ADHD, Methylphenidate and ED - Alt. Drugs: Amantadine, modafinil or bupropion?

[Wizzle]

[B]Pharmacodynamics of methylphenidate and mirtazapine[/B]

edit: I changed the thread title because this seems to be a more interesting discussion. I don't know if these two drug are commonly prescribed together but it dus seem to work for the Erectile Dysfunction I experienced from methylphenidate. I'd like to know more about the mechanisms behind this. I also think ED is quite common with ADHD-meds, although the literature doens't speak of it at all. Maybe because these meds have mostly been tested on kids? (as if kids don't like getting erections )

The tolerance part is still interesting to me though. I wonder if I should ask my pdoc for a prescribed nmda-antagonist to make methylphenidate effective in the long term. Because I've been off it a while, and life is definitely better for me when I do take it.

Recently, I have tried lowering my tolerance to methylphenidate because I felt it wasn't working like it used to. I took DXM Hbr at approx 160 mg's (120 mg DXM equiv.) a day for ten days. After only two days I started waking up at night because while lying on my stomach my erect penis would almost cause me to tip over on my back. %)

I had been suffering from Erectile Dysfunction for almost a year. And it wasn't psychological, because it would be an effort to keep it up while masturbating too. I figured the meds I took (120 mg methylphenidate daily) had nothing to do with it, because the problem was occuring before I got my RX too. Something that might be connected with some extensive GHB abuse and MDD/SAD.

I haven't been taking my meds unless absolutely necessary for a few weeks now, and haven't had a problem getting it up unless I took my meds.. The NMDAR-antagonist trial did restore effectiveness of my meds, but also the side effects (more sweating, dry mouth). Needless to say, ED is an unacceptable side effect, and I'm planning on calling my doctor when I figure out my best options. I have been scouring pubmed and boards for pharmacotherapies and am basically considering three.

1. an NMDA-antagonist (amantadine comes to mind because it has actually been researched for ADHD-treatment)
2. bupropion
3. modafinil

What bugs me is that methylphenidate isn't really known to cause erectile dysfunction. It seems to be caused by vasoconstriction and not by dopamine downregulation because the effect is quite direct.

I really like the idea of using amantadine for adhd. I feel like the DXM has helped my symptoms and there are studies indicating it works quite well:

Hum Psychopharmacol. 2010 Nov;25(7-8 ):560-5. doi: 10.1002/hup.1154. Epub 2010 Dec 8.
Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: a randomized, double-blind trial.
Mohammadi MR, Kazemi MR, Zia E, Rezazadeh SA, Tabrizi M, Akhondzadeh S.

Psychiatric Research Centre, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Abstract
Objective The aim of the present study was to further evaluate, under double blind and controlled conditions, the efficacy of amantadine for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents as compared to methylphenidate. Methods This was a 6-week randomized clinical trial. Forty patients (28 boys and 12 girls) with a DSM-IV-TR diagnosis of ADHD were the study population of this trial. All study subjects were randomly assigned to receive the treatment using capsule of amantadine at a dose of 100-150 mg/day depending on weight (100 mg/day for < 30 kg and 150 mg/day for >30 kg) or methylphenidate at a dose of 20-30 mg/day for a 6-week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent Attention deficit/hyperactivity disorder Rating Scale-IV. Results No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores (df = 1; F = 0.02; p = 0.86 and df = 1; F = 0.01; p = 0.89, respectively). Side effects of decreased appetite and restlessness were observed more frequently in the methylphenidate group. Conclusion The results of this study indicate that amantadine significantly improved symptoms of ADHD and was well tolerated and it may be beneficial in the treatment of children with ADHD. Nevertheless, the present results do not constitute proof of efficacy. Copyright © 2010 John Wiley & Sons, Ltd.

Copyright © 2010 John Wiley & Sons, Ltd.
PMID: 21312290 [PubMed - in process]If anyone can get a full text I would love to have it!

J Child Adolesc Psychopharmacol. 2007 Oct;17(5):657-64.
Open-label amantadine in children with attention-deficit/hyperactivity disorder.
Donfrancesco R, Calderoni D, Vitiello B.

Department of Child Neuropsychiatry, La Scarpetta Hospital, Rome, Italy.
Abstract
OBJECTIVES: The purpose of this study was to explore the possible efficacy and tolerability of amantadine in the treatment of attention-deficit/hyperactivity disorder (ADHD) in stimulant-naïve children.

METHODS: Twenty four children (5-13 years old) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD (4 inattentive, 2 hyperactive, and 18 combined type) entered a 6-week open-label treatment with amantadine (50-150 mg) given as a single morning dose. Parent and teacher ADHD rating scales and the parent Child Behavior Checklist (CBCL) were administered at baseline and at week 6.

RESULTS: Twenty three subjects completed the 6-week treatment. One child dropped out at week 2 because of persistent headache, and another 12 children reported adverse effects, most commonly transient appetite decrease. The parent ADHD score decreased from mean 41.04 +/- D 6.9 at baseline to 28.9 +/- 8.7 at week 6 (p < 0.001, effect size d = 1.5), and the teacher ADHD score from 35.8 +/- 9.6 to 26.2 +/- 9.5 (p < 0.001, effect size d = 1.0). Response rate (a 25% or greater decline in ADHD score) was 58% based on parents and 46% based on teachers.

CONCLUSIONS: These data suggest that amantadine has acceptable acute tolerability at single doses up to 150 mg/day and is possibly efficacious in decreasing ADHD symptoms, although its activity appears to be more modest than that of stimulant medications.

PMID: 17979585 [PubMed - indexed for MEDLINE]If anyone can get a full text I would love to have it!

Seems that amantadine is a little less effective then MPH.. That is acceptable for me though, if there aren't any major side effects.

Then theres the option of bupropion, a drug used to treat MDD (especially SAD subtype) a disorder that I have suffered from before using light therapy and methylphenidate (also a great antidepressant). It seems to me though that Bupropion is far less effective as stimulants and probably also less effective as amantadine or perhaps other NMDAR-antagonists.

Last but not least there's modafinil. which according to some studies is just as effective as methylphenidate. I wouldn't be surprised if it also caused ED with me.

A randomized, double-blind and placebo-controlled trial of modafinil in children and adolescents with attention deficit and hyperactivity disorder
Manijeh Kahbazia, Aboulfazl Ghoreishib, Fatemeh Rahiminejadc, Mohammad-Reza Mohammadic, Abbas Kamalipourc and Shahin Akhondzadehc, ,

aDepartment of Pediatrics, Arak University of Medical Sciences, Arak, Iran
bDepartment of Psychiatry, Zanjan University of Medical Sciences, Zanjan, Iran
cPsychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
Received 22 April 2007; revised 30 November 2007; accepted 12 June 2008. Available online 12 May 2009.
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, with an estimated prevalence worldwide of 7%–17% among school-aged children. Modafinil is a centrally acting agent that is structurally and pharmacologically different from stimulants such as amphetamine and methylphenidate. It has been reported that modafinil is effective in diminishing the symptoms of ADHD. The aim of the present study was to further evaluate, under double-blind and placebo-controlled conditions, the efficacy of modafinil for ADHD in children and adolescents. Patients were 46 outpatients, children (35 boys and 11 girls) between the ages of 6 and 15 who clearly met the DSM-IV-TR diagnostic criteria for ADHD. All study subjects were randomly assigned to receive treatment with modafinil in a film-coated tablet, 200–300 mg/day, depending on weight (200 mg/day for < 30 kg and 300 mg/day for >30 kg) (group 1) or placebo (group 2) for a 6-week double-blind, randomized clinical trial. The principal outcome measure was the Teacher and Parent ADHD Rating Scale-IV. Patients were assessed by a psychiatrist at baseline, 14, 28 and 42 days after the medication started. At 6 weeks, modafinil produced a significantly better outcome on the Parent and Teacher Rating Scale scores than placebo. Decreased appetite was observed more often in the modafinil group. The results of this study indicate that modafinil significantly improved symptoms of ADHD, was well tolerated, and may open a new window in the treatment of children with ADHD.
Keywords: Attention-deficit/hyperactivity disorder; Clinical trial; Modafinil

Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents.
Biederman J, Pliszka SR.

Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, MA, USA.
Abstract
OBJECTIVE: This secondary analysis evaluated the efficacy of modafinil in children and adolescents by subtype of attention-deficit/hyperactivity disorder (ADHD) using pooled data from 3 double-blind, placebo-controlled studies.

STUDY DESIGN: The patients were boys and girls age 6 to 17 years. ADHD subtype diagnoses (ie, inattentive, hyperactive-impulsive, combined) were based on criteria published in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Patients received modafinil (170 to 425 mg) or placebo once daily for 7 to 9 weeks. Efficacy assessment used the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions, Clinical Global Impression of Improvement scale (CGI-I), and Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S).

RESULTS: A total of 638 patients received modafinil (n = 423) or placebo (n = 215). The inattentive, hyperactive-impulsive, and combined subtypes included 187 (30% ), 27 (4% ), and 403 (65% ) patients, respectively. Modafinil (vs placebo) significantly improved mean total scores for the ADHD-RS-IV School and Home Versions for the inattentive (change from baseline: School, modafinil, -15.7, placebo, -7.1; Home, modafinil, -13.8, placebo, -5.9) and combined subtypes (School, -16.5 vs -8.8; Home, -15.7 vs -7.6). Modafinil was associated with greater improvements on the CGI-I and improved CPRS-R:S subscale scores in inattentive and combined subtypes.

CONCLUSIONS: Modafinil improved ADHD symptoms and behaviors in patients with the inattentive and combined subtypes as determined by teachers, investigators, and parents.If anyone can get a full text I would love to have it!

Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study.
Boellner SW, Earl CQ, Arora S.

Neurology and Clinical Study Center, Little Rock, AR 72205, USA. [email protected]
Abstract
OBJECTIVE: In a 4-week, double-blind, placebo-controlled study, the attention-promoting agent modafinil improved symptoms of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents and was well tolerated. To assess the continued efficacy of modafinil and obtain additional safety data, an 8-week, open-label study was conducted as an extension to the double-blind study.

METHOD: Two hundred and twenty children and young adolescents (age range, 6-14 years) with ADHD who had completed 4 weeks of the double-blind period or had withdrawn for reasons other than an adverse event were enrolled. Patients received individually titrated doses of modafinil (100-400 mg), administered once daily or as a divided dose. Patients visited the clinic at open-label weeks 2, 4, and 8 for assessments of efficacy. Efficacy was assessed using the parent- or clinician-completed ADHD Rating Scale-IV (ADHD-RS-IV) Home Version, the parent-completed Conners' ADHD/DSM-IV Scale Parent Version (CADS-P), and the clinician-rated Clinical Global Impression of Improvement (CGI-I) scale. Adverse events were monitored.

RESULTS: Modafinil improved symptoms on all ADHD rating scales and subscales during the open-label extension. Mean change (baseline to final visit) in Total score on the ADHD-RS-IV was -14.6 (95% CI: -16.40 to -12.70); and -7.6 (95% CI: -8.65 to -6.62) and -6.9 (95% CI: -7.90 to -5.94) in the Inattention and Hyperactivity-impulsivity scores, respectively. The mean Total score [SD] on the CADS-P decreased from baseline (74.4 [10.3]) to the final visit (63.2 [13.1]) (change: -11.2, 95% CI: -13.08 to -9.65). Fifty-three percent of patients were rated as much or very much improved on the CGI-I. Insomnia (13% ) and headache (10% ) were the most common adverse events. No clinically meaningful changes were observed in physical examination findings, electrocardiography, blood pressure, pulse, or body temperature. Clinically significant changes (increase or decrease) in body weight of 7% or more were observed for 30 patients (14% ), with decreases (mean, 3.2 kg) reported for 22 patients (10% ) and increases (mean, 3.7 kg) reported for eight patients (4% ).

CONCLUSION: Modafinil remained efficacious and well tolerated in children with ADHD, improving ADHD symptoms and overall clinical condition during the open-label study. Limitations of the study include open-label dosing and lack of a placebo control.

The marked part in red leads me to believe there are less issues with vasoconstriction, so that modafinil might not have the same side effects. It might not mean anything though, my blood pressure was a nice 120/70 when still on methylphenidate.

So, I'm considering my options here. Thinking Modafinil would be the best option but not sure if it will cause the same problems. Amantadine would be great if it actually worked. What do you guys think? Does anyone have experience with some of the alternative treatments? Does anyone have any other suggestions?

 

[Wizzle]

Just found out that modafinil is only insured for narcolepsy.. So that one is pretty much useless for me @ 2 euro's per 100 mg tab [normal pharmaceutical market, no illegal price discussion].

I could still get em grey market, but I'd rather get my indicated meds through legal channels.

 

[Wizzle]

pdoc prescribed me 15 mg mirtazapine to combat ED. It seems to take the rough edges of the MPH and definitely helps with keeping erections. I hope the effect is sustainable and it doesn't get all weird when the antidepressant effect kicks in in a few weeks. Does anybody have experience with combining methylphenidate and mirtazapine?

 

[twelvesevndi]

did you ever get copies of those articles? i can probably find the PDFs through school for you if not...

 

[...]

pdoc prescribed me 15 mg mirtazapine to combat ED.

How does that work?

Jesus Christ mirtazapine has a well-cited Wikipedia article!

 

[Wizzle]

How does that work?

Jesus Christ mirtazapine has a well-cited Wikipedia article!

I believe it works by antagonising 5HT2A and 5HT2C receptors, these receptors regulate dopamine release into the nucleus accumbens.

It is indeed a good wiki article!

I don't really understand the mechanism behind this but I think it also reduces vasoconstriction induced by methylphenidate.

did you ever get copies of those articles? i can probably find the PDFs through school for you if not...

Didn't get them. If you could get them for me that would be great.

Mirtazapine gives me headaches in the morning, they are subside quickly after waking up and I suspect it might have something to do with the melatonin I take too. Might as well stop melatonin because mirtazapine is a really good sleep aid. I can recommend it to anyone for sleep, at low dosis it is almost a selective H1-antagonist and can thus be used without side effects.

 

[negrogesic]

Mirtazapine is a wonder agent for off-setting the side-effect profile from MPH. I take a ton of mirtazapine for off-label purpose, and I prescribe it with great frequency.

Stick with d-MPH if available in your country (i know racemic form is only available in some), l-MPH does little more than increase the subjective toxicity/side-effect profile.

Do not use MPH inhaled, the short unsustainable peak in plasma levels only exacerbate ADHD.

Consider using clonidine.

 

[Wizzle]

Interesting stuff negrogesic!

Unfortunately, d-MPH is not available where I live. The methylphenidate I get now is XR and generic, it is made by a pharmacy, not a pharmaceutical company and it is not actively marketed, this construction works around the patent infringement issue. I have to take it three times daily instead of twice like I would with Concerta.

Do you suggest using clonidine with the MPH and mirtazapine? The Wiki article links to a case where a patient with hypertension stabilized on clonidine suffered a hypertensive crisis after getting on mirtazapine. This guy had pre-existing hypertension though.

As for the headaches, didn't have one today. ED seems pretty much solved and the MPH seems a lot smoother. What I'm worried about most is the sustainability.. I do not want to switch meds every few months. Preferably, I'd stay on something that works for the rest of my life or until something better comes up. What's your experience with prescribing this combo long term? For the record: I use my MPH as prescribed

There is also the issue of weight gain, apparently caused by antagonising 5HT2C-receptors, but I understand this only influences feeding behavior, so as long as I stay vigilant of caloric intake, it shouldn't be a problem. According to this article, the 5HT2A and 5HT2C receptors will both downregulate from administration of antagonists, so the effects on these targets should get stronger then they are now. I consider this a good thing because the only negative effect is weight gain. According to Stahl, the positive effects are anxiolytic, antidepressant and increased sexual function. The downregulation thing would theoretically make it sustainable as per my limited knowledge of pharmacology.

 

[negrogesic]

I am not a psychiatrist, and have only written perhaps 2-3 prescriptions for stimulant drugs, but if you are in good health and are not abusing the MPH, this combination is relatively safe. There are a few issues, but so long as you are cognizant of them and monitor them, there is no reason why you cannot take clonidine as well.

Personally, I have taken clonidine, mirtazapine and MPH in concert without issue. I took this combo for years without issue. I have never prescribed this particular combination for a patient (again, not my field). A hypertensive crisis from mirtazapine is exceedingly rare. I feel so comfortable with mirtazapine that I prescribed it for my own sister (transient insomnia and postpartum depression).....

I always tell patients to not worry about the weight gain. Easy for me to say, as it is struggle for me to maintain my weight.....and this provides little consolation to women in particular (some of whom would rather be depressed than to gain weight). Tolerance to its appetite stimulant properties unfortunately does not reduce much over-time. However, if you make appropriate lifestyle changes (exercise and diet), it should not be an issue. And once again, I must emphasis that regular exercise is an amazingly powerful anti-depressant, and promotes well-being in general. The key is the regularity. 1-2x a week will have no major effect (better than nothing of course). At least 3-4 times a week of moderate to high intensity exercise is needed to reap the rewards of exercise.....

 

[Wizzle]

Did you use clonidine against MPH side effects or as an extra ADHD-med (or both)?

I really like the hypnotic effects of mirtazapine, even though I don't have insomnia.. I usually have to motivate myself to go to bed, even when keeping the best sleep cycle and using an energy-light in the morning. This stuff is a hundred times better then benzo's in my book, just because it is so much like just being really tired.

The weight gain is not really an issue for me anymore, as I understand the weight gain is associated with bad nutrition (eating more sugar and carbs in general). I myself am on a very good diet and I work out 6 days a week on average. I've made freakish progress in lifting since ceasing drug use about a year ago. I guess I'm still an addict, and happy to be one too!

 

[negrogesic]

Don't label yourself..........

I can't stand the people who say "oh man, today is my 350th day clean".....the American Psychiatric Association actually does NOT recommend AA/NA in their "buprenorphine DATA waiver" testing material (this is the 8 hour test any idiot physician can take to obtain a "waiver" to prescribe buprenorphine for addiction; it gives access to narcotic replacement therapy that was previously limited only to physicians with board-certified sub-specialties in addiction). However, the DATA waiver only allows for the use of Suboxone/Subutex......if you want to be able to prescribe methadone for addiction, you actually have to go through a ton of red-tape.......

 

[nuke]

Modafinil and bupropion okay for ADHD for me, certainly better than atomoxetine.

Some oddities, though, that make them bad choices for me:
-High dose modafinil causes bad vertigo and panic attacks in me.
-Bupropion has worse cardiovascular consequence in terms of pulse/BP compared to methylphenidate.
-Bupropion, after about three months administration, caused me severe abdominal pain that did now cease until I stopped taking the drug.

 

[negrogesic]

Methcathinone is better than atomoxetine.....(not really, methcathinone would be a terrible ADHD med, and its more toxic/reinforcing).

I had the same issues with Modafinil, but I am not sure what Nuke meant by high dose. I never took bupropion for long, but I am surprised that you found it to have a more pronounced hypertensive effect.......were you taking racemic MPH, and were you taking it orally (intranasal MPH causes greater hypertension, particularly the racemate)? Oral MPH already has some wacky pharmacokinetics and a very touchy bioavailability, but intranasal MPH makes it behave even stranger. While intranasal administration 'sort of' addresses the bioavailability issue, the pharmacokinetics become quasi-cocaine like (not quite as peaky), and in my opinion, looses much of its therapeutic value (again, similar to cocaine, which lacks therapeutic value in respect to ADHD). However this is not a fair comparison; oral cocaine or chewed coca leaves are pretty shitty ADHD meds, which is really an issue of pharmacology not pharmacokinetics (cocaine has a high affinity to the SERT, MPH effectively has none).

Maybe I should have taken some focalin today, I am all over the place....

 

[nuke]

Methcathinone is better than atomoxetine.....(not really, methcathinone would be a terrible ADHD med, and its more toxic/reinforcing).

I had the same issues with Modafinil, but I am not sure what Nuke meant by high dose. I never took bupropion for long, but I am surprised that you found it to have a more pronounced hypertensive effect.......were you taking racemic MPH, and were you taking it orally (intranasal MPH causes greater hypertension, particularly the racemate)? Oral MPH already has some wacky pharmacokinetics and a very touchy bioavailability, but intranasal MPH makes it behave even stranger. While intranasal administration 'sort of' addresses the bioavailability issue, the pharmacokinetics become quasi-cocaine like (not quite as peaky), and in my opinion, looses much of its therapeutic value (again, similar to cocaine, which lacks therapeutic value in respect to ADHD). However this is not a fair comparison; oral cocaine or chewed coca leaves are pretty shitty ADHD meds, which is really an issue of pharmacology not pharmacokinetics (cocaine has a high affinity to the SERT, MPH effectively has none).

Maybe I should have taken some focalin today, I am all over the place....

Doses 100-200mg provoked these effects with Modafinil, which were more pronounced when I had a restful sleep.

Wellbutrin was 150mg XR, pulse was often ~85 whereas normally it hovers around 70, BP was routinely 140/85 whereas normally it's 120/80. Was not taking concurrently with any other medications.

This study seemed to indicate it had cardiovascular consequence on par with/greater than amphetamine/methylphenidate although there is incorrect data where the pulse should be stated: http://www.ncbi.nlm.nih.gov/pubmed/15705013

As per intranasal methylphenidate only tried that once in combination with codeine/alcohol, nothing much to report in terms of abuse potential. Intranasal MDPV also doesn't have abuse potential to me though, so I figure I'm more an exception than part of the norm, I have a terrible time abusing stimulants that are not caffeine.

Atomoxetine caused really severe side effects in me two weeks after starting as well, extreme sexual dysfunction (no lubrication/interest), bad vasoconstriction, lots of rushing euphoria, manic states, severe insomnia. Never bothered to check pulse but with vasoconstriction and the studies surrounding it it seems to have cardiovascular consequence similar to methylphenidate. The methylphenidate I use is Concerta so none of the ups and downs of IR, just a smooth, nerdy stimulation that I hate with a passion but that makes me function somewhat normally.

 

[Wizzle]

I hear you on the Concerta, I like that stuff for it's long duration, I couldn't hurt to make a new one that actually lasts about fifteen hours. The stuff I take now has to be dosed every 4-5 hours but it's free, and works just as well.

I don't get the whole NA remark.. I've never been to NA, the 12 steps piss me off. I also wouldn't say that I'm a year "clean", it's just been a year that I had any problematic use. I went to an outpatient rehab and they didn't even try to make me stop drinking alcohol, because it was simply never a problem for me. This is not the US, AA is not common and I've never heard of NA here.

@nuke
I tried to change the thread title to the bold text above my first post. Didn't work out as planned. For me modafinil is not an option, it is only insured as a second line narcolepsy med. Uninsured price: 2 euro's for 100 mg..

I think I'll keep the regimen I'm on, maybe with some clonidine. I meet my GP in a week to see where we're at (GP consults psychiatrist for meds).

To me, intranasal methylphenidate, which I tried before being prescribed it myself, is really fiendish. When extracted it gave me a pretty serious rush at 40mg.. the euphoria could almost match really good coke.