Monday, September 12, 2011

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...

Monday, September 5, 2011

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?

Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication

In paper citation (Kirsch & Sapirstein, 1998)

This paper specifically looks at the effects of the placebo in placebo-controlled drug studies treating depression. This analysis only includes drug studies before 1995 and therefore misses most of the modern drugs prescribed today. However, Kirsch and Sapirstein's results are really shocking. They find that in drug studies, the placebo group improves in proportion to the effectiveness of the drug. The correlation between the placebo response and the drug response is r=.90, p<.001 and the placebo response is 75% of the drug response. So if the drug response in a sertraline drug trial was 2.0, the placebo response in that trial would be around 1.5. These numbers were slightly higher for active placebos... side effects actually may convince people that they are receiving full treatment, and therefore cause them to expect a better response. This is also interesting in light of the more modern Turner and colleagues meta-analysis, which found that 49% of FDA approved clinical trials show no significant difference between placebo and antidepressant trials. Perhaps both the experimental and control patients are improving in proportion to the expected efficacy of the drug, and so only the most effective drugs will come out ahead of their placebos.

Furthermore, the authors compared the effect of taking a placebo pill to receiving no treatment while on a wait-list for psychotherapy trials. For the people on wait-lists, or receiving no placebo treatment at all, their depression scores worsened overall during the course of the study. This shows that the placebo pill is more effective than no treatment.

My remaining questions actually involve the rating scales of depression. It could be that different research centers treat their patients more holistically, and that is why the scores are so well correlated, but it could also be that people respond to the depression interviews in a rote manner. For example, if I know the symptoms of depression, and I want to be a good research subject, I may describe my pre-treatment symptoms in a way so that the doctor will give me the quick fix and treat me with an antidepressant. Then when the doctor asks me follow ups, I also know what improvement should look like, and I've been looking out for that in my daily life, and so I focus on the improvement for my follow up questionnaire. Whether the drug has actually improved my mood is hard to tell, because I started by looking for symptoms to describe to my doctor, and then I started looking for improvements to tell to my doctor. Thus the placebo effect.

Does anyone else think that is totally plausible? I guess Kirsch & Sapirstein would, but they do not mention it in their discussion. In cases of mild to moderate depression, I would like to see a study that looks at various types of placebos to see what works best. Inert substances should be better for our bodies in the long run, and especially useful for pregnant mothers who desire treatment for mood disorders.

Selective Publication of Antidepressant Trials and its Influence on Apparent Efficacy

In paper citation (Turner, et al., 2008).

In groundbreaking work, Turner and his colleagues invoked the freedom of information act to "check up" on the efficacy of antidepressants. Basically, the majority of studies with negative or questionable results about the efficacy of an antidepressant versus a placebo never get published and therefore do not have a chance to influence people's mentality about the efficacy of antidepressant drugs.

Basically, among the published literature, 94% of antidepressant trials conducted are positive. However, among the FDA registered clinical trials of antidepressants, only 51% of antidepressant trials are positive. This gives us great pause for consideration as pharmaceuticals make billions of dollars a year on these drugs.

I personally would trust the FDA effect sizes now that they are out. The effect size compares the difference in means between the control and the placebo group at the end of the treatment period divided by the pooled standard deviation.

The overall effect size was .31 for the modern antidepressants.

Friday, September 2, 2011

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.