Biochemistry & Pharmacology of major depressive disorder (MDD)

Facts

Prevalence = 12.7% in men, 21.3% in women Age on onset = 20-25y (has decreased over the past 2 decades) Can be life-threatening (suicide & anorexia) - 1 million suicides a year (& 10 million attempts) (Mann, 2003) - > 50% occur during an episode of depression - 15% of people with untreated depression die by their won hand (suicide) - treatment doesnt only improve quality of life, but also saves lives! Has huge economic costs - in USA = $43 billion per annum

Theories Strong genetic component (50% concordance MZ) Life stress is a major predictor of MDD Stress-diathesis models (favoured model) Biochemical theories of depression History The Ancient Greeks believed that depression was a result of an imbalance in the 4 humours; too much black bile (this is where the term melancholia comes from). Monoamine is a generic term for the The most common theory = Monoamine Theory neurotransmitters; It has shadowed various theories proposed, and Noradrenaline suggests that depression is caused by a deficit in NA (NA) and/or serotonin

Monoamine theory
Origin (Reviewed by McNeal & Cimbolic, 1986) 1950s Scientists were observing the effect of RESERPINE (drug) on behavioural and psychological effect of blood pressure (its an antihypertensive drug) - By chance, they noticed that it induced severe depressive reactions in normal patients (and precipitates depression in remitted patients) How does it work What they found is; reserpine causes vesicular leakage (damages the membrane) in the presynaptic membrane, so stores of NA and 5-HT are depleted What does that tell us If artificial depletion of NA and 5-HT induces a depressive like state, then it implies that depression itself is caused by a natural depletion in these resources!!!! Therefore, alleviating the symptoms should be achievable by restoring the neurotransmitter levels! Basically depression is caused by less NA and 5HT So increasing levels should cure it!

SUPPORT

Tyrosine MHPG

Dopa Dopamine

NA

Tryptophan 5-HIAA Basic

amino acid in your

5-hydroxytryptophan

Broke down by

5-HT

Metabolite = safe form of the AA, so it can be removed from

Biochemistry = Support Above is the metabolic processes involved in the synthesis and degradation of the neurotransmitters involved. IF (like hypothesised) depression is associated with lower than normal functioning of NA and 5-HT in the brain then there should be lower levels of their metabolite (their broken down components; MHPG &/or 5-HIAA) in blood, urine & CSF of depressed patients (compared to controls) McNeal &Cimbolic (1986) Findings = Hollister & Claghom a) Both are abnormally low in depressed patients (1993) b) 5-HT is particularly low in suicidal depression (5-HT is Fava & Kendler (2000) Mann (2003) associated with a disorder of impulse control)

What else do these findings tell us about the neurochemistry of depression? Depression can be cause be either NA or 5-HT (or both) Maas (1975) Depressed patients can be either normal OR below normal for NA function (*see later notes by Praag) Asberg et al. (1976) Depressed patients can be either normal OR below normal for 5-HT function This implies depression has (biochemical) sub-types Low NA or low 5-HT * Biochemical analysis could be used to confirm/refine diagnosis and aid targeted medication

First generation of antidepressants = Support In the late 50s, the first effective anti-depressant was discovered (by accident, and its mechanism was unknown) They were used because they worked, NOT because they knew how they were working! It was later found, that, the drugs were effective, as they were consistent with the monoamine theory, by increasing synaptic levels of NA and 5-HT by; Blocking degradation Monoamine oxidase Hollister & Claghem inhibitors (MAOI) block the degrading enzyme (MAO) so (1993) the effect of the neurotransmitter can continue

Schloss & Henn (2004)

Blocking the reuptake process Tricyclic antidepressants (TCA) block the reuptake process, so the neurotransmitter is still present in the synaptic cleft, to bind to the post0-synampitc membrane

Sooo Support so far Reserpine depletes NE & 5-HT stores = induces depression Spillman et al, (2001) Neumeister et al. Implies NA & 5-HT deficits cause depression (2004) Depression is associated with low NA & 5-HT, and their metabolites First generation anti-depressants alleviated the effects of depression = increase NA & 5-HT levels = therefore implying low levels causes the deficit itself Blocking the synthesis of NA or 5-HT leads to rapid relapse in patients

This begs the questions; Are both monoamines involved? Is one more important than the other? Are there two biochemical sub-types of depression?
Van Praag (1977) Sub-types Van Pragg extended Maas research (1975) in the possibility of sub-types of depression (* see above). He found that there were, apparently, two subgroups of depressed patients; 1. Patients normal in NA functioning (presumed deficit in 5-HT) (A) 2. Patients deficient in NA function (B) Furthermore, TCAs (Tricyclic antidepressants) vary in their effect on NA and 5-HT a. Amitriptyline (AMI) effective on 5-HT reuptake b. Desipramine (DES) effective on NA reuptake Praag tested both types of TCA on both groups of patients A = responded well to AMI, but not to DES B = responded well to DES, but not to AMI This therefore provides evidence for the division between the subtypes of depression Na deficient depression 5-HT deficient depression This is the story so far. BUT! Theres more

Beyond the first generation

The late 70s provided pressure to develop new antidepressants, this was due to; Treatment resistance in 30% of patients Therapeutic delay (effect of drugs takes about 3-4 weeks, and this needed to be reduced) Predictions were made on sub-types, which was gaining more and more opposition Side-effects MAOI (cheese effect) MAOIs inhibit the breakdown/metabolism (deamination) of dietary amines (eg/ tyramine) in the liver, so that they are not broken into safe components. This basically leaves poisonous acids in the body to circulate, and even cross the blood-brain barrier.

TCA these can cause sedation and cardiac arrests

Because of these problems, rational drug development proceded the first generation antidepressants;

Second generation antidepressants

So how do they work Antidepressants work on either NA or 5-HT receptors; however, the effect they have on either is ultimately the same;
Hollister & Claghorn (1993), Eriksson (2000), Vetulani & Nalepa (2000), Wong & Licino (2001), Papakostas et al.

NA & 5-HT receptors are hypersensitive (Both pre(inhibitory autoreceptors) and post- synaptic receptors) NA pre = 2 & post = 5-HT pre = 5-HT1A & post = 5-HT2A The latter is a consequence of the former; Pre-synaptic auto-receptors remove neurotransmitters too quickly = very little in the cleft = depriving the post-synaptic receptor = they too become hypersensitive Antidepressants normalize the levels of the neurotransmitter levels in the cleft, desensitizing both lots of receptors, so normal levels of the neurotransmitter can be released naturally. The different drugs create this effect in different ways; NA reuptake inhibitors - NARI (eg/ Maprotiline) 5-HT reuptake inhibitors - SSRI (eg/ Fluoxetine (Prozac)) MAO-A inhibitors (eg/ moclobemide) NA/5-HT reuptake inhibitors - SNRI (eg/ venlafaxine) less side effects! Atypical antidepressants (eg/ mianserin, trazodone) dont prevent reuptake or degradation
* For a diagrammatic version, see the next handout!

Evaluation Generally better, as theyre based on understanding, not trial and error NARI and SSRIs have equal effectiveness This therefore questioned the idea of a subtype previously proposed! Fewer and less serious side-effects

Some other stuff Therapeutic delay Antidepressants take approximately 3-4 weeks to begin to take effect. Antidepressants would be much more effective if the therapeutic delay was reduced. With SSRIs (5-HT orientated Antidepressants), the therapeutic delay is due to the initial low 5-HT release, because 5-HT1a receptors have already been activated to initiate the negative feedback. (this can actually cause symptoms to be worse in the early stages of treatment) This is where the 3-4 week delay comes from Reducing the therapeutic delay Pindolol is a drug that blocks (antagonistic) the 5-HT1A receptors, so that the negative feedback system wont be initiated, and so normal levels of 5-HT will be released. By combining this drug with SSRI drugs, the therapeutic delay should be reduced

Perez et al. (1999) & Artigas et al (2001) = confirmed a significantly faster therapeutic response (days in contrast to weeks) when the two were combined = pinolol augmentation therapy

What causes the initial hypersensitivity of NA and 5-HT receptors? Genetic abnormality - Kendler et al. (1996) Stress and failure to cope - Nemeroff (1998) Stress is a strong predictor of MDD MDD is associated with hypercortisolaemia When we are stressed, our hypothalamic-pituitary-adrenal (HPA) axis is triggered, which indirectly causes cortisol to be secreted In acute stress, negative feedback prevents cortisol levels rising too high, but in prolonged/chronic stress, negative feedback is disrupted (Seyle, 1950s) Therefore, there is constant activation of the HPA axis and brains GR receptors. This causes the GR receptors to desensitize, so their negative feedback on the HPA is reduced resulting in high levels of cortisol, ultimately affecting the sensitivity of NA and 5-HT receptors while also causing atrophy and cell death Atrophy is commonly found in the temporal lobes (eg/ hippocampus) Auer et al (2005) Damage to the hippocampus is associated with the memory loss experienced by many depressed patients Loss of gray matter in the temporal lobe is associated with impairments in planning and motivation Therapeutic implications hypercortisolaemia may be a primary biological dysfunction (system coping failure). So reducing HPA hyperactivity may have a therapeutic value Blocking CFR receptors (Zobel et al., 2000) Blocking cortisol receptors (Belanoff et al., 2001) Criticism Not everyone who is stressed become depressed Stress diathesis (interaction) - Caspi et al. (2003); Heim et al. (2004); Taylor et al. (2006) Alleles (Caspi et al., 2003) Deficient 5-HT levels is possibly due to malfunctioning 5-HT transporter cells 5-HT transporter (5-HTT) gene exists in several forms (short and long) SHORT allele = more likely to react to stress with depressive behaviours Future directions Dopamine as recently stepped into the lime light (it is also a monamine) Dopamine is a major neurotransmitter in pleasure/reward, as well as anhedonia (obviously a major factor in depression) by using DA in treatment patients pleasure may be increased, potentially reducing the therapeutic delay!

Diagram page!!!!!
(I hope this makes it a bit easier!) Noradrenaline
Normal NA is released from the presynaptic membrane, into the cleft, where it binds to

 -receptors. Once the message has been sent; NA transporter molecules remove excess NA from the cleft 2-receptors govern a negative feedback system, so detection of high concentrations of NA causes the neurotransmitter to stop being released Deprssion 2 receptors are hypersensitive, so negative feedback kicks in too soon. Therefore, less NA is released Because less NA is released, the -receptors become hypersensitive Antidepressants 2 receptors are desensitized NA release is normalized Therefore, -receptors desensitized (as they are exposed of normal NA levels) * Atypical antidepressants (mianserin) blocks 2 receptors, which also normalizes the NA release Basically the same story

Seratonin

Normal 5-HT is released from the presynaptic membrane 5-HT transporter molecules remove excess autoreceptors govern a negative feedback system Deprssion 5-HT1A receptors are hypersensitive, so negative feedback kicks in too soon = less 5-HT Causing the 5-HT2A to become hypersensitive Antidepressants 5-HT1A receptors are desensitized 5-HT release is normalized 5-HT2A desensitized

Gauntlet believed that depression is fundamentally a seratonin deficit (Blier & DeMontigny (1994): every known antidepressant drug (&ECT) increases 5-HT function in the brain) ** The time scale of this maps on well to the therapeutic delay!!!!!