Biology of depression Flashcards
What is the monoamine theory of depression?
Schildkraut (1965)
- “Some, if not all, depressions are the consequence of an absolute or relative deficiency of monoamines”
- Brought several pharmacological findings together
- The depressed state is brought about by a lowering of monoamine levels in the brain
- The abnormally low levels of serotonin and/or NA may account for the cognitive, behavioural and motivational deficits found in major depression
Heninger, Delgado and Charney (1996)
- Neither catecholamine depletion or monoamine depletion increased depressive symptoms in clinically ill patients off treatment, or produced clinical depression in normal controls
Elhwuegi (2004)
- The acute increase in the amount of the monoamines at the synapse (following ADM treatment) has been found to induce long-term adaptive changes in the monoamine systems
— Results in the desensitization of the inhibitory auto- and heteroreceptors including the presynaptic α2 and 5-HT1B receptors and the somatodendritic 5-HT1A receptors located in certain brain regions
— The desensitization of these inhibitory receptors would result in higher central monoaminergic activity that coincides with the appearance of the therapeutic response
- Blocking the somatodendritic 5-HT1A or nerve terminal α2 receptors proved to increase the response rate in the treatment of major and treatment-resistant depression
— Provides further support to the assumption that the antidepressant effect results from the long-term adaptive changes in the monoamine auto- and heteroregulatory receptors
Piñeyro and Blier (1999)
- Modified monoamine theory of depression = the acute increase in the levels of the monoamines at the synapse may be only an early step in a potentially complex cascade of events that ultimately results in antidepressant activity
Massart, Mongeau and Lanfumey, 2012
- Positive AD responses are transiently reversed in patients under low tryptophan diet leading to 5-HT depletion
— But this depletion does not worsen symptoms in unmedicated depressed patients (Delgado, 2006)
- 5-HT depletion by itself does not cause depression in healthy volunteers, undermining our view about the crucial role of a decrease in the serotonergic tone to trigger depressive episodes
- Therefore, factors beyond monoamine deficiency or imbalance are most probably implicated in the development of major depression
- All available ADs exert their effects only after prolonged administration (several weeks to months)
— This suggests that their short-term effects on monoaminergic transmission are not directly responsible for the clinical efficacy of these drugs
— Long-term adaptations to AD treatment would appear to mediate their therapeutic action
- It is necessary to search beyond the monoaminergic hypothesis because, albeit generally safe, monoamine-based ADs are far from being ideal drugs
— Bad side effects leading to discontinuation
What is the noradrenergic hypothesis of depression?
Bunney and Davis, 1965
- Suggested that depression is caused by low NA activity
- Little evidence of decreased noradrenaline or NA function in post mortem brains of depressed people
- Studies of NA metabolite (MHPG – released when NA is broken down by MAO) in CSF or blood of depressed patients showed variable results
— No consistent decrease in depressed patients, as would be predicted
— Increased MHPG has been observed after successful treatment with antidepressants
Brunello et al., 2002
- Early evidence of a role for NA in depression came from the discovery that drugs that either caused or alleviated depression acted to alter NA metabolism
- Depletion studies carried out in treated and untreated patients indicated a role for 5HT and one for NA in depression
- A number of relatively selective NA reuptake inhibitors have been widely used as antidepressants
— Desipramine, nortriptyline, protriptyline and lofepramine
— But all of these are TCAs hence have many unwanted side effects due to their non-selective interactions
- Reboxetine = a selective NRI
— Has proven efficacy in both short and long-term placebo-controlled studies
— Has a relatively low, and narrow, therapeutic dose range
— Lack of interaction between reboxetine and the cytochrome P450 metabolising enzymes
— The efficacy of reboxetine is comparable with fluoxetine
• Supports the notion that both NA an 5HT have important roles in depression
• But it is unclear whether the 2 classes of drugs treat the same set of patients or a different set of patients
— The efficacy of reboxetine in severe depression suggests an important, but as yet unknown, role for NA in the treatment of severe depression
— The efficacy of reboxetine in anxiety and panic suggests a role for the NA pathway in anxiety/panic
— Reboxetine treatment is well tolerated
— Improved motivation is associated with reboxetine treatment
— The incidence of suicide/attempted suicide with reboxetine was low
- In a reboxetine-desipramine comparator-controlled study, reboxetine was more effective than desipramine (TCA) as assessed on the Hamilton Rating Scale for Depression
— Ban et al., 1998
— But it is possible that the more complicated dose adjustments required with dedsipramine limit its efficacy
What is the serotonergic hypothesis of depression?
Golden and Gilmore (1990) suggested that depression was caused by low serotonin activity
- Serotonin is involved in pain sensitivity, emotionality and response to negative consequences
- Some studies showed the serotonin metabolite, 5-HIAA, was reduced in CSF of depressed patients (inconsistent)
— Low 5-HIAA is associated with aggressive hostile and impulsive behaviour and in violent suicide attempts
- Decreased serotonin found in brains of some depressed patients at post mortem
- Blood platelet uptake studies:
— Blood platelets have a transport mechanism similar to that in the brain
— Most studies find reduced uptake of 5HT in depressed patients, with normalisation following treatment
- Decreased serotonin may be associated with suicidal tendencies in depression
- No consensus as to whether low 5-HIAA is associated with depressive symptoms other than suicide
Romero, Bel, Artigas, De Montigny, Blier (1996)
- Preclinical studies have shown that co-administration of SSRIs with pindolol (a mixed β-adrenoceptor/5HT1A receptor antagonist) prevents the suppressant effects of SSRI treatment on dorsal raphe nucleus cell firing in the rat and produces a greater elevation of extracellular brain 5HT levels compared with SSRI treatment alone
- Hence suggests that the blockade of 5HT1A autoceptors in combination with SSRIs may produce a faster onset of antidepressant effect in man
Middlemiss, Price and Watson (2002)
- Preclinical evidence suggests a good rationale for particular 5HT receptor subtypes as molecular targets for this disease
- Studies involving the co-administration of 5HT1A receptor ligands with SSRIs are currently being performed in the clinic
- 5HT2A receptors have been linked to depression, with respect to changes in receptor density and function in response to antidepressant treatment
- 5HT2A receptors may mediate some of the antidepressant effects seen in putative animal models of anxiety and depression
— Skrebuhhova, Allikmets, Matto (1999)
- Du, Bakish, Lapieere, Ravindran and Hrdina (2000) suggested that a polymorphism in the 5HT2A receptor gene is primarily associated with suicidal thoughts in patients with severe depression
Schecter, McGonigle, Barrett (1999)
- The antidepressant effect achieved by nefazodone provides clinical support for targeting 5HT2A receptors in depressive disorders
— Nefazodone = an antidepressant that has combined 5HT reuptake inhibition with 5HT2A receptor antagonism
— Effective as an antidepressant in the clinic
— Claimed to have a low propensity for side effects such as weight gain or sexual dysfunction
Discuss the neuropsychology of depression
Roiser JP, Rubinsztein JS & Sahakian BJ (2006)
- In unipolar depression there is a mixture of temporal lobe and frontal lobe dysfunction, which affects:
— Pattern and spatial recognition memory
— Rapid visual information processing (sustained attention)
— Delayed/simultaneous match to sample (short-term visual memory)
— Visuo-spatial planning
— Cognitive flexibility
- The degree of cognitive impairment in unipolar depression increases with age, relative to age-matched controls
— It typically disappears on remission from the depressed state
• This suggests that an individual’s current mood interacts with their ability to perform a cognitive task
— But some recovered patients continue to show impairment in the domains of verbal/visual memory and response speed, though the degree of impairment is related to age
- One theory to explain the broad pattern of cognitive impairment seen in unipolar depression is that depressed patients may not respond to test feedback in the way that non-depressed subjects do
— This may reflect a dysfunctional reward system
— Cold, or emotion-independent, processing = thought to utilize neural networks including the dorsolateral prefrontal cortex
•E.g. working memory tasks such as rehearsing a series of digits
— Hot, or emotion-dependent, processing = thought to utilize neural networks including orbitofrontal, anterior cingulate and ventromedial prefrontal cortices
• Hot processing includes tasks that make use of affective material
• These areas of the brain have extensive connections to the limbic system - known to be involved in depression and anxiety, particularly amygdala and nucleus accumbens
— Hot processing distinguishes mania from depression
• Those who are depressed show good quality of decision making, but take significantly longer to decide than controls (reflects difficulty in making decisions)
• Bipolar patients in the manic phase also take longer to decide, but in addition also show poor quality of decision making, tending to bet on more unlikely outcomes
• Rubinsztein, Michael, underwood, tempest, sahakian (2006)
— Several studies have shown that depressed subjects recall negative words or stories more accurately than neutral or positive material
• In addition, subjects recall information that they learnt while depressed more successfully when they are depressed than in remission
• Implies that mood can interact very strongly with the recall process
