# Improving quality of life



## Nathanael.A. (Apr 16, 2013)

The role of medication in the treatment of DP/DR

So little is known about dp, that when it is diagnosed (rarely) and your doctor attempts to treat the condition, alot of medications tend to remain inert. Of the few studies on the medicative treatment of dp/dr, There are a few pioneers in the field. In general mental illness is little understood even in the 21st century, obviously due to the complexity's of conciousness itself, which I will not delve into here. In general mental illness tends to my grouped into criteria based on the patients subjective state of wellbeing, as well as the doctors judgement based on his/her observation of the patient. Principally first there are mood disorders such as unipolar depression which can be succesfully treated with medication currently available. However states of atypical depression, whereby the depression itself is caused by and link to more primary, persistent symptom, tends to be more difficult to get rid of. Atypical depression itself is prominent in DP/DR, as well as such other disorders such as schizophrenia, and the corresponding criteria which it is categorized into, centred around the long held concept of psychotic disorders. Psychosis itself tends to cover an extremely broad spectrum of symptoms, and In general due our lack of knowledge of the working of ourselves, can be seen by some as a blanket term.

Schizophrenia is a debillitating illness, which is most often accompanied by atypical depression, as well as some times unstable mood changes such as mania and depressive episodes. Ignoring the different diagnostic terms used in the context of the more broader term 'psychosis', schizophrenia is generally grouped into 3 different categories of the same disorder.

These are as follows:

Paranoid Schizophrenia

Disorganised Schizophrenia

Catatonic Schizophrenia

Of the three, paranoid schizophrenia is generally thought to have the best prognosis in terms of remission rates, the reason for this however remains a mystery. Schizophrenia is an extremely complex disorder, involving a multitude of genetic, hereditary and environmental factors which contribute towards its pathogenesis. In reality the 'different' types of schizophrenia may not even be the same disorder, but although the diagnosis itself can be seen as somewhat of a pigeon hole, the categorise aid in the treatment of the different varieties of symptoms that psychotic patients present with. Disorganised and catatonic schizophrenia are generally accepted to have a worse prognosis, are characterised by complex, debillitating symptoms, as well as a number of neurocognitive deficits. It is thought that a large hereditary component plays a decisive role in the development of both of these varieties of the illness, some studies even indicating a 50/50 chance of inheriting the disorder if either of your parents have succumbed to it.

Large developments in psychiatry have been made towards the treatment of this illness, as well as neuroscientific studies trying to examine the micropathology of the disorder itself in the brain. This kind of interpetation of the mechanisms of the disorder is quite crude considering the limitations both of the knowledge of the brain itself, and the technologies used to examine it on a functional, molecular level. Some disorders have been considered as mechanisms used by the brain in response to trauma, evolved as a survival strategy over many millenia. DP/DR itself is considered to be one, along with the illness known as Post traumatic stress disorder. It could be said that these disorders have a purpose which could be thought of as a psychological survival strategy. In my experience, whether longlasting or short, I consider DP/DR to be a regenerative mechanism utilised by the brain to cope with large amounts of stress/trauma. In general the disorder is mostly treatment refractory, although there have been some medications trialed for its treatment. A well known one of these is lamotrigine, commonly used in the treatment of Bipolar disorder, otherwise known as manic depressive episodes. How it has an ameliorative effect in these disorders is unknown, but extrapolating from what we known of its pharmacology, some of the scientific community have constructed basic models of how the drug has a theraputic effect on the aformentioned conditions.

Aswell as being a psychiatric medication, lamotrigine is used in the treatment of epilepsy and is an anticonvulsant. A prominent study based on the treatment of DP/DR utilised lamotrigine as the primary theraputic agent. One of the specialist leaders in the field performed a study on a large group of people suffering from dp/dr, and discovered that there was a reduction in symptoms in 60% of the participants, ranging from mild improvements to complete remission.

The study itself was based on an idea surrounding the mechanisms of dp/dr. The idea behind the use of lamotrigine originated from a friend of the specialist leader who had himself indulged in the usage of a dissociative drug. The man is said to have reported that when he consumed ketamine, he experienced the common effect of dissociation, aswell as concurrent feelings of what he said resembled depersonalisation and derealisation. Through the course of events, he desired an end to the unpleasant effects which the drug had, and happened upon some lamotrigine.

Possibly after several personal experiments, he reported that the consumption of lamotrigine had an ameliorative effect on the dissociative state induced my the drug. This has been theorised to be linked to lamotrigines ability to reduce glutamate release in the brain, as well as dampening the rate of its synthesis. This mechanism is thought to also aid in the drugs therapeutic effects on epilepsy. As a moodstabiliser, I consider lamotorigine itself to be relatively nonspecific in its action, compared to some other anti-psychotic medications which have binding affinities for receptors of several different neurotransmitter systems. Lamotrigine itself is not thought no act specifically on any receptors, nor is it thought to inhibit any reuptake transporters, thereby increasing levels of certain monoamine neurotransmitters in the brain, compared to other medications which do have this effect on synaptosomes in vitro and in vivo, which are generally thought to be behind these drugs theraputic effects in depressive conditions.

Lamotrigines general mechanism of action remains a mystery, similar to other mood stabilising agents such as litihum and valproate. In the treatment of dp/dr though there has evolved a theory behind its therapeutic effects. This also ties in with its ameliorative effect on ketamine induced dissociation.

Basically, it is thought that due to ketamines tendency to block Glutamate receptors (the NMDA one in particular), that this concurrently causes a large rise in bioavailable glutamate. So although on the one hand ketamine blocks glutamate from activating the NMDA receptor, this indirectly causes a large increase in glutamergic neurotransmission at all the other types of receptors. This increase in glutamergic transmission is thought to lead to a suppression of the limbic system by the prefrontal cortex. In an extremely crude example we could say that the 'intellectual brain' of the frontal cortex is inhibiting the 'emotional brain' of the limbic system, although in reality so such functional neurological segregation exists.

This process is theorized to underly the organic dissociation in dp/dr as well as that seen in drug induced states. Based on this pretense, the ability of lamotrigine to attenuate a possible hyper-glutamergic state in clinical dp/dr is the most up to date model of how specialists think the drug works therapeutically.

Another medication which has been trialed in the treatment of dp/dr is an opioid receptor blocker known as naloxone.

Although this agent was found to be the most effective, its possible to administer the agent via Injection which in terms of daily treatment is unrealistic, so its sister drug Naltrexone was also trialed in a similar manner. It has similar pharmacology, but was found to be slightly less effective than naloxone.

It is well known in neuroscience that the pain pathways of the brain which regulate both psychological and physical pain are the same. Therefore some might theorize that dp could possibly be summarized as a function of the brain which tries to dampen psychological pain, but in doing so overcompensates and reduces all other emotions along with it.

It is unknown to me at the current time if there was any biological pretense to using an opioid blocker in treating dp/dr, but I can only theorize that opioid receptor ligands such as endorphins and enkephalins probably act to dampen pain signals in the brains circuitry, so mayb by blocking this mechanism we are opening the brain up to feeling more. Still, this remains only conjecture. In addition, opioid antagonists are known to induce anxiety and other uncomfortable symptoms, so in general a pro/ con judgement must be made.

As far as treating the primary condition is concerned, thats as far as we have come in researching treatments for the disorder. Antideppressants can be used to ameliorate the accompanying depression, and in even more ghastly instances psychiatrists have been known to prescribe antipsychotic drugs in an attempt to treat it. This kind of approach is generally known to decrease quality of life for such patients and increase emotional numbing on a whole.

Antipsychotics encompasse a broad range of compounds primarily developed to treat psychotic states, but which are also used off label for a variety of other conditions. They are known to have antidepressant effects, aswell as inhibitory effects mainly on dopamine neurotransmission which is thought to underly paranoid psychotic states and delirium. However, on the flip side the most debilitating effects of psychosis tend to rear there head in the form of neurocognitive deficits and other abnormalities in behaviour known as 'Negative symptoms'. Current medication available for the disorder is widely known for its worsening effect on these negative symptoms, seeing as while the majority may be pharmacologically geared to suppressing dopamine somehow, concurrently dopamine mediates pleasure, wanting, motivation, enjoyment and reward in the brain.

When talking about schizophrenia, there is a large question mark over the role of glutamate neurotransmission in the disorder, specifically in how abnormalites in glutamate function contribute to the symptoms, as well as possible targets for drug therapy in this area. The' Glutamate' hypothesis of schizophrenia has risen to become a prominent theory alongside the more widely accepted dopamine hypothesis of schizophrenia. It is likely that a fuller understanding of the mechanisms behind the condition requires a unification of the two theories. Baring this in mind, while dopamine belongs to a family of neurotransmitters known as neuromodulators, which comprise only 5 percent of the neurochemical traffic in-brain, the other 95% being made of glutamate and of the inhibitory transmitter GABA (Gamma-Amino-Butyric-Acid).

In complex cases, such as Psychotic- depression, major primary symptoms can be paired up together, such others being Manic-deppressive psychosis. In general there is also a type of illness which mainly results in a large instability of mood, resulting in days where a patient will experience bouts of prolonged mania and hyperactivity, and then followed by extended periods of low mood and depression, being unable to get out of bed. Generally known as Bipolar disorder or Manic-depressive illness, it is thought to have a significant hereditary component behind it, but can also be well-treated with current medications (Lithium, Valproate, Lamotrigine) and patients can lead relatively normal lives while living with the disorder.

There are some conditions which are still debated over in psychiatry due to they're very nature, such as the Personality disorders, and others which by many are thought to not even exist due to their outlandish nature, such as Dissociative Identity Disorder.

In general, whether long term or short, my perspective points toward DP/DR as being a regenerative mechanism for the soul. In general as we grow up, our senses of ourselves aren't static, they are constantly changing, accumalating into a dynamic system of memories and experience. We are our memories, you could say. When someone experiences trauma in there lives, wether short term of prolonged, either form has its own impact on the person, and somehow the body has to cope. The developement of the personality and a sense of self is an extremely long term thing, and if trauma is prolonged, inconsistencies may be introduced into the person, instabilities may appear in the mind, which then become ingrained in the habitual routine of daily life. If severe enough, or triggered by adverse events or drug abuse, the self becomes unstable, and may even succumb to its own inefficiencies and collapse. This takes time, and if the damage inflicted is severe enough, life may have to be learned all over again. DP/DR can be quite persistent, but at the end of the day there is no quick fix for something which has been damaged deeply and progressively. The only thing that the mind needs to heal and recover is time, the power of the mind is boundless, if it has brought you into being once, it can certainly do so again. In the depths of the engines of reality, there are no laws, no limits, there are only choices, and out of it u can become a a better person, grow in unlimited new ways, and find enlightenment in a world of experiential tumult.

At the end of the day, medication cannot cure, prevent, or generally even quicken the rate of recovery from dp. The cure to dp is dp itself, the only treatment time, compassion and effort. In general the only thing medication can do in dp/dr is lessen the discomfort, increase quality of life, and basically make it a little bit more bearable. The cure itself comes from you, you can heal, evolve, change and adapt. Thats what life does, it adapts.


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## drew-uk (May 22, 2009)

Thank you for taking the time to write this. It's hard to find information that explains effects of medication in a way that's easy to understand.

Iv never heard about how lamotrigine was discovered before, do you have a link to your source?


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## odisa (Sep 2, 2013)

Wow that's a long post. You covered Lamotrigine and Naloxone; the two most implicated medications for DP.
If indeed the issue at hand is not the antagonism of the NMDAR, but of the remaining glutamate binding to other glutamatergic receptors, then one would think that perhaps an antagonist at these sites would help. Unfortunately, antagonizing glutamatergic receptors is psychotomimetic in many cases. Moreover, agonism of these receptors has, to date, not been linked to dissociative states (thinking Ampakines etc.). Thus, NMDAR agonism is well worth trying (I'll be trying this myself soon with a novel NMDAR glycine site partial agonist).

As for Naloxone/Naltrexone; you are aware that the key receptor being blocked by these nonselective antagonists is the KOR, right? Mu and Delta receptors have very little to do with it afaik, though I guess the Nociceptin receptors could be involved.
This is why Naltrexone fails frequently; doses needed to acquire significant KOR antagonism are often not tolerated, whereas Naloxone has a higher affinity for KOR than Naltrexone (err.. not too sure on that. Memory is a bit foggy, but I think that's what I deduced a while back. It could have been less affinity at other receptors; thereby having a relatively higher affinity for KOR.)
Anyway; KOR agonists are well known for their dissociative effects (e.g. Salvinorin A), hence KOR antagonism definitely warrants experimentation. I will be trying a selective KOR antagonist a.s.a.p. as well.

Ohh, and another way to reduce glutamate levels in the brain would be to enhance glutamate decarboxylase; this would enhance the transformation of Glutamate to GABA, hence killing to birds with one stone. I haven't looked in to this that much yet, but it may be warranted to explore, certainly if you believe DP to be a case of hyperglutamatergia. Perhaps Pyridoxal-phosphate could be of use.

I must say you are correct; in that currently available medications are quite inferior inventions and generally don't help people out too much. But there are more roads that lead to Rome; something to keep in mind before stating there is only one treatment for something. There are many stones left unturned regarding the neuropsychopharmacology of DP, and albeit having generally been fruitless efforts up to now, that needn't equate to similar outcomes in the future. Neuroscience has only recently begun evolving towards better practical implications; many of which are not available to the general public yet.

edit: I just read that extracts of Gotu Kola and Valeriana Officinalis have shown to increase glutamate decarboxylase; perhaps investigating their phytochemicals, and isolating the responsible one(s), may be of use.


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## Nathanael.A. (Apr 16, 2013)

KOR? Sounds interesting, although I have taken both Mu-receptor based opioid painkiller and salvia, and both had an equally detrimental effect on my dp, so maybe theres some interplay going on here.


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