Lecture 4 - Depression

Question 1

Name some of the main symptoms for major depression according to the DSM-IV diagnostic criteria.

Answer 1

Depressed mood
Irritability
Low self-esteem
Feelings of hopelessness, worthlessness and guilt
Decreased concentration
Decreased appetite
Weight loss or weight gain
Insomnia or hypersomnia
Low energy, fatigue
Decreased interest in pleasurable stimuli
Recurrent thoughts of death and suicide

Question 2

What percentage of the UK population experience depression in any one year?

Answer 2

Between 8% and 12%

Question 3

What is the monoamine theory of depression?

Answer 3

5HT1A receptors (sub-type of serotonin receptor) mediate mood, anxiety and temperature Therefore, a decrease in serotonin in the system leads to dysregulation of the above factors.

Question 4

What is one piece of evidence for the monoamine theory of depression?

Answer 4

Young et al., (1985) found higher levels of symptoms of depression in normal males given a tryptophan-free diet, compared to those given a balanced or excess tryptophan mixture.

Question 5

What is the first line of treatment for depression?

Answer 5

SSRIs, selective serotonin reuptake inhibitors - drugs which block serotonin reuptake, and noradrenaline.

This reuptake blocking would leave greater amounts of extracellular serotonin, enabling more to bind to receptors and allow regulation of mood, anxiety, etc.

Question 6

What is the function of noradrenaline?

Answer 6

Noradrenaline increases blood pressure by narrowing blood vessels and by affecting the heart directly. It also increases levels of glucose and immune cells (i.e. T cells)

Question 7

What is social adaptation?

Answer 7

The ability of an individual to adapt their behaviour to make it appropriate for the social situation they find themselves in.

Question 8

What is social support?

Answer 8

People who are emotionally close to the individual and provide understanding, encouragement and generally positive feedback.

Question 9

What percentage of depressed patients remit following citalopram treatment?

Answer 9

33% remitted following 14 weeks of citalopram treatment

Question 10

What are other methods of treatment for depression?

Answer 10

• CBT
• ECT
• TMS
• DBS

Question 11

What percentage of the risk for depression is genetic?

Answer 11

40%-50%, which is at least as heritable as type II diabetes, hypertension and asthma.

Question 12

What did Kendler et al., (2001) find about major depression as a progressive illness, and using previous episodes to predict risk?

Answer 12

The more the previous depressive episodes, the greater the odds ratio (risk) of depression onset.

The more the previous depressivesodes, the lower the likelihood that recent stressful life events is the cause of the depression (suggests that the later episodes are set off by previous/early episodes, rather than directly from life stressors)

Question 13

What did Kendler et al., (2001) find about major depression as a progressive illness, and using previous episodes to predict risk?

Answer 13

The more the previous depressive episodes, the greater the odds ratio (risk) of depression onset.

The more the previous depressisodes, the lower the likelihood that recent stressful life events is the cause of the depression (suggests that the later episodes are set off by previous/early episodes, rather than directly from life stressors)

Question 14

Which areas have been consistently implicated in mood disorders since work in patients with secondary mood disturbances resulting from acquired brain injuries?

Answer 14

Frontal lobes and basal ganglia - greater incidence of depression following strokes which damaged the PFC or basal ganglia, especially the left side of the brain. Also associated with rare cases of secondary mania (sub-category of bipolar that is caused by trauma or physical illness).

(Clark, Chamberlain and Sahakian, 2009).

Question 15

Why might lesions to frontal lobes and the basal ganglia be implicated in depression?

Answer 15

Potential difficulty for regions of the PFC to be able to regulate responses of the amygdala to negative or positive feedback.

Basal ganglia may be implicated due to dopaminergic abnormalities…?

Question 16

Which other neurological conditions are associated with elevated levels of depression?

Answer 16

PD and HD - conditions affecting the basal ganglia. Increases support for the implication of the basal ganglia in underlying mechanisms of depression.

Question 17

How is executive control affected in mood disorders, specifically in major depressive disorder (MDD)?

Answer 17

Executive control is diminished in unmedicated cases of MDD, and are exaggerated in bipolar depression.

Functional imaging evidence finds that dorsal and lateral PFC is dysregulated in depressed patients performing executive tasks (e.g. stroop/WM task), with PFC hypoactivity on tasks where performance was impaired.

On tasks where performance was no different to controls, PFC activation was greater, suggesting that cortical efficiency is lower in depressed patients.

(Clark, Chamberlain and Sahakian, 2009)

Question 18

How is memory affected in mood disorders, specifically in major depressive disorder (MDD)?

Answer 18

Mnemonic impairment is predictive of functional outcome, and correlates with the extent of chronicity of the depression - Gorwood et al., (2008) found a 2/3% decline in delayed paragraph recall with each depressive episode, up to the 4th (i.e. memory worsens with each episode)

Reduced hippocampal volume is the most robust neuropathological finding in MDD. No differences in volume between controls and untreated first-episode cases of MDD but large reductions in patients who had experienced multiple episodes (MacQueen et al., 2003).

Reduction in volume may occur due to the vulnerability of the hippocampus to hypoxic effects. Depressive episodes are associated with increased cortisol levels, which seem to cause the hippocampus to resemble an aged brain (Sapolsky et al., 1985).

(Clark, Chamberlain and Sahakian, 2009)

Question 19

How is affective processing bias affected in mood disorders, specifically in major depressive disorder (MDD)?

Answer 19

Depressed patients are impaired at recognising happy facial expressions (Lembke & Ketter, 2002)

Depressed patients respond more rapidly to sad word targets, compared to happy word targets, on the affective go/no-go task, and compared to healthy controls (Murphy et al., 1999).

Depressed patients showed increased subgenual cingulate responses to sad targets, and a distinct response to sad distractors in the right OFC (Elliott et al., 2002).

Increased amygdala response in MDD patient groups, in response to negative emotional faces (Fales et al., 2008)

(Clark, Chamberlain and Sahakian, 2009)

Question 20

How does the positivity of memory recall differ in depressed patients?

Answer 20

Patients with depression have an increased tendency to recall negative autobiographical memories. When they do recall positive memories, they are lacking in detail (Brittlebank et al., 1993).

Question 21

How might connectivity be relevant in depression?

Answer 21

Connectivity between the amygdala and multiple PFC sites may be affected in depressive states.

Negative correlation between amygdala and ventrolateral PFC activity in controls, when performing an emotional reappraisal task. In MDD patients, there was either no correlation, or the correlation was positive

(Chen et al., 2008) in Clarke, Chamberlain and Sahakian, 2009).

Question 22

What is one of the few pieces of causal evidence that reduced serotonin function is linked to depression?

Answer 22

Smith et al. (1997) - finding that acute tryptophan depletion in remitted MDD patients causes a temporary relapse of low mood.

Question 23

How is feedback sensitivity affected, specifically exaggerated responses to negative responses, in mood disorders, specifically in major depressive disorder (MDD)?

Answer 23

Depressed patients have exaggerated responses to negative responses during lab testing:

Elliot et al., (1997) found that depressed patients who responded incorrectly on a given trial of a working memory task would be disproportionally likely to fail the following trial.

Reduced top down control of the amygdala due to hypoactivity of the PFC and a failure to decrease amygdala activity in response to misleading negative feedback (Tavares et al., 2008).

Question 24

How is feedback sensitivity affected, specifically numbed responses to positive feedback, in mood disorders, specifically in major depressive disorder (MDD)?

Answer 24

Anhedonic symptoms:

Reductions in ventral striatal activity in MDD in response to happy facial expressions and positive words (Surguladze et al., 2005).

MDD patients showed decreased ventral striatal activity in response to correct feedback, and reduced ACC activity in response to incorrect feedback, suggesting a deficient/lacking positive reinforcement/recognition of success, and an attenuated use of negative feedback to improve task performance (Steele et al., 2007).

Question 25

How have studies implicated serotonin in the feedback sensitivity domain of depression?

Answer 25

They implicate serotonin in the modulation of affective processing and feedback sensitivity, putatively associated with the medial and ventral fronto-striatal circuitry.

Question 26

What does RTD stand for?

Answer 26

Rapid tryptophan depletion

Question 27

What is anhedonia?

Answer 27

The inability to feel pleasure in normally pleasurable situations.

Question 28

What did Talbot and Cooper (2006) find about brain activity in healthy males when sad?

Answer 28

Previous research had suggested that RTD caused changed in cognition without influencing mood, implying separate mechanisms underlying the two main domains of depression.

Found that changes in happiness were related to increased rCBF in the subgenual (affective) ACC and associated regions, including the ventral striatum and caudate nucleus.

When the variance in rCBF associated with mood change was removed, RTD
was associated with decreased rCBF in the left dorsal (cognitive) ACC.

Suggests that the neurological bases of mood and cognitive deficits in depression are precipitated by distinct underlying mechanisms.

Question 29

What did Liotti et al., (2002) find about a mood challenge in unipolar euthymic patients in full remission?

Answer 29

Evoked sadness (mood challenge involving writing an autobiographical memory of sadness; most pps cried) leads to activation and deactivation patterns in several brain areas in depressed patients in remission are more similar to acutely depressed patients than to healthy controls, implying that such activity represents aberrant activity/trait markers in depression.

Activation includes: dorsal ACC, Globus pallidus, premotor, sensorimotor and visual cortex.

Question 30

According to Chen et al., what does a trait marker represent?

Answer 30

A trait marker represents the properties of the behavioural and biological processes that play an antecedent, possibly causal, role in the pathophysiology of the psychiatric disorder.

Question 31

According to Chen et al., what does a state marker represent?

Answer 31

A state marker reflects the status of clinical manifestations in patients.

Question 32

What did Mayberg et al., (2000) find about functional changes with antidepressant treatment?

Answer 32

Clinical improvements were associated with decreased activity in limbic and striatal regions; subgenual cingulate, hippocampus, insula, and pallidum, as well as increases in brain stem and dorsal cortex; prefrontal, parietal, anterior, and posterior cingulate.

If no response to the antidepressants was seen clinically, this was associated with a lack of changes in subgenual cingulate or prefrontal regions

Question 33

What is the efficacy of DBS in treating depression? Why might this be?

Answer 33

Concluded to be ineffective, after the BROADEN (BROdmann Area 25 DEep brain Neuromodulation) study.

Targeted at ventral striatum, lack of consistency by the researcher and the probe in reaching the specific area targeted - gray matter. Found that many of the targets ended up being white matter tracts.

Question 34

What is executive function?

Answer 34

The ability to carry out goal-directed behavior using complex mental processes and cognitive abilities (such as working memory and impulse inhibition)

Question 35

What is the relationship between hippocampal volume and duration of untreated depressive illness? Compare between on vs off antidepressants. What might this suggest about the antidepressants?

Answer 35

When not under antidepressant medication, the greater the hippocampal volume the shorter the duration of untreated depressive illness.

When on antidepressants, the volume of the hippocampus remains more constant. Suggests that effective antidepressants could have neuroprotective factors that alleviate the effects of cortisol toxification on the hippocampus.

Question 36

What does ATD stand for?

Answer 36

Acute tryptophan depletion