Sapolsky: The Biological and Psychological Link to Major Depression

Depression is crippling, pervasive, prevalent and worth studying.  Depression is also a major cause of disability.

The focus of this article /lecture : What has biology, what has psychology got to do with depression?

What is depression? Depression is suffered by people who don’t recover from major setbacks.

Symptoms of major depression: a biological disorder with genetic predisposition with early childhood influences.  Sapolsky means this because we can compare people who stay positive

  • *Anhedonia: the inability to feel pleasure,
  • *grief & guilt severe to take on “delusional quality” (unable to see things in positive light and choose to dwell on negatives).
  • *self injury
  • *psychomotor retardation… too exhausted to do stuff.
  • *not able to cope / heal.

Vegetative symptoms of depression:

  • *trouble sleeping: wake up early and not able to go back to sleep.
  • *Different way of being alseep
  • *decreased appetite
  • *overactive stress response: increased metabolic rate / muscle tone
  • *rhythmic patterns of depression (cycles / seasonal)

What goes on in the brain with major depression?

15:30 Neurotransmitters. In depression, implicated are

  • * Norepinephrin (NA): Drugs which are MAO inhibitors inhibit deactivation of NA. Tricyclic antidepressant, increase effect of NA. Blood pressure drug that decrease NA, patient gets depressed. Lack of NA has something to do with anhedonia. NA has effect on pleasure sensation. Antidepressants of this sort takes long to work on depressed people.
  • * Dopamine : has something to do with anhedonia
  • * Serotonin: SSRI Prozac works on serotonin re-uptake. Helps with Psychomotor retardation / obsessive sense of grief.
  • * Substance P (neurotransmitter) is about pain.  When drugs supress substance P, depressives get better.



This is a neurochemical-mobile diagram showing the relationship between key neurotransmitters and their receptors (Tretter et. al. 2010).  The neurotransmitters described here belong to the activation of the left side of the diagram. So, in major depression, can we say that the mobile would be tilted to the right?

23.30 Neuroanatomy: Lymbic system, Cortex.

Depression is rumination, and the body responds to it, as if there were a real danger / setback. “What depression is is the body getting too many sad thoughts and the body going along with it. The brain stimulates the body to activate the fright-flight mode.

Sapolsky mentions the Anterior Cingulate Cortex, implying that it is a part responsible for depression.  This part, when severed from the rest of the brain, also removes pleasure sensation.


Cg25 is the subgenual cingulate . it is part of the pleasure-depression regulated region. As we can see in the diagram, the connected regions are complicated. The goal of pharmacology is to get involved in the modulation of activity in these different regions.

One can see here the balance between the vegetative-somatic controls and cognitive centers of the brain. In depression, the cognitive centers become “depressed” while the active somatic control contribute to the tension felt in the body. 



(Mayberg 2005). Regional cerebral blood flow changes (CBF PET) in patients being treated by deep brain stimulation (DBS) for major depression at baseline (row 1) and after 3 months (row 2) and 6 months (row 3). Treatment was considered successful based on psychological tests (Hamilton). Sagittal (left) and coronal (right) views. Baseline CBF abnormalities are seen relative to age- and gender-matched healthy control subjects (NC): increases in subgenual cingulate (Cg25) and decrease in dorsolateral prefrontal (F9), ventrolateral prefrontal (F47) and anterior cingulate (Cg24) cortices (row 1, patients 1–5). Three months of DBS relative to baseline (row 2, patients 1, 3, and 5): decreases in Cg25, hypothalamus (Hth), anterior insula (ins), medial frontal (mF10) and orbital frontal (oF11); increases in prefrontal (F9/46) and dorsal cingulate (cg24). This basically shows the difference between the depressed state in the brain where Cg25 is over-activated and the anterior cingulate and prefrontal areas are under-activated, and the more normal state where the activity is opposite.  


Hormones involved in depressive episodes:

  • *Thyroid hormone. Hypothyroidism is also associated with major depression.
  • *Female hormonal cycles. Ratio of estrogen to progesterone.
  • *Stress hormone: adrenaline, glucocorticords/cortisol  36:00  — depletes Dopamine.

Biology, however is not enough.

39:00 Freud on melancholia. The difference between mourning and melancholia (Freud , 1922). Mourning allows one to recover. Melancholia is the rumination and wallowing, which is depression. Absence of mourning leads to guilt, followed by aggression turned inward to the self. Depression is described by Sapolsky as such.

Screen Shot 2017-12-16 at 08.53.32

How does one explain the biological with Freudian ideas?

42:00 Experimental Psychology

Psychological stress is pathological extremes of learned helplessness, loss, lack of control. One has no possibility to release the stress, by doing something, or talking to someone who is willing to listen.

E.g. loss of parents before 10 yrs of age, there is more tendency of suffering major depression.

Stress is the intersection of the bio and psychological. Depression seem to be genetically linked, but there also other components that are equally relevant.

47:00 Serotonin re-uptake genes? No empirical proof to show that “relevant” genes alone leads to depression. Childhood experiences have as much to do with incidence of major depression (Ogilvie 1996).

Glucacorticoids regulate the function of this gene. Hence stress has an influences (Caspi et al 2003).

In the study of Mayberg which treated patients with deep brain stimulation, the patients, following treatment, describe their experiences as :
“All patients spontaneously reported acute effects including “sudden calmness or lightness,” “disappearance of the void,” sense of heightened awareness, increased interest, “connectedness,” and sudden brightening of the room, including a description of the sharpening of visual details and intensification of colors in response to electrical stimulation. ” This is similarly described when individuals are effectively treated with psychotherapy (see the student say, “the colors are bright”, to which Perls call it the mini satori in this video of therapy session with Fritz Perls) and also described in psychedelic experiences.  Many meditative exercises also provide for this change of experience.


Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., … & Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science301(5631), 386-389.

Freud, S. (1922). Mourning and melancholia. The Journal of Nervous and Mental Disease56(5), 543-545.

Ogilvie, A. D., Battersby, S., Fink, G., Harmar, A. J., Goodwin, G. M., Bubb, V. J., & Smith, C. D. (1996). Polymorphism in serotonin transporter gene associated with susceptibility to major depression. The Lancet347(9003), 731-733.

Sapolsky, R. (2009). Stanford’s Sapolsky On Depression in U.S. (Full Lecture). Youtube. url:

Tretter, F., Winterer, G., Gebicke-Haerter, P. J., & Mendoza, E. R. (Eds.). (2010). Systems biology in psychiatric research: from high-throughput data to mathematical modeling. John Wiley & Sons.

Leave a Reply

Your email address will not be published. Required fields are marked *