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