June 19, 2007

Nuvigil is Approved For Excessive Sleepiness - Effects in Schizophrenia to be Studied

Some patients with schizophrenia/schizoaffective disorder are currently taking Provigil (modafinil) for problems with excessive sleepiness including sleepiness due to some sleep disorders.

Now, the manufacturer of Provigil has just had a slightly modified version of it, called Nuvigil (armodafinil) approved by the FDA for excessive sleepiness due to narcolepsy, sleep apnea, and shift work.

As these are non-amphetamine based medications that specifically target the sleep area of the brain, they are considered to be safer than stimulant medications which more broadly affect the brain and which may be contra-indicated for use in people vulnerable to psychosis. The manufacturer will soon be additionally testing the effects of Nuvigil on bipolar depression, cognition in schizophrenia, and excessive sleepiness in certain medical conditions such as Parkinson's.

Below is an excerpt from the company's press release:

Cephalon Receives FDA Approval of NUVIGIL(TM) for the Treatment of Excessive Sleepiness Associated with Three Disorders

Cephalon, (Nachrichten) Inc. today announced that it has received approval from the U.S. Food and Drug Administration to market NUVIGIL(TM) (armodafinil) Tablets [C- IV], a non-amphetamine wake-promoting agent for the treatment of excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS), narcolepsy, and shift work sleep disorder (SWSD). In OSAHS, NUVIGIL is indicated as an adjunct to standard treatment(s) for the underlying obstruction. NUVIGIL is the single-isomer formulation of modafinil, the active pharmaceutical ingredient contained in PROVIGIL(R) (modafinil) Tablets [C-IV], which was approved by FDA in 1998 to improve wakefulness.

"FDA approval of NUVIGIL is a major accomplishment and the result of collaborative efforts with the scientific and regulatory communities," said Dr. Lesley Russell, Executive Vice President, Worldwide Medical and Regulatory Operations. "We are excited about the future of NUVIGIL and we have initiated additional clinical work to explore its potential in a wide range of medical disorders."

Cephalon's clinical program will evaluate the use of NUVIGIL as a treatment for serious medical conditions such as bipolar depression, cognition associated with schizophrenia, excessive sleepiness in medical conditions such as Parkinson's disease, and fatigue in patients who are being treated for cancer. The company currently plans a commercial launch of NUVIGIL once additional clinical data has been amassed.

The agency has approved final labeling for NUVIGIL, including a bolded warning, which is consistent with the draft labeling received by the company in March 2007. Full prescribing information will be available on the FDA website or on the company's website at: http://www.cephalon.com/newsroom/assets/Nuvigil_Prescribing_Information.pdf. As expected, the agency also has indicated that it will request similar language in the label for PROVIGIL.

Read the full press release: Cephalon Receives FDA Approval of NUVIGIL(TM) for the Treatment of Excessive Sleepiness Associated with Three Disorders

For information on the clinical study of Nuvigil on cognitive function in people with schizophrenia, click HERE.


" Shift work sleep disorder ". This is nuts ! if people sleep a long time it is because the body is carrying out necessary duties to ready its constitution for the next day.
Good sleep is essential for health, and whether amphetamine like or not drugs that reduce sleep are likely to speed up thinking, as sleep deprivation in absence of drugs, itself, speeds up thinking eventually leading to psychosis.
The only useful application of this drug as far as SWSD is concerned, (The other applications may be valid) is to line the pockets of the shareholders. I guess the next target for drug therapy will be " Abnormal Prolonged Happiness Disorder "

Posted by: Robert at June 19, 2007 05:38 AM

The drug keeps those shift workers alert while they are awake. It does not deprive them of sleep. It also helps with the excessive sleepiness caused by narcoleptic conditions and perhaps even other types of disorders including side-effects from medications (this is an off-label use).

The problem is that people need to be awake to work. They may work in spite of being in a sleepy haze. Or - they may not work at all because of the excessive sleepiness. This medication allows the people to function. It is not taken during sleep hours. It is not meant to replace sleep.

Also, sometimes feeling sleepy does not always mean the body or brain requires the sleep. Sometimes the sleepiness is due to medication side-effects or due to some strange malfunction in the neurobrainhormonal system.

I know people who take Provigil and at least can function now, having fun, going to school, etc. whereas before they had no life because they were sleeping their life away.

Personally, I am very happy that a medication that may help with alertness will be studied for schizophrenia and bipolar.

For instance - will it help with the tendency some people with mood disorders have that whenever stressed they fall asleep? It is a reaction that is so similar to some forms of narcolepsy. I hope they will find out if it will help that.


Posted by: Naomi at June 19, 2007 08:48 AM

In the Nuvigil Prescribing Information, it is written that stop taking Nuvigil if u have mental illness, and also Nuvigile may cause the mental symptoms as the possible side effects of Nuvigile. I wonder how Nuvigil may help people with SC in these conditions?

Posted by: ilker at June 19, 2007 09:55 AM

Many medications can cause "mental" symptoms. Asthma medications can cause mental symptoms, as can medications for allergies, for insomnia, for vomiting, for seasickness, and even antianxiety medications can CAUSE anxiety and even psychosis.... in some people.

So of course - stop taking a medication if it causes mental symptoms.

For the people I know who have schizoaffective disorder plus sleep issues, and who take Provigil, it has helped them tremendously. I am sure many others would not be helped by it. That's how it is with most of these medications.

The point for studying it, though is that it may help many people without causing the side-effects of the stimulants which seems to hurt too many people, and too severely.


Posted by: Naomi at June 19, 2007 01:36 PM

I'm interested in the possible correllation between REM sleep in regards to contributing, coinciding and predisposing factors for schizophrenia and psychosis.
Imagine that REM sleep is a process that occurs in the hippocampus and is like an airline control tower that is trying to organise the landing of airoplanes into a busy airport for a short period during the night while you are sleeping. The airoplanes represent many scattered emotions and non-concrete information that is spread throughout the perceptual areas of the brain . The landing of the planes is like the collection of random emotional data in the form of impulses , then sorting ,disposing or placing of data into emotional memory banks using previously stored emotional memories to assist the process.

Human research supports the function of rapid eye movement (REM) sleep in memory formation. German scientists at the University of Bamberg stated, "Results are consonant with a supportive function of REM sleep predominating late sleep for the formation of emotional memory in humans."
Studies with deep electrodes have established that while the EEG of the neocortex is low in voltage during the REM sleep state, the EEG of the hippocampus is increased in size at a 4-10 Hz (theta) frequency.

It is known that Successful REM sleep removes extranenous connections to D1 receptors. - CHECK THIS

Slowing of noradrenergic cells may be responsible for some of the symptoms of sleep deprivation, since norepinephrine release has been shown to increase the "signal to noise ratio" of information processing in a number of brain regions

I suggest that In shizophrenics, REM sleep is unable to successfully remove extraneous connections to D1 receptors, resulting in overabundance of connections. This leads to hallucinations and/or disorganized thoughts. Schizophrenics have too many D1 receptors [research in mid 90's confirms this, reasearch in mid 2000's contradicts this] so if REM sleep is not functioning properly for any individual, then psychosis occurs. The reason for malfunction would dictate the duration and type of psychosis.
Ie. Too much emotional data overloading REM, poor foundation memories needed for sorting. Poor quality fluid and chemical combinations creating difficult pathways for impulses to leave their point of origin and head towards the hippicampus.

The Multiple ascending neurotransmitter systems participate in the regulation of behavioral state. For example, noradrenergic, cholinergic and serotonergic systems increase EEG and, in
some cases, behavioral indices of arousal.
If the mechanism or chemical and electrical freeway that controls the process of REM is not functioning properly, could this cause psychosis, due to the possible overflow of stored emotions and non-concrete information? Could this be in the form of dreamlike perceptions spilling out onto our real or awake perceptual experiences that are sorted in a neighbouring area of the brain?.
Could this create a dream/nightmare state (Psychosis) that exists while awake?
Possible overloading reasons:
Sleep deprivation resulting in less REM sleep .
Perhaps the Rem Data could be too much for the REM mechanism to process during stressful times.
Ruminations that occur during periods of high anxiety might overload the REM process.
Double bind parenting could cause increased emotional stress and result in an overflowing Rem process.
Perhaps even hypersomnia during stressful times can be insufficient for the sorting out and emptying of the areas.
In schizophrenia and certain types of severe depression, the hippocampus shrinks.
Anxiety and depression can lead to psychosis due to an increase or overflow of the REM data sites.
Anxiety and wakening during sleep decrease the effective clearing of data sites because there is less REM sleep.
It's commonly known that sleep deprivation causes psychosis, if the Rem mechanism can't function due to lack of sleep, it overflows [rewrite]. Overloaded REM in a normal individual will spill out onto daytime wakening and perceptions in these circumstances,possibly in the areas they are waiting to be collected from.
Poorly functioning REM might result from nightmares which wake the person up and so they never actually continue with an adequate cleansing of the REM sites.
Possible reasons for REM mechanism failure .
Perhaps a genetic predisposition to a faulty mechanism .
A poorly functioning REM system could also be caused by dehydration, high fructose junk food, coca cola, coffee, cigarrettes, poor vitamin intake, low phosphorus levels. Higher levels of nutrients have been shown to affect REM and are linked to better sleep.
Some poorly functioning REM mechanisms could be caused by maternal infections during pregnancy , head injury or other illnesses during childhood.
Schizophrenia might occur after childhood because the REM takes a while to become overloaded. Perhaps in some cases of high chronic stress or low mood or poor sleep REM data never completely clears so it eventually floods certain areas of the brain, polluting perceptions while the individual is awake .
This could explain why prodromal schizophrenics withdraw and become socially autistic, perhaps the cloudiness they complain about is like a polluted stuffiness from over stuffed REM sites that interfer with the processes necessary for the person to take in external information and seperate it from their internal overflowing REM data sites.
Excessive intake of Junk food, high fructose diets, cola and coffee are common amongst Scizophrenics.Perhaps these diets adversly affect the mechanism or homeostasis required for emptying of the can. It could be as simple as chemical imbalances in the brain resulting in a poorly functioning REM mechanism or flow of impulses. Recently, considerable progress has been made in our understanding of the function and regulation of the brain-specific sodium-dependent inorganic phosphate transporter 1 (NPT1), which is found to exist principally in cerebrum and cerebellum. A high phosphate diet caused an increase in serum Pi accompanied by a decrease in calcium, and a decrease in body weight coupled with a decreased relative weight of cerebellum. A study showed the specific radioactivity of the phosphatides was depressed in sleeping as compared with waking animals. These observations suggest that the physiological conditions attributable to environmental, emotional or other determinants can influence shifts in brain metabolism during the sleep-wakefulness cycle.

* Regular coffee and caffeine caused REM sleep to shift to the early part of the night and stages 3 and 4 sleep to shift to the later part.
Infection can lead to psychosis . Fact: Sleep deprivation may enable bacterial growth and that sufficient sleep impedes bacterial growth.What's even more interesting is that di-muramyl peptides created during infection enhance non-REM sleep (but not REM sleep).

Other possible connections:
Siblings of schizophrenics often complain of vivid nightmares.
Post traumatic Stress disorder clients complain of terrible nightmares.
Antipschotis Medications that are sedating have a faster acting effect than non-sedating antipsychotics .
Some antidepressants can cause psychosis and some antidepressants have been shown to block REM sleep.
Hypersomnia may be the body's way to try to empty/sort the REM data, as is sometimes seen in mild depression or prodromal schizophrenia. Researchers from Quebec, Canada say sleeping late increases REM
It is rare to find a schizophrenic that doesn't smoke. Epidemiologic investigations indicate that, compared with never smokers, current smokers experience greater difficulty in initiating and maintaining sleep and are generally more dissatisfied with their sleep quality .
A series of human and animal investigations has suggested that altered expression and function of the {alpha}7-nicotinic cholinergic receptor may be responsible for the auditory sensory gating deficit characterized in schizophrenia patients and their relatives as diminished suppression of an auditory-evoked response (P50) to repeated stimuli.
The mechanism of sensory gating involves feed-forward and feed-back inhibition of the stimulus perceived. It involves GABA-ergic and α7 nicotinergic receptor-mediated inhibition of the pyramidal neurons in the cornu ammonis (CA3) region of the hippocampus. Nicotinergic receptors are effected by cigarette smoking.
Side effects of antipschotics can be parkisonian in nature. In recent studies it has been shown that smoking can protect you from parkinson's disease.
Some illicit drugs have been shown to decrease REM Sleep. Smoking marijuana can induce psychosis in certain populations (such as persons with schizophrenia) At low doses, marijuana may cause drowsiness, but at higher doses it seems to interfere with sleep. Specifically, it tends to decrease total REM time and also decrease eye movement during REM sleep.
A striking phenomenon is that the amount of REM sleep seen after such transections is a function of central temperature. Schizophrenia patients may exhibit thermoregulatory disturbances, resulting in increased or decreased body temperature.
ECT has been beneficial in treating psychosis perhaps only because it interfers with memory tasks in the brain. A decrease in recent memories decrease the load on the REM.
Several abnormalities have been documented in depressed patients such as: decreased sleep continuity (fragmented sleep), diminished slow wave sleep (NREM) and alterations of rapid eye movement (REM) sleep, including decreased REM latency (too early onset), and increased REM density.
Results of objective polysomnographic studies showed that individuals with high anxiety and worries, even without depression or other psychiatric problems, have documented changes: It took them longer to fall asleep. When they sleep, the percentage of NREM sleep (that is a resting sleep in which growth hormone is released) is decreased with more frequent transitions from deep sleep to light sleep (stage 1 of NREM), more microarousals and a lower REM density (frequency of rapid eye movements per unit of time). (*needs quote refferrence)
Individuals who keep their stress levels low may become adults who seem excentric. If the Rem Data doesn't overflow maybe they are able to escape positive symptomology. Perhaps certain at risk individuals never get schizophrenia due to their low life stress levels despite a defective mechanism.
Depression does not always lead to psychosis possibly because anxiety and depression are purely an overflowing System and not a faulty one so therefore there is a good chance the person can go back to normal once the system is cleared and the stress decreased ..
Maybe some potential schizophrenics could have their schizophrenia risk lessened by picking out high risk children in schools and educating them about emotional and nutritional health, avoiding caffiene and illicit drugs . Perhaps using melatonin to promote REM sleep. Avoiding benzodiazepams and as an adolescent avoiding alcohol (Both of which suppress REM.)
Narcolepsy may be somehow related , the symptoms include...Cataplexy: sudden episodes of loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Attacks may be triggered by sudden emotional reactions such as laughter, anger or fear, and may last from a few seconds to several minutes. The person remains conscious throughout the episode. Sleep paralysis: temporary inability to talk or move when falling asleep or waking up. It may last a few seconds to minutes. Hypnagogic hallucinations: vivid, often frightening, dream-like experiences that occur while dozing or falling asleep.
REM sleep is present caudal to midbrain transections and absent rostral to such transections. Therefore, one may conclude that structures rostral to the midbrain are not required for REM sleep and that structures caudal to the midbrain are sufficient to generate REM sleep.
When the pons and caudal midbrain are connected to mid- and fore-brain structures, some signs of REM sleep are seen in these rostral structures. When the pons and caudal midbrain are connected to the medulla and spinal cord, as in the midbrain decerebrate animal, the defining signs of REM sleep are seen in caudal structures.
The pons and the caudal midbrain region are both necessary and sufficient to generate some of the basic phenomena of REM sleep.
Electrolytic lesions that destroyed the bulk of the RPO, permanently eliminated REM sleep
The lateral region (L2-4 in the cat) of the RPO, ventral to the locus coeruleus, is the brain region most critical for REM sleep.
it has been questioned that periodic cessation of discharge [during REM sleep] prevents desensitization of aminergic receptors, which are continuously activated in waking.

Posted by: Petr at August 16, 2007 11:02 PM

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