Effects of REM sleep awakenings and related wakening paradigms on the ultradian sleep cycle and the symptoms in depression

In paper citation (Grozinger, Kogel, & Roschke, 2002).

In 1975, Vogel and colleagues executed a "heroic" experiment whereby severely depressed inpatients were chronically REM-sleep deprived for three weeks. They found that suppressing REM sleep had an antidepressant effect on patients with endogenous depression, namely depression that does not result from a stressful event. They used fifty-two patients, and the patients that responded to the REM deprivation treatment were less likely to require rehospitalization or another form of treatment in the future.

As the literature linking depression and sleep has progressed, many scientists have called for a confirmation of this study. Unfortunately, it takes a lot of time and resources to monitor sleeping patients. To work around this problem, Grozinger and colleagues developed a computer algorithm that wakes a patient up as soon as it detects REM sleep. Unfortunately, this system does not catch the initial moments of REM, and it only reduces REM sleep by about 50%.

Grozinger and colleagues do not replicate Vogel's results. Interestingly though, they show that both REM deprivation and sleep deprivation dramatically decrease a subject's self-reported symptoms of depression (both groups lowered their average score by ~7 points (out of an average of 22) after 11 days of treatment). I think that this is pretty strong evidence for the placebo effect. Every subject who participated in this experiment would have assumed that they were in the "treatment" group getting REM sleep deprivation because both sets of subjects were woken up almost 50 times each night. Thus each subject would want to deliver good news to the experimenter, and would thus focus on the progress that they had made since they started in the experiment. I also believe that the paradigm is so unique that it might "give hope" to a patient who has been treatment resistant.

I do not completely buy the theory that REM suppression is one of the main mechanisms of antidepressant therapy. For cognition, researchers are always trying to increase REM sleep to promote memory consolidation. I still assume that REM sleep deprivation is caused by something deeper that actually mediates the antidepressant effects of most medications/placebos.

'Til next time...

Selective Serotonin Reuptake Inhibitor (SSRI) treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction

In paper citation: (Ishiwata, Shiga & Okado, 2005).

The last review that I read about SSRIs in development talked about their paradoxical effects, and the long-term damage that they can cause. This paper comes in from a completely different angle and looks at the benefits of SSRIs immediately after birth. I have to say that I am simply fascinated at the extent to which SSRIs seem to affect development.

Important background:

• Serotonin concentration and synaptic density in the hippocampus, as well as spatial learning ability are reduced after prenatal stress (Hayashi, et al., 1998)
• 5HT and noradrenaline (NA) are involved in the regulation of mineralocorticoid (MR) and glucocorticoid (GR) mRNA expression (Seckl & Fink, 1992)
• SSRIs suppress HPA axis activity, decrease CRF mRNA expression and increase neurogenesis in the hippocampus of adult rodents.
• There were five groups in this study:
• Mice from non-stressed mothers, no SSRI treatment (C)
• Mice from non-stressed mothers with SSRI treatment from 1-3 weeks (CS)
• Mice from stressed mothers with no SSRI treatment (S)
• Mice from stressed mothers with SSRI treatment from 1-3 weeks (SS)
• Mice from stressed mothers who received SSRIs at 6-8 weeks of age (L-SS)

The new findings from this paper:

• Corticosterone levels:
• Mice from group S had 21% higher circulating corticosterone after restraint stress at week 3.
• Mice from group SS had corticosterone concentrations similar to controls.
• Monoamine concentrations:
• Mice from group SS and CS had significantly higher levels of serotonin (5-HT) than controls at postnatal week 3 and 6 by about 30% in the control treated mice and 60% in the stressed treated mice. 
• The 5-HT metabolite, 5HIAA was elevated in S mice compared to C mice. 
• Thus the 5-HT turnover rate was markedly elevated (77% greater) compared to controls. 
• Dendritic spine and synapse density:
• At week 3, spine density at the stratum radiatum in the S mice was 21% less than the control mice.
• At week 3, the SS mice had significantly more spines than S mice and resembled the control mice.
• At week 9, the S mice had 19% less spine and synapse density than controls.
• At week 9, the SS mice looked like normal mice.
• The mice with later SSRI treatment increased their spine density by 10%, but this was not significant.
• Spatial learning:
• C, CS, and SS mice all performed equally well at the Morris Water maze, but the S and LSS mice had learning impairments at the second and third exposure to the maze. These two groups also showed impairments at the reversal. 

Further information:

• Neonatal handling also reverses prenatal stress-induced behavioral deficits (Wakshlak & Weinstock, 1990).
• Chronic tianeptine treatment also reverses immobility time in the forced swim task (Morley-Fletcher, et al., 2003) *I'm surprised that this wasn't mentioned in the animal model overview.
• Hippocampal glucocorticoids are reduced in prenatally stressed animals, which is not what you would expect at first for cell death (Szuran, et al., 2000).
• The age of the rat may account for its stress response differences between prenatally stressed rats and controls (McCormick et al., 1995). 
• The first 3 postnatal weeks are very important for the development of the HPA axis. The concentration of GR in the rat hippocampus is low during week 1, then increases to adult values (Olpe & McEwen, 1976; Clayton, et al., 1977). The HPA axis reached adult levels of functionality by postnatal week 3. 

Remaining questions:

What happens to mice from stressed mothers who are raised by surrogates? Is it the mother's glucocorticoid levels that programs these mice or is it the mother's caregiving behaviors?

What happens to female rats who are in the same paradigm?

How did they get monoamine concentrations from both week 3 and week 6? Did they just plow through mice?

If mice postnatal week 0- postnatal week 2 correlate to the third trimester of primate births, could SSRI therapy actually help reverse learning impairments if administered acutely and early?

Animal models of Depression

In paper citation (Deussing, 2006).

I have been curious about what sorts of animal models of depression exist because I am already thinking about developing experiments related to depression and sleep.

First of all, I am thoroughly dissatisfied by the two most common methods for assessing despair in rodents: the forced swim test and the tail suspension test. This is because they are acutely sensitive to the administration of antidepressants, and we know that antidepressants typically take about four weeks to display therapeutic effects. Furthermore, when suspending a male rodent from his tail, he receives a huge surge of testosterone from his testes because this is the area manipulated by the tail-suspension test. Tail suspension is very abnormal, and so are testosterone surges.

Also, do humans show an immediate decrease in despair after taking antidepressants? I feel like I would have heard about it if this were the case, but I have not. I have heard that more people commit suicide in those first few weeks, but I have never heard this directly linked to acutely increased motivation (like the motivation to swim or struggle in the rodent tests). We should have a better human correlate than the motivation to kill oneself.

My three favorite tests of depression are the sucrose preference test, the novelty-induced hypophagia test, and the dexamethasone suppression test. The sucrose preference test measures a rodent's motivation to seek rewarding stimuli (such as sugar in the water) and is sensitive to chronic antidepressant treatment. The novelty-induced hypophagia measures a rodent's anxiety level by presenting the rodent with a conflict. The rodent is faced with a desirable food item inside of a novel environment. It can either avoid a novel environment, or enter the novel environment and consume the food. The biggest problem with this paradigm is that it measures anxiety, not depression, and some rodents never choose to consume the novel food. The dexamethasone suppression  test looks at the ability of a synthetic glucocorticoid to downregulate glucocorticoid expression.This basically measures the neuroendocrine health of the rodent.

In terms of creating depression in a rodent, my three favorite methods are via social stress, maternal deprivation in the first two weeks of life, and olfactory bulbectomy. Social stress is most like human stress, but is not as reproducible as learned helplessness paradigms. Similarly, early life stress is less reproducible, and has not been tested with the typical antidepressants yet (which I find shocking!). Finally, the olfactory bulbectomy is easiest to do in mothers shipped from the rat factory.  However, I am not so certain how to make rat mothers depressed and not just stressed. Is it even possible to isolate the two? Time will tell.

REM sleep reduction effects on depression syndromes

In paper citation: (Vogel et al., 1975)

New conclusions:

1. N-REM sleep deprivation does not produce REM deprivation and REM rebound on recovery nights, but REM sleep deprivation does. (NREM sleep deprivation was acheived by waking participants up 10 minutes after they finished REM at the same rate as their REM-deprived partner)
2. In both endogenous and reactive depression, REM deprivation treatments caused REM deprivation, but only in the endogenous depressives did it also induce REM rebound on the recovery night.
3. Total sleep time was lower by about 40 minutes for everyone who received REM deprivation treatments  compared to controls.
4. EST did not reduce REM sleep the first two nights after treatment.
5. Endogenously depressed patients showed significant improvement with 3 weeks of REM sleep deprivation, but they did not have a significant difference in self-ratings of psychomotor activity (a symptom of depression)
6. 17 of 34 patients improved sufficiently for a hospital discharge after 7 weeks of increased REM pressure. Of these patients, 3 required rehospitalization within nine months of discharge, and 13 patients showed continued improvement.
7. 7 of 34 patients did not respond to sleep treatments or imipramine and received EST. Of these patients, 3  required rehospitalization within nine months of discharge, one went to a long-term care facility, and two showed consistent improvement. 
8. The unimproved patients were REM deprived, but did not show REM rebound. It may be that REM pressure is the force behind this healing process.

Other Important Information:

• Reactive depression is depression induced by a stimulus. Endogenous depression has a "spontaneous" onset.
• Tricyclics and monoamine oxidase inhibitors suppress REM sleep.
• EST has also been reported to decrease REM sleep. 
• If woken during REM, the patient was woken immediately at the onset of REM and kept awake for 3 minutes.
• If woken during NREM (controls) the patient was woken 10 minutes after the offset of REM so as to not disturb the normal REM sleep.

Remaining Questions:

• Is it REM deprivation, or increased REM pressure that relieves the depression?
• Is this method safe to use as a long term treatment?
• How could this treatment be made more efficient, affordable, and effective?

Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

In paper citation: (Mavanji, Meti, & Datta, 2002)

All rats in this paper were made depressed using neonatal clomipramine treatments. All rats were male. Controls were treated with saline, but handled in the same manner.

The new findings from this paper are:

1. REM sleep onset latency is significantly shorter in depressed rats than in controls. Rats spend ~25% less time in SWS before their first REM cycle.
2. The total number of REM sleep episodes is significantly (~2X) higher in depressed rats than in controls.
3. The total amount of REM sleep in depressed rats is significantly more than controls (>2X more REM).
4. mCPP, a serotonin agonist, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes and increasing the REM sleep onset latency.
5. mianserin, a SSRI, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes. 

Other important information:

• REM sleep deprivation in humans alleviates symptoms of depression (Vogel et al., 1975).
• REM sleep deprivation in rats normalizes deficits in sexual activity and aggression, which are symptoms of rat depression (Vogel et al., 1990).
• mCPP is known to increase serotonin release (Bauman et al., 1993) and reduce REM sleep in humans ( Lawlor et al., 1991).
• Clomipramine treated rats have less serotonin in their brain than control rats (Mavanji & Meti, 1999).
• Serotonin inhibits REM sleep (McCarley, 1982) and so serotonin agonists reduce REM sleep (Quattrochi et al., 1992; Stickgold et al., 1993)
• mCPP normally reduces REM in the controls if it is injected systemically because it inhibits acetylcholine release (Vizi et al., 1981) It didn't in this case because it was injected  ICV.
• Mianserin typically reduces REM in both depressive patients and normal subjects (Mendlewicz et al., 1995; Tormey et al., 1980).

Remaining questions:

• How does the clomipramine rat model work? Would this still be the case in social stress depressed rats, or learned helplessness rats?
• The CLI+mianserin group seemed to have low wakefulness and high SWS in my opinion. I'm surprised that it didn't come out significant.