Posted by ed_uk2010 on October 12, 2014, at 20:51:46
In reply to Re: Sure this problem can be resolved. » ed_uk2010, posted by mogger on October 12, 2014, at 0:01:23
Hi Joseph,
>Today was pretty rough with quite a bit of depression coming back. I have been at .5mgs from .75mgs for 10 days now. I have tried zyprexa, seroquel, latuda and saphris. I have been a non responder and initially risperdal put me almost in remission for about 3 months until the lack of libido popped up. I shall talk to my doctor on monday and get his thoughts.
Well, Risperdal is a very potent drug in terms of what can be achieved with low doses. Clearly, small changes in dose can make a lot of difference. I'd like to give you are few idea to discuss with your pdoc.
Even in psychotic illness, there's been a change in dosing over time. Risperdal was initially launched with a 4-8mg/day target dose for schizophrenia. This was not a good idea. It's now recognised that first episode psychosis often responds well to about 2mg per day and even in chronic unremitting psychosis, increasing above 4mg doesn't usually offer much additional benefit. It's now known from brain scans (PET) that even 2mg per day of Risperdal can block around 65% of D2 dopamine receptors in the brain. This is about the minimum needed to treat psychotic illness or acute manic episodes. Of course, you are not psychotic, nor are you manic, so the optimal dose for you will be different, and based on your response so far, considerably less.
You could of course try paliperidone PR (Invega) next. Overall, the effects are usually very similar to risperidone because most of the risperidone you take is metabolised to paliperidone anyway. In terms of side effects, risperidone causes a slightly higher incidence of post-dose drowsiness and hypotension/dizziness. Paliperidone's much slower absorption makes dizziness uncommon. At equivalent doses, paliperidone is slightly more likely to elevate prolactin but YMMV! Insomnia is also more frequent with paliperidone, probably because night time doses of risperidone can help sleep. Risperidone has a mild antihistamine sedative effect which paliperidone almost completely lacks. Apart from that, the pharmacological properties are similar.
The main issues I think you should consider before looking to switch meds are:
1. For someone sensitive to small doses, paliperidone offers much less flexibility than risperidone. The lowest tablet strength of Invega is 1.5mg, which cannot be halved, and there is no liquid formulation. Invega 1.5mg generally has an effect similar to your current 0.5mg to 0.75mg dose. Unlike risperidone, which is very well absorbed, oral paliperidone is poorly absorbed - this accounts for the higher doses needed. The amount of paliperidone you absorb also depends a great deal on what you eat with it, consistency is therefore important. Risperidone is well absorbed regardless. Invega 1.5mg plus a burger might = risperidone 0.75mg. Invega 1.5 plus a glass of water might = risperdone 0.5mg!! This isn't precise but you get the idea. In studies, bioavailability could be increased by as much as 60% just by taking Invega alongside a normal sized meal with some fat content.
2. What are the cost implications of Invega? No doubt it's expensive. Would your insurance cover it? It would be great if your doc had some samples of 1.5mg to try, but I think he's more likely to have samples of say 6mg, which probably aren't suitable. No doubt Janssen have produced a lot of 6mg samples, they recommend it as the starting dose for almost all adults. The 1.5mg tablet is supposed to be for those with kidney impairment.
If you try Invega 1.5mg, it might suit, it might not :) There is no lower strength if 1.5mg is too strong, and I doubt the higher strengths would be suitable considering your sensitivity to risperidone. If I were you, I might just base my decision on the presence or absence of 1.5mg samples.
Sadly, it's already clear that 0.5mg Risperdal is not enough. 0.75mg was a bit too much - great efficacy, some side effects. You could try anything in between using the risperidone liquid. Many people will say 'don't bother, these doses are placebos'. That's BS. Lower doses potently block 5-HT2a receptors.... but you already get that from mirtazapine 60mg so it doesn't really explain risperidone's benefits or side effects for you. Risperidone also blocks 5-HT7 receptors, which *may* be antidepressant. Latuda didn't help you though and it's very potent at this receptor. Hmm. I think you're actually benefiting from the mild D2 antagonism created by the low dose of risperidone. Too little D2 blockage won't help, too much D2 blockage can reduce libido - you need to get the dose right. Ultra-low doses of antipsychotics are hardly a new strategy for anxiety and depression. Flupenthixol 1mg per day used to be a popular antidepressant in the UK, it often worked within days. Doses used in psychosis were much higher. It fell out of favour since the SSRIs were launched though, and atypical APs took over. Even low doses of typical APs can cause tardive dyskinesia. This is not likely with risperidone. The Italians use 50mg amisulpride for depression, the effects appear similar to flupenthixol but I guess there's less risk of TD.
The advantage of risperidone over Invega is that it's cheap and very flexible dose-wise. Now that it's licensed for so many different age groups, the 1mg/ml oral solution provides an excellent way to adjust the dose. Assuming you have a generic version like we do here, price is not an issue. The pack is likely to come with a pointless oral syringe which only measures common doses eg. 0.5mg. Throw it away and ask the pharmacist for a proper 1ml syringe. It will either be free (if they're nice) or maybe a dollar or two. Pharmaceutical 1ml oral syringes can measure anything from 0.01ml to 0.99ml, not that you'll need to be that accurate but you get the idea. Not only are they great for awkward doses and awkward children, they can make tapering a breeze. You could start by trying 0.65mg risperidone and see what happens. Don't make any decisions for *at least* a week. You need the drug to reach steady state levels at the very least. If you continue to have libido problems in spite of dose titration, it might be worth seeing what a urologist or endocrinologist has to say. They could measure testosterone etc. to check for any problems.
3. If you decide not to stick with risperidone, would you switch to Invega, or try Abilify? Something similar, or something different?
Abilify is a licensed add-on in resistant depression, it appears to be of moderate utility. It has certainly been widely prescribed in spite of its price tag.
Sexual dysfunction is rare and it never elevates prolactin. Classic EPS movement disorders are uncommon, except perhaps at very high doses. Initial restlessness and nausea are common. Unless the dose is too high, they usually pass. Do not decrease your benzo at this time!
Aripiprazole has a variable effect on bodyweight. If you gave it to someone off the street, it would often cause moderate weight gain. It occurs over time, more slowly than the rapid fat explosions typical of Zyprexa. When added to antipsychotics with strong 5-HT2c antagonism, eg. clozapine, aripiprazole seems to cause weight *loss* and some improvement in metabolic parameters. The same may apply when it's added to olanzapine (Zyprexa). The theory goes that aripiprazole is a partial agonist at 5-HT2c receptors. Compared with placebo, this increased weight, but when it binds in place of a full antagonist (clozapine etc) it reduces weight. Aripiprazole also appears to reduce the risk of weight gain in those treated with mirtazapine, at least in the short-term..... whereas mirtazapine seems to reduce the probability of aripiprazole causing akathisia.
I don't know many people who've taken aripiprazole for OCD or anxiety disorders but I did find this...
Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial).
ABSTRACT
BACKGROUND:
Obsessive-compulsive disorder (OCD) is a chronic disorder with unknown etiology. Failure in OCD treatment is common and finding effective augmentations in the treatment of OCD will benefit patients. Antipsychotic augmentation is a common strategy for treatment resistant OCD. This trial evaluated the efficacy of adding aripiprazole in patients whose OCD was insufficiently responsive to an adequate SSRI treatment.
METHODS:
Thirty-nine adult outpatients, who met the DSM-IV-TR criteria for OCD and had treatment resistant OCD were evaluated in a double-blind randomized clinical trial. The patients received either aripiprazole 10 mg/day or placebo, for 12 weeks. Data were analyzed using intention-to-treat analysis with last observation carried forward. All statistical tests were two-sided, and were considered statistically significant at P < 0.05.RESULTS:
A significant reduction in total scores of Y-BOCS (P < 0.0001) was found in the aripiprazole group. Aripiprazole was generally well tolerated. There was no significant difference between the two groups in terms of observed side effects.CONCLUSION:
Results of the present study indicate that aripiprazole could be an effective augmentation medicine in treatment resistant OCD.'If you choose Abilify, I'd go with the manufacturers recommendations for 'augmentation of ADs'. They suggest starting at 2mg or 5mg. If you're rxed 5mg tabs, you could take half a tab for a few days. The usual therapeutic dose seems to be about 5-10mg/day, rarely 15mg. I've not heard of anyone taking more than this for non-psychotic illness. Although low doses of setraline do not interact with Abilify, you can expect some potentiation from 150mg. Be cautious with the Abilify dose.
Abilify has a long half life. Apart from the common practice of using 2mg as a test dose for a couple of days, at least a week should occur between dose increases.
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I've looked at your other meds in detail, in an attempt to work out whether any of them might lead to unexpectedly high risperidone/paliperidone levels in spite of your low dose. And to examine the adverse effects of these meds in their own right.
I've searched manufacturer's data sheets (UK and US), pharmacy textbooks, drug interaction textbooks, online journals and psychiatric treatment guides.
Overall, none of your other meds in isolation have a major effect on risperidone or paliperidone blood levels. In combination, there *may* be some effect (small increase), but probably nothing dramatic.
Experts in pharmacokinetics claim that the likelihood of drug interactions increases almost exponentially according to the number of meds in a combination. The reason is that each additional drug may either potentiate the mild enzyme inhibition produced by an existing med or inhibit a different drug metabolising enzyme entirely. On top of this, additive side effects occur whenever drugs acting in similar ways or at the same receptors are Rxed together.
Fortunately, many drugs have more than one means of elimination and so small combos, even involving interacting drugs, are often tolerated reasonably well (except by the elderly or renally impaired!). Large combos can alter so many different aspects of drug metabolism, distribution and elimination that unexpected results may occur.
Even so, none of your existing combo contains any obvious metabolic interactions which would dramatically increase risperidone/paliperidone blood levels.
Sertraline inhibits the enzyme CYP 2D6 mildly at low doses (eg. 50mg) .....but rather strongly at high doses (eg. 150mg). Although risperidone is reliant on this enzyme for conversion to paliperidone, the overall impact of CYP 2D6 inhibitors on the effects of risperidone would not be be expected to be large. This is because paliperidone and risperidone are both active drugs with similar effects. Generally, there would be an increase in the blood level of risperidone, but a corresponding decrease in the level of its active metabolite paliperidone, therefore reducing the impact of this interaction. A small increase in the combined risperidone + paliperidone blood level may occur - mild potential of risperidone's effects would be expected, possibly requiring a small dose reduction. The true interaction, may be more complex, however...
Quite recently, it was discovered that both sertraline and its metabolite act as inhibitors of the well known drug transporter p-GP (p-glycoprotein). p-GP is also called the multi-drug resistance protein. This is because its natural role in the body is to pump drugs out of areas (like the brain) where the body does not expect foreign substances to be present. Certain drugs, such as risperidone and paliperidone, are predominantly removed from the brain by p-GP, thus reducing the concentration of drug available to exert a therapeutic effect.
Studies of various antidepressants and other drugs have shown sertraline to have unexpectedly high potency as a p-GP inhibitor. If sertraline was able to inhibit p-GP in patients, at the blood-brain bariier, it would increase the concentration of risperidone and paliperidone in the brain. This has been demonstrated in mice. Whether it is significant in humans is not known. If it's true, pts on sertraline may require lower risperidone/paliperidone doses than normal.
Anyway, I remember you mentioning a possible decrease in your sertraline dose, perhaps to 100mg? I think this is worthy of further consideration because two drugs associated with sexual/libido issues may be worse than one. Just a thought.
The other enzyme which metabolises risperidone is CYP 3A4. None of your meds inhibit this enzyme, except perhaps to a very minor degree. Buspirone, clonazepam and mirtazapine and all highly dependent on CYP3A4 for their own metabolism, but are not known to inhibit it.
Buspirone is an odd drug. Standard doses, amongst other things, weakly block pre-synaptic D2 receptors. Exceptionally high doses block post-synaptic D2 receptors and can cause antipsychotic-like side effects. Although your dose is high, it isn't *that* high, so I doubt it's potentiating risperidone.
.........................................................................................Only read if you're looking at tapering clonazepam soon.
As you well know, clonazepam can be an difficult med to taper because its exceptionally high potency makes small dose reductions difficult. Personally, I don't think you should even attempt to taper until you've got the Risperdal/Invega situation sorted (hopeful with good success).
But, if you do want to continue tapering in the future, I've written a few tips. I expect you know most of this anyway.
Clonazepam tapers:
Ideally, for anyone with continuing anxiety who has taken benzos for years, tapering will need to be very gradual. The Klonopin 0.125mg wafers are a help but I have a feeling they are not currently in production. I don't know what's going on with the Klonopin brand, Roche are still selling clonazepam in the UK (brand Rivotril). Rivotril 0.5mg are round and quarter scored to facilitate tapering and adjustments, creating an accurate 0.125mg dose is easy. I hear Klonopin 0.5mg tabs have a massive K cut out of the middle. I'm sure this looks 'cool' but it's hardly a help when you need to cut the tablets. Perhaps some of the generics are better designed.
Unfortunately, because clonazepam's water solubility is very poor, it's difficult to use oral syringes as a aid to tapering. Over here, we have a clonazepam oral solution, ideal for tapering. It includes a touch of alcohol (20mg/ml) and some triglycerides to dissolve the clonazepam. Although it's easy to measure with a syringe, regular replacements may be necessary as the alcohol slowly dissolves the numbers on the measuring scale! It's clear that some pharmacists in the US will compound a liquid form if needed. Is this expensive? I assumed it would cost loads but it sounds like it's worth shopping around, if the need arises. I read online that one pharmacy made up a bottle for only $35 using the tablets they'd dispensed for that patient.
Some people go through none of this hassle, however, and find it relatively painless to taper just by cutting the tablets and reducing every few weeks. I think SLS 'bit' little pieces off the tablets at the end of the taper, and had great success with minimal symptoms. It's very individual. If you reach a low dose and find that you can't go any lower without unpleasant symptoms, a switch to a low dose diazepam can be very helpful. The super long half-life of its active metabolite and the low strength scored tablets make tapering in small steps a lot more feasible. A liquid is available if necessary, but it's usually easy to reduce in small steps just by cutting the 2mg tablets. Some clonaz users say diaz makes them tired. I still think diaz is the best benzo ever invented :)
poster:ed_uk2010
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