumbens
                  1. Eisch et al (2003)

                     Nota:

                     • direct infusion of BDNF into the VTA–NAc increases depression-related behaviours
                     1. pro-depression
                  2. Berton et al (2006)
                     1. knockouts- antidepressant

                        Nota:

                        • knockout of the gene encoding BDNF from this circuit has antidepressant-like effects
               4. Region specific?

                  Nota:

                  • BDNF has different effects on depression-like behaviours depends on where its acting and function in the background of other potent genetic and environmental modifiers
               5. polymorphism

                  Nota:

                  • complex interactions between the Bdnf G196A polymorphism, a polymorphism in the serotonin transporter gene, and stressful life events
                  1. Kaufman et al (2006)
   3. Cytokines

      Nota:

      • e.g. interferon- or interleukin  IL-6 / IL-1 etc increases
      1. side-effects>> depression

         Nota:

         • Roughly 30% of individuals treated with recombinant interferons develop depression as a side effect of treatment
         1. Loftis & Hauser (2004)
      2. Animal studies- inconsistent
         1. Dunn et al (2005)

            Nota:

            • examining depression-associated increases in serum cytokine concentrations have been largely inconsistent
            1. Administration of cytokines

               Nota:

               • Administration of cytokines such as interferon- or IL-6 to rodents does not cause consistent depression-like features
         2. Knockouts
            1. Simen et al (2006)

               Nota:

               • Mice with targeted deletions of the gene encoding IL-6 or those encoding the TNF- receptors show antidepressant-like behavioural phenotypes
3. ENVIRONMENTAL
   1. pre-natal
   2. Stress
   3. Major life event
   4. Drug abuse
   5. Ilness
   6. Exercise
4. NEUROANATOMY

   Nota:

   • it has been hypothesized that in the depressed state the balance amongst the structures within the neurocircuit is disrupted probably as a result of decreased activity in the PFC which impairs its regulatory (inhibitory) action on the limbic structures which in turn are overactive

   Adjunto:

   • Depression
   1. PREFRONTAL
      2. PET
         1. increased activity
            1. VMPFC and LOPFC

               Nota:

               • ventromedia, lateral orbital
         2. Drevets (1998)
         3. decreased activity
            1. DLPFC

               Nota:

               • dorsolateral
      3. Morphometric
         1. reduction in neuronal and glial-orbitofrontal DLPFC
   2. AMYGDALA
      1. Correlates with depression

         Nota:

         • Abnormal activation of the amygdala correlates with the severity of the depression. They have been implicated in the tendency to ruminate and may also play a role in bipolar depression and anxiety
      2. meta-analysis MRI
         1. Himilton et a (2008)

            Nota:

            • A recent meta-analysis of MRI studies, which took into account the possible role of medication on the size of the amygdala, demonstrated that this is actually reduced in unmedicated depressed patients
         2. reduced volume in unmedicated patients
   3. HIPPOCAMPUS
      1. meta-analysis MRI
         1. Large volume reductions in Depression
         2. Koolschijn et al (2009)
      2. meta-analysis MRI-
         1. Volume reductions correlated with multiple episodes
      3. clinical improvement

         Nota:

         • Clinical improvement is believed to be associated with the reversal of structural changes as remitted patients have larger hippocampal volumes compared with non-remitted patients

Nota:

• see Advances in the Treatment of Depression

1. DRUGS
   1. NMDAR anta
   2. MELATONIN
      1. animal models

         Nota:

         • Exogenous melatonin has some antidepressant-like actions in animal models.56 Daily treatment with melatonin reverses the adverse effects of chronic stress in mice.57
      2. Humans

         Nota:

         • By contrast, treatment with melatonin alone in human beings does not seem to be an effective antidepressant strategy.58 Although melatonin might improve sleep–wake timing and increase sleep duration in patients with major depressive disorder, there seem to be few more specific antidepressant effects.59 Addition of chronobiotic drugs such as melatonin to currently used antidepressant therapies can, however, improve overall outcomes.
         1. combination with antidepressants
   3. GLUCOCORTICOIDS/ CRF
   4. SP

      Nota:

      • substance P
   5. MONOAMIMES
   6. BDNF
2. STIMULATION
   1. DEEP BRAIN

      Nota:

      • for treatment-resistant depression
      1. Kennedy et al (2010)
         1. 6 year study

            Nota:

            • The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3—6 years), the average response rate was 64.3%. Functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit. No significant adverse events were reported during this follow-up, although two patients died by suicide during depressive relapses.
         2. Safe and effective in long term
   2. VEGAL NERVE
   3. FOCAL BRAIN
   4. TRANSCRANIAL MAGNETIC
3. MAGNETIC SEIZURE THERAPY
4. YOGA

   Nota:

   • See How Might Yoga Help Depression? A Neurobiological Perspective
   1. Kinser et al (2012)

Nota:

• See- Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression