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Major Depressive Disorder and Sleep

Linking Major Depressive Disorder to Sleep

  • Disturbed sleep patterns are a common feature in individuals with major depressive disorder (MDD).

Sleep Patterns in Non-Depressed vs. Depressed Individuals

  • Non-Depressed Person:
    • Typical sleep progression through stages 1, 2, 3, and 4 (slow-wave sleep) followed by REM sleep.
    • Cycling between slow-wave sleep and REM sleep throughout the night.
    • Longer periods of REM sleep as the night progresses.
  • Person with Major Depressive Disorder (MDD):
    • Shorter sleep latency (falling asleep more quickly).
    • Reaching REM sleep too soon after falling asleep.
    • More REM sleep than typical, occurring earlier in the night.
    • More interrupted sleep with frequent awakenings (indicated by arrows on the diagram).
    • Reduced or absent slow-wave sleep (stages 3 and 4).

Key Aspects

  • REM Sleep Entered Too Early: REM sleep occurs sooner than it typically would in a non-depressed person.
  • REM Sleep Deprivation: Selectively depriving patients of REM sleep can help with depressive episodes.
    • Requires monitoring EEGs and EMGs in a sleep lab to wake individuals during REM sleep.
    • Can lead to long-lasting remission from depressive episodes for some patients (several months).
    • Not a universal solution, as it doesn't work for all patients.
  • Antidepressants & REM Sleep: Many antidepressants suppress REM sleep.
    • Question: Is REM sleep deprivation mimicking the effects of SSRIs, or vice versa?
    • Exercise can also reduce REM sleep.

Neurotransmitters and REM Sleep

  • During REM sleep, concentrations of noradrenaline and serotonin are especially low.
  • Acetylcholine levels are high during REM sleep, contributing to various features of REM sleep.
  • Histamine levels should be low to facilitate sleep but are not directly involved in REM sleep regulation.
  • Dopamine does not have a direct role in regulating REM sleep.
  • REM sleep deprivation may keep serotonin and noradrenaline levels higher than they would be if REM sleep were allowed.
  • SSRIs also maintain higher concentrations of serotonin and noradrenaline.
  • Exercise may prevent REM sleep by keeping adrenaline and serotonin levels high.

Monoamines and Depression

  • Chronic activation of the stress response leads to constant activation of the alertness system in the brain, which relies on noradrenaline and serotonin.
  • Prolonged activation can deplete these monoamine neurotransmitters, potentially including dopamine.

Evidence for the Monoamine Depletion Theory of Depression

  • Reserpine:
    • A drug that prevents monoamines from being loaded into vesicles, thus inhibiting their release into the synapse.
    • Used to treat high blood pressure by reducing noradrenaline release.
    • Side effect: 15% of patients developed depression, suggesting a link between monoamine depletion and depression.
  • Measurement of Monoamine Breakdown Products:
    • Measuring 5-hydroxyindoleacetic acid (5-HIAA), the breakdown product of serotonin, in cerebrospinal fluid.
    • Depressed patients tend to have lower concentrations of 5-HIAA, indicating lower serotonin levels.
  • Tryptophan Depletion:
    • Tryptophan is an essential amino acid and a precursor for serotonin synthesis.
    • Experimentally depleting tryptophan by providing a diet low in tryptophan and high in other competing amino acids.
    • In patients who had recovered from depression using SSRIs, tryptophan depletion led to a relapse, suggesting that serotonin plays a role in maintaining their improved state.

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • SSRIs are commonly prescribed to treat depression by targeting serotonin levels.
  • They are manufactured to be taken orally (pills) and are lipophilic to cross the blood-brain barrier.
  • Examples: Fluoxetine, citalopram, and others.
  • Different SSRIs have different chemical structures, half-lives, uptake speeds, and affinities for binding molecules.
  • Inhibit the reuptake channel for serotonin, increasing serotonin levels in the synapse.
  • More specific than cocaine: Cocaine blocks the reuptake of all monoamines, while SSRIs selectively block serotonin reuptake.
  • Not psychologically addictive because it is selective for serotonin and noradrenaline but not dopamine.
  • Blocking the reuptake channel leaves the neurotransmitter in the synapse for longer, mimicking the effect of releasing more neurotransmitter.

Delayed Effects of SSRIs

  • SSRIs increase serotonin levels in the synapse relatively quickly (within hours).
  • However, patients typically start responding to SSRIs only after 4-6 weeks.
  • The disjoint is due to adaptation of auto receptors of the serotonin neurones.

Mechanism of Action and Adaptation of Auto receptors

  • Diagram Explanation:
    • Cell body of a serotonergic neurone in the rafay nuclei.
    • Axon and synapse that it makes on its target areas.
    • Serotonin receptors (yellow rectangles) including auto receptors on the cell body.
    • Reuptake channels (blue) in the presynaptic terminal and near the cell body in the rafay nuclei.
  • Normal circumstances: Serotonin is released and binds to serotonin receptors and auto receptors.
  • Auto receptors: Serve a negative feedback function, preventing the cell from releasing more serotonin when enough serotonin binds to them.
  • Reuptake channels: Recover serotonin, bringing it back into the cell for repackaging and reuse.
  • When an SSRI is taken:
    • The reuptake channels are blocked.
    • The concentration of serotonin outside the cell increases.
    • The auto receptors detect the higher concentrations of serotonin and prevent the cell from releasing as much serotonin.
    • This brings the concentration back to normal levels, even though the reuptake is inhibited.
  • Internal negative feedback control mechanisms keep serotonin levels steady.
  • Only with repeated and long-term stimulation do these auto receptors slowly adapt to the high concentrations of serotonin.
  • The negative feedback system becomes less sensitive, either through a reduction in the number of auto receptors or a change in their type.
  • Higher concentrations of serotonin are released, and because they are not being re uptake, the total concentration of serotonin becomes higher than before starting the drug.
  • The process takes about two weeks.

Long-Term Effects and Alternative Hypotheses

  • If low serotonin levels were the direct cause of depression, effects would be observed after two weeks.
  • Adaptation to the higher concentrations is necessary to reduce depression.
  • The target in the brain needs to adapt to the higher levels of serotonin by becoming less sensitive.
  • The low serotonin levels may be causing some kind of damage in the brain, and the damage is what leads to the depression.
  • Increasing serotonin levels doesn't immediately undo the damage.
  • Analogy: if someone gets stuck with a knife, pulling the knife out doesn't heal the person immediately.
  • Brain needs time to recover from that damage.
    • HPA axis, which is disrupted in depression, needs to come back to a normal negative feedback cycle.
    • The hippocampus is one of the few bits of the brain that adds new neurones, which is called neurogenesis.
    • Humans also have neurogenesis.
    • Chronic stress decreases these new neurones.
    • Depression also decrease new neurones.
  • In rodents, the neurogenesis symptoms are roughly the same as humans, 4 to 6 weeks.

Effectiveness and Limitations of SSRIs

  • SSRIs are not always effective, and many people do not respond to them.
  • Even those who respond may experience side effects.
  • SSRIs do better than placebo, but not by a significant margin.
  • Targeting serotonin seems to work for enough people to make it the dominant treatment.
  • It is a slow process because we are not really targeting the direct cause of depression.
  • By normalizing the process, we allow other processes to recover and potentially come out of depression.
  • If your body has built up a tolerance, and you just stop taking them, if you've been taking them for months, you'll be in a way worse position than you were beforehand.
  • Has to be under the supervision of your doctor.

Ketamine

  • Recently, people have been studying other drugs that are showing really interesting, promising effects.

  • It is an anesthetic and analgesic and very commonly used by veterinarians but also is used on human surgeries.

  • Clinical use is injected but when people take is as a drug of abuse, they will snort it.

  • Initial biological half-life is 10 to 15 minutes overall and averages about 45 minutes.

  • NMDA receptors

    • Special kind of Glutamate receptors.
    • NMDA receptor responsible for anesthesia.
    • Amnesia because it is an important part if memory formation in the hippocampus.
    • Analgesia because it is used in the spinal cord pain circuitry