Professor Glenn Wilson, Gresham College, London

1. THE BLACK DOG THE PSYCHOLOGY OF DEPRESSSION Professor Glenn Wilson, Gresham College, London

2. SYMPTOMS OF DEPRESSION .

3. BIPOLAR MOOD DISORDER Unipolar depression is distinguished from bipolar mood disorder: alternating periods of depression and “mania”. The manic phases include euphoria, impulsivity and “flight of ideas”. Depressive symptoms much the same as unipolar. Other variants are post-nataldepression and seasonalaffective disorder (winter depression).

4. GENETIC INPUT Some 10% suffer major depression at some point in their lives. Twin studies suggest that 40-50% of the variance is genetic. Could mean that each case is half genetic and half environmental, or that some are entirely genetic and others not at all (Levinson & Nichols, 2013). Having a depressed parent or sibling raises risk 2/3x. If their depression is recurrent and of early origin, risk is elevated 4/5x. Overlap with bipolar disorder and anxiety (but also some separation).

5. ORCHIDS vs DANDELIONS Gene/environment interactions in depression evoke comparison between orchids and dandelions (Dobbs 2013. Dandelions thrive in almost any environment; Orchids do well in ideal conditions but wilt under bad. Depression-prone people genetically predisposed as sensitive to emotional knock-backs during development. Child abuse, neglect, unstable relationships and lack of social support in adulthood may all be implicated.

6. LIFE STRESSES No one gene is responsible for depression (many involved). Certain gene locations have attracted particular research interest, e.g., the serotonin transporter gene5-HTTLPR (or SERT). People with short versions of SERT more susceptible to life stresses, increasing vulnerability to depression (Caspi et al, 2010).

7. WHAT IS STRESSFUL? Any change in our lives seems to be stressful, negative events slightly more so. Stressful events are related to the onset of major depression (Kendler et al, 1999). Mainly causal (misfortune) but about one-third down to depression-prone individuals making bad life choices (mismanagement).

8. EMOTIONAL BRAIN CONNECTIVITY SERT effect is linked with an emotional processing circuit in the brain. The cingulate cortex and amygdala show less gray matter volume in short SERT carriers. Also less functional coupling between the two areas under fear stimulation, suggesting that amygdala response is poorly regulated in s-SERT people (rendering them more stress-prone). Brain areas where s-SERT carriers have reduced gray matter: amygdala (L), Cingulate cortex (R). (Pezawas et al, 2005)

9. MONOAMINES Neurotransmitter activity is implicated in depression, esp. serotonin (modulates mood), nor-epinephrine (alertness) and dopamine (pleasure/reward). Organised as circuits running from brain stem and limbic regions to many cortical areas. Most anti-depressants amplify these “monoamines”. Effects of psychological therapies may also be observed in brain chemistry.

10. SSRIs Selective serotonin reuptake inhibitors (e.g., Prozac) work by blocking the reuptake of serotonin at the synapses, thus prolonging its positive effect on mood (contentment). Effect not immediate – may take several weeks to work (if indeed they do).

11. DO THE DRUGS WORK? Value of antidepressants much debated. They have side-effects and may be addictive. Not effective with mild depression; placebos just as good (Fournier et al, 2010). At severe levels of depression on HamiltonRating Scale, drugs outperform placebo but mainly because placebos are less effective (Kirsch et al, 2008).

12. ST JOHN’S WORT Extract of hypericum works as well as standard drugs for major depression. An SSRI with fewer side-effects? (Linde et al, 2009). Studies from German-speaking countries (where there is a long tradition of use) usually more positive. Drug companies little interested because herbs cannot be patented. Commercially available forms vary enormously; probably not all effective. Being “natural” does not make them “safe”. Can interact with other drugs and cause photosensitivity.

13. LEARNED HELPLESSNESS Seligman (1967) observed that dogs subjected to inescapable shock failed to take effective action when escape later became possible. Had learned to be helpless. Depression construed as a feeling of powerless (lack of control over events acquired from unhappy life experiences. Later recognised that causal attribution mediates effect. Pessimists tend to blame themselves rather than bad luck for negative outcomes, hence adopt submissive attitudes.

14. THE VICIOUS CIRCLE Cognitive Behaviour Therapy based on premise that depression arises from negative, self-destructive thoughts. Low mood regarded as a consequence of maladaptive attitudes and beliefs. e.g., A person losing their job might say “economic conditions are difficult”, and look for a new job, or they could conclude “I am a useless – no one will ever employ me again”. CBT aims to alter irrational and pessimistic thought patterns so that constructive action and improved mood will follow.

15. HORSES FOR COURSES Patients with major depression are usually prescribed drugs but only 40% get better after 2/3 months; then another approach is tried. Would help to find a way of predicting response to treatment. Depressed patients with higher PET activity in the anterior insula did better with drugs (12 weeks escitalopram); those with low AI activity responded to CBT but not drugs (McGrath et al, 2013). Less intrusive ways to personalise treatment being sought, e.g., gene markers (Lester & Eley, 2013). People with short SERTs benefit more from CBT. Anterior insula activity observed by PET-scan (McGrath et al (2013).

16. RECOVERY IN THE BRAIN Clinical improvement observed in PET-scans differs for drugs vs CBT. Recovery with paroxetine mostly seen as increases in prefrontal activity and decreases in hippocampus and cingulate. CBT improvement went with increased activity in the hippocampus and dorsal cingulate and decreases in frontal cortex. Difference: “bottom up” chain of events vs “top-down”? (Goldapple et al, 2004).

17. BRAIN REPAIR Once thought we are born with all the brain cells we ever have. Carbon-14 dating of hippocampal cells in deceased persons shows new cells are spawned in their lifetime. (Radioactive C-14 in atmosphere has declined since 1960s nuclear test ban). Clinical depression is associated with reduced neurogenesis in the hippocampus, apparently stress induced (since glucocorticoids are implicated). Failure of new cell growth may help account for low mood and memory impairment. Anti-depressant drugs promote neurogenesis (Anacker et al, 2011).

18. LET THERE BE LIGHT Bright light alleviates depression, especially earlier dawn simulation for seasonal affective disorder (Golden al, 2005). Restoring blue wave-lengths missing in artificial light may be important. Effects as strong as Prozac but not additive if light therapy used as adjunct to medication. Apparently due to suppression of the release of melatonin, a sleep hormone that seems to be depressogenic.

19. EXERCISE About as effective in treating depression as drugs and talk therapy (Rimer et al 2012; Silveira et al, 2013); can be an adjunct to either. Long-term effects are questionable however (Krough et al, 2011). Benefits could be due to improved health, fitness, self-image, diversion of negative thoughts, exposure to fresh air/sunshine or social contact. Severe cases usually difficult to persuade to take exercise, so may be some circularity.

20. PETS Animals provide companionship often missing in people’s lives (e.g., elderly, widowed, bullied children). Pets are non-judgemental & make unconditional bonds. Their dependency adds purpose to life (child surrogates) and dogs need to be walked (= exercise). Many studies show benefits of animal contact in reducing stress and depression (self-report and physiological measures). Nepps et al (2011): animal-assisted therapy effects comparable to behavioural stress reduction programme.

21. IN VINO FELICITAS Gea et al (2013) followed 5500 Spanish adults, aged 55-80, over 7 years. Moderate consumption of wine (2-7 glasses/week) went with 32% reduced risk of depression (although heavy drinking increased risk). Same factors which protect against cardiovascular disease (e.g., resveratrol) may prevent depression. Other possibilities: Mediterranean diet (previous finding by same authors), general health, wealth, life-style & social context of light drinking may mediate effect.

22. A STIFF UPPER FACE Contriving facial expressions appropriate to particular emotions can induce the actual feeling of that emotion. By freezing the muscles needed to produce a frown, Botox may reduce symptoms of depression (Wollmer et al, 2012). Reverse likely to apply; freezing laugh lines around eyes may obstruct happiness (Finzi, 2013). Danger that impairment of empathy could damage social relationships (appearance of insensitivity). Inability to express surprise could lead to gullibility?

23. TRANSCRANIAL MAGNETIC STIMULATION Electromagnetic induction of weak currents in selected brain areas (esp. frontal) usually over several sessions. Non-invasive compared with ECT or surgery. Side-effects: occasional seizures/headache. Some evidence for efficacy with depression but still largely experimental (Slotema et al, 2010). Mechanism unclear and many variables remain to be explored. Difficult to devise sham control to mimic sound/scalp sensations.

24. RECREATIONAL DRUGS Not all environmental effects are psychological. MDMA (ecstasy), widely used in dance clubs, depletes the serotonin system in the brain, making the user more prone to depression. May be short-term (“suicide Tuesday”) or permanent. Briere et al (2012): adolescents’ use of ecstasy & speed doubled subsequent depressive symptoms (5 year follow-up). Previous users of ecstasy may be most at risk of depression (Roiser & Sahakian, 2004).

25. “SPECIAL K” Ketamine is another drug used for night-club highs/trances. Approved use as anaesthetic but current interest in possibilities as a fast-acting anti-depressant (Murrough et al, 2013). SSRIs usually take weeks to work; intravenous ketamine may lift depression in hours. Enhances glutamate transmission, raising neuron excitability. Parallel to effects of ECT and transcranial magnetic stimulation? Dangers include addiction, hallucination & bladder damage but already used “off-label” in some US clinics for treatment-resistant depression (Stix, 2013). Ketamine-induced increases in neural connectivity observed in a rat brain (Ronald Duman, Yale Univ.)

26. SUICIDE RISK Depression increases risk, esp. when severe and long-lasting (20x norm). Anorexia, drug use, chronic pain, PTSD, anxiety & impulse-control disorders also raise risk. May be preceded by threats/jokes, tying up loose ends, sudden mood elevation. Risk factors: family history, poor social support, availability of means. Women attempt 2x men (drug overdose); men succeed 2x women (firearms). LGBTs > avge. Age: <14, and 65+ have higher rates. Previous attempts: esp. predictive when violent mode – hanging, drowning, jumping, shooting (Runeson et al, 2010). Nightmares following a suicide attempt are a bad sign but not other sleep disturbances (Sjostrom, 2009). Comedian Stephen Fry, who suffers from bipolar disorder, has attempted suicide on more than one occasion.

27. COMPUTER TASKS Interviews re suicidal plans unreliable because patients conceal their intentions (78% deny intent just before killing themselves). Word associations and reaction times give subtler clues. Stroop and Implicit Associations tests used to measure attention to and ease of association between critical words Those with strong associations between “self” and “death/suicide” 6x more likely to attempt suicide within 6 mths (Nock, 2010). Better than known predictors (depression, history of suicide-attempts, own & clinician expectations).

28. BIOMARKERS A protein encoded by a gene on the X chromosome (SAT1) has recently been reported as a possible blood biomarker of suicide (Niculescu et al). This protein is associated with cellular damage and stress. Work so far has only involved small samples of men, mostly bipolar. If replicated, might have potential as test for suicide risk.

29. ADAPTIVE VALUE? Women about 2x as susceptible to depression as men. Not just social factors; depression in men goes with feminised finger ratios (Bailey & Hurd, 2005). Depression proneness may be price paid for greater emotional sensitivity (empathy and social communication skills). Similar selection might apply to s-SERT genes. Not eliminated over many thousands of years, hence likely to confer some advantage. Belsky et al (2009): people with s-SERT genes are susceptible to adversity but function better in supportive and enriching environments. Vulnerability better construed as plasticity?

30. MEDICALISING MISERY Concern that anti-depressants are over-prescribed for mild depression. (1) Lack of resources for alternatives like talk therapy. (2) Fashionability among celebrities. (3) Commercial interests blur distinction between unhappiness and profound depression. There is an enormous amount of money to be made from prescribing marginally effective medications to large numbers of people (Wright, 2013). Danger of masking deprivation and social problems by “medicalising” them. In certain Welsh valleys, where unemployment is high, 1/6 adults are medicated – thus qualifying them for “disability benefit”.