SOCIALIZATION FACTOR (PART 4)

“SOCIAL INHIBITION ” AS A UNIVERSAL PROPERTY OF THE BRAIN – THE LESSONS OF THE MECAMYLAMINE/ INVERSINE EXPERIENCE

4- A) THE CONCEPT OF PROSOCIALIZATION MEDICATIONS. The previous sections dealt with inhibited socialization seen in schizophrenia, autism and social phobia. There was the hint that these examples related to each other and to some broader understanding of what the socialization factor is– but from the scattered bits of understanding assembled, it was impossible to develop a consistent theory. Then a major breakthrough occurred with the use of the medication mecamylamine/ Inversine. It has provided prosocialization benefits in an unexpectedly wide sphere and thus lent support to the concept that all brains have a control mechanism for activating or inhibiting the socialization factor —and that many brains have a disturbance of function because irregularities in that control. The social isolation of schizophrenia and autism on one side and mania on the other may simply represent extremes of behavior patterns present in the function of every brain.

4- B) Inversine (mecamylamine) is a nicotinergic receptor blocker. Beginning in the year 2002, Inversine has been prescribed in this clinic to a number of developmentally disabled individuals – originally with the aim of helping to control their impulsive type behaviors. The effect on impulsivity was quite irregular, but a large number of those treated demonstrated major improvements in their capacity to socialize –especially their ability to participate in conversational speech. This benefit occurred not just in the autistic and the schizophrenic but also in many whose socialization patterns had previously been considered acceptable.

4-C) THE PROSOCIALIZATION EFFECTS SEEN WHEN INVERSINE WAS GIVEN TO DEVELOPMENTALLY DISABLED INDIVIDUALS.
Four months after beginning to use mecamylamine/ Inversine, I wrote the observation that there was ----“the increasing impression that mecamylamine/ Inversine enhances unexpected functions—especially improvement in speech. In the last months, there have been additional observations from caregivers that the patients receiving Inversine seem to be happier.” The following are various comments that were made concerning the change brought about by mecamylamine/ Inversine therapy.

4-C1) Descriptions of effects of mecamylamine/ Inversine treatment from histories given by caregivers: “Increased spontaneous talk.” “Happier, can be corrected, acts like a different person.” “Less violence.” “Less excess obsessive talking” “Less aggressive.” “Increased communication; said ‘What’s that wonderful smell.’ ”. “Manic highs are less severe” “Personality less rigid.” “Attempting to talk for first time; said, ‘Mower broke; fix it.’ ”. “More alert, more singing, lowered obsessions.” “Increased talk, no upsets.” “More social, less compulsive eating, increased speech.” “Better talking, less violence.” “No injurious self abuse.” “Speaks 2-7 word sentences.” “Opened up, more verbal, repeated things learned in past, less nonsense talk, seeks out people to talk with.” “Less shouting, more social conversing.” “More mature.” “Less self abuse.” “Less manic talk.” “No rages or aggression, more interest in joining in social situations, more talking.” “Less nonsense talking, more mature.” “Increased descriptive talk.” “Formerly talked some only to mother, now talks to others and cannot shut up.” “Is able to maintain control and work through his stuttering.”

4-C2) History of one individual’s change. One mother wrote the following about the change in her son after being treated with mecamylamine/ Inversine.

Case Twenty one
K AND INVERSINE – Letter from his mother.
My son, K, has a diagnosis of Fragile X syndrome. He has rage and impulse control problems. K and his brothers were diagnosed with Fragile X in 1990 and K started his treatment with Dr. Ankenman to help him control his rage. Dr. Ankenman has helped K make great progress over the years, but he still had a lot of problems with stuttering repetitive speech and tactile social interactions.
In August of 2003, Dr. Ankenman asked about starting K on Inversine at a low dose. As he had always done, he explained what the medication was used for in most of the population that it was given to and what his use for it was. (What he had observed the outcome to be for other clients like K) K started taking this new medication in August.
K lives with his brothers in their home with providers. I work at the same workshop that K attends 5 days a week. Within 6-8 weeks, I started to see some positive changes in K. He crossed his fingers and patted his legs less. His small vocal outbursts started to decrease. By December, his speech had improved greatly. When he would stutter, instead of continuing, he would stop speaking, drop his head and mutter something like, “Xxxx”. Then he will start his conversation again without the speed and stutter he had just worked up to.
By February, K had improved so much it has been amazing to his family and friends. For instance, when K is at the workshop he has always been under the same supervisor and sits with the same small group of employees in a relatively quiet area, sectioned off from the main area of the workshop, away from a lot of noise. He never ventured out of his area. . The only place he would go is to the restroom. Then he would only go when is supervisor was with him. He wouldn’t even venture to my office, which is in the production area approximately 20 feet from K’s work area.
K will now go to the restroom completely across the workshop alone. He comes to visit me. When finished working or taking a break he’ll come around the wall, out of his work area, sit on a bench and speak to and tease clients and staff.
He’ll walk to his grandmother’s house, a block from his own and sit and have a conversation with her and her friends. I had told her about his improvement, but when he came over and she saw and heard the changes for herself, she called me crying. She could not believe the difference in his speech and behavior.
He not only speaks more clearly but has actual conversations. He allows people to touch him. His supervisor of seven years is amazed he will massage S’s neck and then asks Scott to massage his and allows him to.
His provider jokingly told me a week ago, that she thought K should regress and go back to shutting himself in his room while he is at home. Now he wants to stay out and help cook and visit and converse. K’s personality is starting to emerge. The bus driver told me last “Thursday, March 13, 2003, after picking K up he had on a new shirt, was shaved and looked really nice.” She remarked to him how nice he looked, something she would not have done 3 months ago. He said, “Oh yeah? Here smell my neck” He had after-shave on!! She said “K, boy you're lucky I’m already married “ to which K relied, “Yeah, I know you want me!”
Just last night, March 1, 2003, K asked his provider, B. R if he could ask a female co-worker, to go to Ponderosa with him for dinner when he got his workshop check. “She said “Okay K, how are you going to -get there?” K said,” Ill take you and you drive, dufus”
These only a few of the striking changes in my son, K. They may not seem big to you, but to all of us who know K,. and especially to us who love him. these changes are nothing short of a miracle.
Thank You Dr. Ankenman and Inversine
K’s mother

4-C 3) Examples of developmentally disabled individuals seen in a routine day in the outpatient clinic. Note that too high a dose caused behavioral side effects.

Case Twenty two
4-C3.a) 35-year old male who showed response at one half tablet of mecamylamine/ Inversine a week. Previously his conversation had been limited mostly to his obsession about clocks.

4- C3.a1) Conversation reported by caregiver:
Careg. “Look at all that moss in that pond.” (algae)
Pt. “ What’s moss?”
Careg. “That green stuff that grows in the water when it’s hot.”
Pt. “That’s interesting. I must tell someone about it.”
4- C3.a 2) Conversation in office:
Doc. “ How did he do on vacation with his folks?”
Careg. “He was much less nervous. but he slept a lot.”
Pt. (interrupting spontaneously) “ There wasn’t much to do there.”

Case Twenty three
4- C3.a3) 22-year old female with a trisomy chromosome abnormality. On 0.75 mg. of mecamylamine two times a week her conversation increased and was more mature. When given an increased dose of 1.25 mg, she developed excessive talking with obsessive ideations, poor sleep and some violence. This was treated by stopping the mecamylamine and starting 200 mg of quetiapine/ Seroquel a day.

4- D) Where did mecamylamine /Inversine come from? From about 1955 to 1980, mecamylamine /Inversine was used for difficult cases of hypertension – during a period when today’s safe, effective blood pressure medications were not available. In high doses, it blocked the nicotinic class of anticholinergic receptors which stimulate the sympathetic nerve cells along the spine. This blockade lowers the blood pressure. As other medications became popular, its production was stopped; but in 1997 a group of clinicians and scientists at University of South Florida began doing research on its nicotine receptor blocking action. They investigated Inversine after the gaining the realization that some of the benefit that Nicotine produces in treating Tourette’s Disorder is related to its effect in acting as a blocker of the nicotine receptor. ® (B1).
This group, including Dr. Archie Silver, Dr. R. Douglas Shytle, and Dr. Paul R. Sanberg, discovered the multiple therapeutic effects of Inversine. They found manufacturers willing to bring it back to the market as an “orphan” treatment for Tourette’s disorder. They have published several articles about the multiple benefits seen in long-term treatment of Tourette’s disorder. ®(B2) Although the original reason for using Inversine was to help stabilize the tics seen in Tourette’s, they reported a number of behavior benefits. Currently, Inversine is marketed by Targacept Inc, a company in North Carolina which specializes in pharmaceuticals related to nicotine.
® (B1): Silver AA, Shytle RD et. al. (2001) Multicenter, Double-Blind, Placebo-controlled Study of Mecamylamine Monotherapy for Tourette’s Disorder. J. of Amer Acad of Child and Adolescent Psych. Vol.40 :, 1104)
® (B2) Silver AA, Shytle RD, Sanberg PR (2000)Mecamylamine in Tourette’s Syndrome: A Two-year Retrospective case Study. J Child Adolesc. Psychopharmacol. 10:59-68)

4-E) WHAT IS DIFFERENT ABOUT THIS USE OF MECAMYLAMINE/ INVERSINE?
This clinic’s experience using mecamylamine/ Inversine has been different from that described by others. The dosage tolerated, the therapeutic benefits and the side effects are considerably different from that reported in the Tourette’s trials. Though there have been many benefits using Inversine, it has been difficult to use for the following reasons.
4-E1) Inversine represents a new and unfamiliar class of medication: Most physicians and pharmacists have never heard of it; therefore they have difficulty evaluating its effects in individuals receiving it. Furthermore, it has so many potential ways of acting in the body that the prescribing physician cannot alert the patient to all possible effects.
4-E2) Inconvenient dose size: Inversine is marketed in a 2.5 mg tablet. This tablet can be cut in half fairly easily but smaller doses are difficult to obtain. Inversine is soluble in water and homemade solutions can be used, but no standardized liquid preparations are available. Some pharmacies have agreed to make special preparations of a lower dose. The preparation is a capsule containing 1/10 the commercially produced tablet. (one capsule = 0.25 mg). It is always more difficult to initiate therapy of any medication which may require non-standard dosing.
4-E3) Inability to predict responders: Three patients seem to have the same symptoms (such as intense compulsions). When one is given mecamylamine/ Inversine, he is instantly improved; the second gains no benefit from the drug; the third becomes agitated.
4-E4) Unpredictable length of action. About four months after this clinic started using mecamylamine/ Inversine therapy, the supply of Inversine was temporarily cut off. Those who had positive results were suddenly without the medication. Many of these retained the benefits even though they did not receive mecamylamine /Inversine for several months. This finding is similar to the effects of glycine-serine agonists treating negative symptoms of schizophrenia and of Secretin in autism. This prolonged effect has also been seen in a number of patients in whom the mecamylamine/ Inversine had been discontinued because they had become too activated.
4-E5) “Reverse” behavioral effects: Some individuals will have a worsening of their condition when given mecamylamine/ Inversine. When given Inversine for aggression, obsessive compulsive behavior, or mania, several individuals became worse while others demonstrated rapid improvement. Some individuals have temporarily acted wildly psychotic for hours after receiving one dose.

Two autistic boys under the age of 12 demonstrated instant violence, which lasted several hours. They had different outcomes.

Case Twenty four
4-E5.a) One of these boys (who was 11 years and autistic was so violent and psychotic after receiving one half a tablet (1.25 mg.) that his parents required police help for several hours until he calmed. Previously this individual shown a more subdued agitation when he had been placed on any of the prosocializing atypical antipsychotics. Eventually he was treated successfully with a fairly high dose of the typical antipsychotic Haldol/ haloperidol.

Case Twenty five
4-E5.b) The other boy (also 11 years old and autistic) calmed after nearly a day of agitation. His Inversine/ mecamylamine was stopped, but in the following three months his social behavior improved markedly. He was more attentive and responsive to commands and had far less self-abuse. This improvement lasted over four months. When it began to lessen, he improved after being started on a very low dose of Inversine/ mecamylamine, but became aggressive if he missed his daily dose. There may also be some individuals who have had more disinhibited behavior after receiving mecamylamine/ Inversine and maintained it even after discontinuation.

4-E5.c This poor tolerance generally has not been reported by others. In the multicenter double-blind trial for treatment of Tourette’s disorder, it was observed that the doses of 2.5 to 7.5 mg a day were “well tolerated”—but in a talk page one mother describe the experience of her son:

Case Twenty six
Website address: neuro-mancer.mgh.harvard.edu or www.braintalk.org (posted 07-30-2000 07:34 PM ) My son participated in a double-blind mecamylamine trial during the 1999 summer. It was obvious to all that he got the real med, not a placebo. It helped him for one of the 8 weeks. His tics, already reduced considerably by vitamin supplementation, went to zero. However, after one week, he completely lost his appetite, such that he only ate about a palm-size of food per day. By the third week, he started the most outrageous rage tantrums, lasting through the night. At that point, I had insisted on a reduction in the "pills" or we were out of the trial. The physician agreed with a reduction. After the trial was over, he said that my son's experience was typical of others.

4-E6) Individual variation of dosage and side effects: The standard recommended dose for mecamylamine /Inversine to treat Tourette’s is 2.5 to 7.5 mg a day, and when it was used years ago for hypertension the dose was as much as 10 to 75 mg a day! However, some psychiatric patients cannot tolerate even a very small dose. Now this clinic often starts it at the dose of 1/10th tablet ( 0.25 mg) 2 times a week. Starting with such very small doses tends to minimize the number of individuals who have difficult behavioral reactions—and some individuals actually respond to a dose that small.

4-E7) Lack of tolerance for increasing doses. Some individuals will gain a good response at a very low dose. If the dose is raised, there will often develop a problem behavior—generally disinhibition.

In the first 100 individuals with Developmental Disability treated in this clinic, about one in six had difficult behavioral reactions when started on a mecamylamine /Inversine dose of 1.25 mg/day or higher (one half tablet). There seems to be an extreme difference how mecamylamine/ Inversine affects the function of different brains, and there is no absolute way of predicting the response.
® (E1) Silver AA, Shytle RD et. al. (2001) Multicenter, Double-Blind, Placebo-controlled Study of Mecamylamine Monotherapy for Tourette’s Disorder. J. of Amer Acad of Child and Adolescent Psych. 40.3)

4- F) THE SOCIALIZATION FACTOR IN THE VERY YOUNG AND MECAMYLAMINE/ INVERSINE.

Since the atypical antipsychotics have been shown to help the very young improve socialization, and since mecamylamine/ Inversine generally demonstrates more prosocialization potential than the Atypicals, it is reasonable to consider its use in this age group. The effect has been very beneficial – but not in itself curative.

Case Twenty seven

This non-verbal four-year-old girl who had very limited motor function, began to increase verbal babbling, was more alert to human interaction, and seemed to have wider interests in watching television when placed on mecamylamine/ Inversine, which was raised over time to one half tablet a day (1.25mg/ day). Her capacity to cooperate with physical therapy improved, but she had not developed speech. Her parents attribute to Inversine/ mecamylamine as having contributed 30% to her progress. This case points out a concept that is new to the field of caring for the autistic and other developmentally disabled. [30] The new “pro- socialization medications would seem to be indicated for early use, as soon as the socialization block is noted – not started as a last resort when all else has failed.

4-G) SUMMARY OF THE ATYPICAL RESULTS SEEN IN THE USE OF MECAMYLAMINE /INVERSINE IN DEVELOPMENTALLY DISABLED:
[31]
4-G1) Some individuals became agitated and appear psychotic when given mecamylamine /Inversine.
4-G2) Some individuals instantly became more socialized with improved conversational skills.
4-G3) In some individuals, the benefits of the treatment persist after the treatment stopped.
4-G4) Some individuals who stopped the medicine because of agitation later demonstrated improvement in socialization and conversational skills.
4-G5) Even very low doses of mecamylamine /Inversine could produce changes—both positive and negative.
4-G6) Some individuals had no response to the therapy.