Потенциальные механизмы лечения депрессии

EMERGING THERAPEUTIC TARGETS


Consider the following novel mechanisms that may become the basis for creating entirely new antidepressants in the foreseeable future, by design, not by serendipity:

• corticotropin-releasing factor (CRF) and glucocorticoids

         – CRF antagonists
           – vasopressin receptor antagonists
           – glucocorticoids as agonists or antagonists

• neurokinin system
• brain derived neurotropic factor (BDNF) and other neurotropins, such as fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF)
• phosphodiesterase inhibitors
• glutamate pathway modulators

        – ketamine (IV infusion with immediate efficacy)
          – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor modulators
          – glycine

• hypothalamic feeding peptides
• circadian gene products
• other evolving antidepressants

        – K-opioid receptor antagonists
          – CB1 cannabinoid receptor agonists/antagonists
          – cytokines
          – melatonin receptor agonists
          – galanin
          – neuropeptide Y
          – histone deacetylase inhibitors
          – tissue plasminogen activator

 The hazards of serendipity

Режим сна в предупреждении обострений БАР с быстрой сменой фаз

BACKGROUND:
The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night.
METHODS:
We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings.
RESULTS:
The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark.
CONCLUSIONS:
Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients.

 Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

Зависимость эпилептических приступов от времени суток

OBJECTIVE:
To evaluate whether the distribution of seizures throughout the day is the same in ambulatory outpatient conditions as observed in inpatient conditions.
METHODS:
We analyzed records from consecutive patients who had ambulatory EEG monitoring for 24 to 72 hours using Digitrace™ EEG recording system. The participants maintained a log of symptoms and signaled the time when symptoms occurred by pushing an event button. Additionally, automatic seizure and spike detection was performed on each record using Persyst detection software.
RESULTS:
Of 831 reports analyzed, 44 unique patients had definite ictal events. There were a total of 129 electrographic seizures (34 subclinical) with timing as follows: frontal (31), temporal (71), and generalized, posterior, or central (27). Frontal lobe seizures occurred more frequently between 12 am and 12 pm as compared to temporal lobe seizures, which occurred more frequently between 12 pm and 12 am (p = 0.017). Analysis of frontal lobe seizures revealed a cluster of 10 seizures centered at 6:33 am (range 5:15-7:30 am) with p = 0.0064. Temporal lobe seizures had a cluster of 24 seizures centered at 8:49 pm (range 6:45-11:56 pm) with p = 0.0437.
CONCLUSION:
In ambulatory outpatient conditions, electrographic seizures follow day/night patterns similar to those observed in hospital conditions. Frontal seizures occur preferentially in the early morning hours and temporal lobe seizures occur in the early evening hours.

 Diurnal pattern of seizures outside the hospital: Is there a time of circadian vulnerability?

Нарушение циркадных ритмов у больных шизофренией

In order to take a systematic look at the circadian rhythms of people with schizophrenia, Foster and his colleagues recruited 20 people with the disease and instructed them to wear movement-detecting wristwatches for six weeks. The amount of motion detected can be analyzed to determine whether the person is asleep or awake, given the vastly different movement patterns between the two states.
The patients also filled out questionnaires and kept daily diaries of their sleep and activities. All of the patients were taking medication to control their symptoms, and they had all been stable on that medication for at least three months. Finally, the patients gave 48 hours work of urine samples to be tested for melatonin, a hormone that regulates sleep (melatonin makes a person sleepy).
For comparison, the researchers asked another 21 mentally healthy but unemployed adults to wear the same watches and keep the same records as the people with schizophrenia. Unemployed people were chosen because the patients with schizophrenia were all unemployed, and employment can alter sleep patterns by forcing people to get up with an alarm clock.

A comparison between the two groups revealed that while unemployed people keep fairly regular sleep hours, every person with schizophrenia in the sample had a sleep problem.
"What became very clear is that they are massively and completely disrupted," Foster said.
This disruption did not follow a common pattern. Some people with schizophrenia went to bed late and got up late, with their melatonin release patterns delayed by several hours compared with healthy counterparts. Others would get up later and later every day, their circadian rhythms "drifting" through time. The most severely affected showed no normal 24-hour sleep-wake pattern at all. They'd alternate sleep and activity throughout the day and night.

The results weren't the result of unemployment, because the unemployed-but-healthy group did not show them. Nor could they be linked to any specific medication or dosage level, Foster said.

Better Sleep May Help Improve Schizophrenia 

Литий и циркадные ритмы

According to Dr. Qing-Jun Meng in the university’s Faculty of Life Sciences, the extreme mood swings in bipolar disorder are associated with disruptions in circadian rhythms — the 24-hour rhythms controlled by our body clocks that govern our day and night activity.
“By tracking the dynamics of a key clock protein, we discovered that lithium increased the strength of the clockwork in cells up to threefold by blocking the actions of an enzyme called glycogen synthase kinase or GSK3,” he said.

Lithium Impacts Bipolar Disorder by Strengthening Body Clock