What are the Different Types of Antidepressants AND How Do They Work? | Mechanisms of Action

[@HAThorsten]

I am a chief physician in psychiatry and I am deeply impressed by the wide scope of his explanations. Fantastic psycho-education.

[@PsychiatrySimplified]

Thank you for your feedback 🙏🏼

[@LoveMajani]

I am preparing for my residency in psychiatry and your video was really helpful! It is hard to find good material, that isn't too basic or too complex, but you hit the spot. I'm gonna check out your other videos, too! Thanks again for taking the time and sharing!

[@PsychiatrySimplified]

Thank you for your feedback. If you are a psychiatry resident and want to take your learning to the next level check out academy.psychscene.com .

[@dkotaz]

I'm currently on treatment. And I've been trying to find something to learn so I can better choose my meds and understand my conditions. And all your videos have been helpful. Good job bro

[@dixon_dean]

excellent video. I'm taking a course in psychopharmacology so this video was extremely helpful.

[@itsonlyjm]

Thank you for the detailed and informative explanation for the different types of anti-depressants! As a patient who have taken a few types of antidepressants and experienced many different kinds of bad side effects, I truly agree that a proper clinical assessment needs to be assessed and understand appropriately before prescribing a specific type to the patient. Otherwise the patient will be suffering from the medication instead of helping them to be better.

[@PsychiatrySimplified]

Thank you for your feedback 🙏🏼

[@swarajjoye]

Made some very interesting points, BDNF, Astrocytes, Why are we still focusing on Monoamine hypothesis for depression. Let's start to put more emphasis on Glutamate based intervention to treating depression. That's should be the new model of care. SNRI, SSRI and the rest DON'T work.

[@PsychiatrySimplified]

There are multiple mechanisms now and they are converging. Neurosteroids, glutamate based, gut brain modulation. Dopaminergic, serotonergic and not adrenergic aspects still play a crucial part but they are moving towards more selective receptor modulation rather than general aspects like ssri. E.g vortioxetine as a new multimodal mechanism of action.

[@kimberlietaylor6943]

Auvelity targets glutamate!!

[@daye15385]

Current PMHNP student!! Thank you!

[@PsychiatrySimplified]

Pleasure

[@НААТ]

Ive abused a lot of mdma and amphetamine back in the days. What ended up making me depressed for years. Ive tryed tca and ssri before without succes untill i came acroos bupropion. Ive been mostly depression free for a year now!! Also really interesting how bupropion worked on day 1. It has also helped my insomnia by waking up earlyer and actually being able to stay up. I still use benzos tho but hoping to kick them soon

[@JayJay-tb5cw]

Am sure it ls the benzo that helps with insomnia

[@phillipnorman7423]

Good info, well explained and presented.

[@PsychiatrySimplified]

Thank you 🙏🏻

[@harmanss6077]

Very informative ! Thank you very much for explaining different types of antidepressants used in treating for different symptoms of pychaitric patients.

[@KitaLee5464]

Im so happy I found your videos. Current PMHNP student. ❤❤❤ so helpful

[@PsychiatrySimplified]

Thanks for your feedback 🙏🏼. Wish you well on your journey.

[@ahlamaljabry4674]

Thank you for the informative lectures ,kindly make somw videos on opioid use disorder.than you

[@Idmoment]

More on lithium please- dr Hussani Manji spent 30 years studying lithium benefits…no profit in Li therefore it’s often overlooked

[@PsychiatrySimplified]

Agree. Will keep on list. Written about it in more detail here - psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

[@orsolyalazar7663]

Very easy to understand. Thank you.

[@PsychiatrySimplified]

Thank you for the feedback 🙏🏻

[@atisoy83]

If pcos throws off females hormones and can bring on depression, anxiety, insulin resistance, weight gain, low energy etc… does one see a psychiatrist, gyno or an endocrinologist? It’s hard to tell what came first. The chicken or the egg ni just feel like I’m stuck in a never ending cycle. Thank you for your response in advance doctor and for your wonderful content as well.

[@PsychiatrySimplified]

It depends on the issues at hand. In some cases the psychiatrist may be able to manage these with communication or advice from Endo or gyn. Communication between specialists Should be present - the most distressing issue should be the one that defines the initial specialist in most cases. Wish you well.

[@deant6361]

Hello there I’m on mirtazapine and have put on 40kg in 4 years, I really want to get off the stuff and will talk to my doctor. But was wondering if I started to exercise and change my diet would I be able to lose this weight or would it be difficult to lose. Mirtazapine I wish I had never started this medication.

[@PsychiatrySimplified]

There are ways to address the weight gain. Several options exist. Have you discussed this with a doctor? Each option has to be discussed and individualised to you.

[@RajnishSisodiya-o2b]

Great video sir, much appreciated. My wife is taking full on tablet and pexep plus 12.5. she has fibromyalgia type symptoms like neck and shoulder pain. She is ok with this tablet but having weight gain. Doctor has prescribed clonotril and pexep cr so that she does not gain weight but no releif. Neck pain started. We don't want to take full on tablet, is there any better tablet which works similar but no weight gain

[@bzbeezme9492]

Hi doc. How can we measure level of these critical items in our body i.e neurotransmiter, dophamine ?

[@PsychiatrySimplified]

There is no way to measure this in routine clinical practice. In research binding of receptors etc can be carried out by specialised scans. So the way this is evaluated is by clinical response. Also there are several other mechanisms that may be involved beyond these neurotransmitters. Measuring these levels do not provide clinical utility hence not routine

[@boris9331]

@@PsychiatrySimplified Then how is a Psychiatrist going to benefit the patient any more than a GP can since there is no diagnosis tools such as scanning, testing the brain etc, then it all seems to be trial and error of prescribing meds which anyone can do, which can for some people take forever that is the problem im facing surely some sort of test can be done to a patient to see what chemical imbalance they have. Empirical evidence doesn't take a genius to figure out, e.g this reported to work.... continue it, that reported no do nothing..... try something else.

[@jillradovanovic3460]

Dr Sanil I've had persistant dizziness for 4 years now...started with bppv. I was told they use antidepressants to treat it mostly effexor and pristiq. As l a bit sensitive to medications do you think valdoxan could help as it more tolerable

[@PsychiatrySimplified]

It’s difficult to answer that as a full evaluation is needed . Is BPPV the only condition; is dizziness the only symptoms. Any postural drops, fatigue , mood changes , sleep difficulties, pain, arousal Sx ( agitation, anxiety, nightmares dreams) , medical conditions additional etc. as you can see many aspects have to be taken into consideration. Valdoxan in general is less activating and more tolerable that the SNRI. But venlafaxine at low doses is prescribed for migraine and pain, vertigo as at low doses it is not so activating.

[@jillradovanovic3460]

@@PsychiatrySimplified Thank you for your reply Bppv was the start of it the developed into pppd persistent dizziness. Swaying,pushing off balance cotton wool feeling around my head floaty... I've been to many drs and finally a neurologist. Just need to get help to treat this condition

[@Michelle76767]

Hi. ​@@jillradovanovic3460Did you end up taking Effexor? Did it help experience any side effects?

[@stevo5000]

excellent explanations! thank you

[@PsychiatrySimplified]

Glad you enjoyed it!

[@czarnyksiezycrogaty]

Maybe You could make a video on a peptides in treatment of depression and anxiety. Selank and semax with analogues; bpc157 and few others. In my opinion are game changers, after few cycle of use i see big changes without all side effects of medicines You mention in this vid

[@PsychiatrySimplified]

Thank you for the suggestion. This is a new area. Thanks again.

[@czarnyksiezycrogaty]

@@PsychiatrySimplified oh Yes! Cant wait:)

[@jlappin6277]

Well said

[@manelhassani1292]

Hi doc , I took clomipramine 10mg for 20 days . Will my brain go back to it's normal state?

[@PsychiatrySimplified]

This is a small dose for a short period. Please discuss this with your doctor if any concerns.

[@GeoffreyPilkington]

Great video. For several years now adderall hasn’t worked as effectively as it once did for me for adhd. We’ve tried all sorts of medications. Guanfacine, Concerta, etc. None worked. He also tried Zoloft, Luvox And Trintellix. Zoloft and Luvox gave me sexual dysfunction and fatigue and they didn’t work. Trintellix I had no side effects, it just didn’t work. Adderall worked so well back in 2015 when I started it and worked for several years. It’s faxed somewhat in recent years so we’ve tried everything with it. Also took a week break. Strangely I had zero withdrawal. I’ve been quite frustrated as it seems I’m never as productive as I once was and my mood has suffered too from this. Extreme frustration basically. 10 days ago we started Wellbutrin and it seems to be having the biggest effect of any drug since adderall. I’m currently taking Vyvanse 70 mg in the morning and an adderall booster 20 mg later in the day. My theory is that my brain had gotten so use to adderall and dopamine release that it was swallowing up the extra dopamine very quickly before I could utilize it. Correct me if I’m wrong but it would seem I’m the perfect candidate for Wellbutrin as doesn’t it help the dopamine stay around longer? It seems instead of serotonin not hanging in the synapse maybe for me it was dopamine and this is what Wellbutrin does? If brain plowing through it the adderall wouldn’t be as effective so need a muffler like Wellbutrin to keep it around in the synapse . Much like the ssri’s do with serotonin. Is this accurate? I’m 10 days into taking Wellbutrin and it seems to be working.

[@DanielSRosehill]

Another extremely important video. Thank you sir!

[@PsychiatrySimplified]

Pleasure 🙏🏼

[@sanelprtenjaca9147]

Great video! I have a question tough. You said that for chronic pain it is needed more than 60 mg of Duloxetine, but I thought that there is no evidence that more than 60 mg of Cymbalta is more effective. It is therapeutic dose for fibromyalgia. I have chronic pain & low motivation so your answer would be very useful to me.

[@PsychiatrySimplified]

For pain and particularly in fibromyalgia the key neurotransmitter that we are trying to target with Duloxetine is NA - at 60 mg there is a bit of NART inhibition with much greater SERT ( serotonin ) inhibition but higher doses needed to get a more potent NA increase. This is also seen clinically. Here is what 2001 nature study in healthy volunteers showed - the present study has demonstrated that duloxetine acts as a selective 5-HT reuptake inhibitor in non-depressed human male volunteers, and that, at doses up to 60 mg/day, it failed to inhibit the tyramine pressor response, as would be otherwise expected of a NE reuptake blocker. The possibility therefore remains that a dose of duloxetine of 60 mg/day may represent the threshold for NE reuptake blockade. ( Turcotte, J., Debonnel, G., de Montigny, C. et al. Assessment of the Serotonin and Norepinephrine Reuptake Blocking Properties of Duloxetine in Healthy Subjects. Neuropsychopharmacol 24, 511-521 (2001). Ps not medical advice

[@fazizullah5343]

Can 75 mg venlafaxine increase dopamine in prefrontal cortex pls reply...

[@PsychiatrySimplified]

Less likely to do so as it has predominant action on SERT so increase in serotonin in synaptic cleft.

[@fisherni]

I find it extremely hard to switch anti depressants. Often all my symptoms eg: anxiety, insomnia and depression will come back. Even somtimes missing a dose can cause these symptoms. I am currently taking paxil. Which works well but causes sexual dysfunction and fatigue. So i am interested in changing but can not tolerate the change and withdrawals.

[@PsychiatrySimplified]

We can't provide advice but in such cases one may not need to switch completely but rather consider an augnetstion strategy. E.g reduce dose of agent causing SE but not stop ( SSRI withdrawals occur most at lower dose drops) AND add new agent to target illness Sx and reduce side effects of 1 St AD. Serotonergic agents should not be combined. This can be done with an experienced psychiatrist. Ps not advice

[@fisherni]

Thankyou.also Is it possible to cross taper when switching AD in the same class(SSRIs or snirs) with the guidance of a professional obviously.

[@davidmayo5876]

Could being on a high dose of methadone cause an antidepressant to not ever start working somehow? Zoloft and Wellbutrin in particular..

[@PsychiatrySimplified]

It's a difficult question to answer - in general no reason why not - but there may be other factors - what Sx are being targeted - nature of diagnosis etc. Your doctor would be in the best position to answer this. There are some interactions with methadone CYP enzyme metabolism that need to be taken into account.

[@davidmayo5876]

@@PsychiatrySimplified I would but unfortunately I don't have a general practitioner at the moment. All I have is access to the medication, and what knowledge I can gain online.. It's been 6 weeks and 2 days since I started the Zoloft and Wellbutrin and I'm pretty sure I feel a difference, but not a big one by no means.. I've been diagnosed with depression, social anxiety disorder, and opioid addiction. Just using what I have at hand.. Thanks a lot for the reply sir...

[@michaelthau1007]

Great videos Dr and thank you! Do you feel Mirtazapine at 7.5mg is a good option for chronic insomnia? Safer than long term use of Lunesta? Been taking lunesta 3mg for 2 months. It makes me sleep, but im exhausted the next day. 1mg and 2mg don't work. Looking for a better long term option Thank you sir!

[@PsychiatrySimplified]

Thank you for your feedback. With insomnia ( I have done a video on neurobiology of insomnia - that should help understand the various pathways involved) - also will release another one soon. But when it comes to insomnia - there are so many variables to take into account. I'll summarise it here briefly. In order to fall asleep we have a circadian part and a homeostatic part. Circadian is where melatonin increases naturally at night and dopamine goes down. Homeostatic is where adenosine builds up as a sleep pressure and then puts us into the first stages of sleep. Initial states of nrem sleep - gaba is released to shut all neurotransmitters that are activating - DA, NA, histamine, ach and orexin. So at this stage antihistamines ( zopiclone works through gaba and reduces histamine), Mirtazapine is antihistaminergic at low doses, benzo ( gaba release ) , clonidine ( reduce NA) help. Then comes rem sleep - here dopamine is present and necessary ; but if individuals dream too much or are active ( superficial sleep) or move about etc - then NA is usually the reason or in severe rem sleep movement it's due to dopamine dysregulation. So clonidine promotes Nrem sleep Rx vivid dreams and nightmares. Prazosin also does this. in depression - rem sleep increases. Nrem decreases. And sleep is not restful. Here depression should be Rx. Early morning awakening is usually a clue towards agitation ( as part of depression) - wake early and are very wired. here Rx of agitation may be necessary. as part of sleep also it is important to build day time activity to remove too much adenosine during day. Activity converts adenosine to atp for energy. Orexin and dopamine are needed during day. So sunlight hits retinal cells and dopamine is released and melatonin is shut - then it reverses later in evening. This is a rhythm that is necessary. Also other sleep breathing disorders should be ruled out. Like obstructive sleep apnea. As you can see there is no single answer. It depends on the symptoms and the specifics of insomnia. Is it early insomnia ( difficulty falling asleep), middle ( waking up, nightmares, etc), early morning etc. Are there racing thoughts during day. what is mood like? What is activity and motivation like etc etc? Sorry it's not an easy answer. Ps not medical advice Neurobiology of Sleep - Circadian Rhythms, Sleep-Wake Cycle and Insomnia kzbin.info/www/bejne/jmauoXylrpmqgpo

[@michaelthau1007]

@@PsychiatrySimplified thank you for such an informative answer. Much appreciated !

[@deant6361]

Just a note I’m on mirtazapine and have been on for 4 years it’s great for sleep but I have put on 40kg in that time. If I had a choice I would not touch the stuff. Good luck

[@mieero]

what symptoms might occur to the person if he abuse antipsychotic drug like olanzapine to reduce the dopamine in the mesolimbic pathway. does it relates to emotional blunting or motivational ?

[@PsychiatrySimplified]

Have a look at this video where the dopamine pathways are covered. kzbin.info/www/bejne/rXmvdmmKibGbfK8

[@goldentimes7731]

Sir, you're one of the best educators in Psychiatry! I have a question- I was on PAROXETINE for generalized anxiety disorder for 2 years, then after I stopped it cold turkey, I started to have severe withdrawal symptoms like electric shock sensations, tremors, facial parasthesias, extreme muscle twitches in legs etc. So after that my doc tried me on Fluvoxamine,Sertraline,Venlefaxine but these parasthesias remained the same or even increased a bit with them. So is it possible to have SSRI withdrawal symptoms to persist for years & longer ?

[@PsychiatrySimplified]

Thank you for your feedback. We have done another video on antidepressant withdrawal - kzbin.info/www/bejne/Z6i6dHWGiM9qkKM this can be persistent in some individuals - however, in such cases, the mechanism may be linked to a different process - in paraesthesias - ruling out Vit B 12 , folate def, and ruling out a mixed state, agitation, insomnia becomes important. in some individuals, the withdrawal can trigger off amygdala activation so using mood stabilisers, and alpha2 agonists (e.g clonidine video done) may help. This however requires a detailed evaluation. PS not medical advice. Wish you well.

[@goldentimes7731]

@@PsychiatrySimplified I'm fascinated by your explanation of this !! Yes, my doctor asked me to take B vitamins, and once he prescribed me (BENFOTIAMINE + B12), sir can one have any issues with intestinal B12 absorption when taking SSRIs ? Also can you please tell a little bit about "withdrawal can trigger off the amygdala activation" ?

[@fazizullah5343]

Highly appreciated ur videos. Sir I am taking agomelatine and venlafaxine. Venla agonise 5ht2c while agomelatine antagonise. How long it takes to downregulate 5ht2c receptors with venlafaxine. Thanks

[@PsychiatrySimplified]

The combination of venlafaxine plus agomelatine - is an established augmentstion strategy. Venlafaxine at low doses

[@PepeNolasco315]

@@PsychiatrySimplified agomelanite can cure Pssd?

[@PsychiatrySimplified]

@@PepeNolasco315 Agomelatine is an antidepressant which is not associated with sexual dysfunction. Bupropion also . It’s worth discussing with doctor.

[@biggcwrldtv]

Is it possible to for someone to use anti depressants in the form of colognes/perfumes ?

[@boris9331]

Hello. Is Amitriptyline still an effective anti depressant since it's very old but some studies appear to show it high up in efficacy , in comparison to say newer introduced tablets like Brintellix. Since amitriptyline doesn't appear to say to do much to benefit Dopamine, is it known or has it been combined with other medications that do benefit Dopamine as such to cover all bases ?

[@jenwahl-y7y]

Very interesting. I have been taking prozac for years 40mg daily and never once contracted Covid or even tested positive and I am a nurse who worked closely at the San Diego borderwith refugees and on movie sets at Warner Brothers testing hundreds of persons with active covid.

[@PsychiatrySimplified]

Very interesting!

[@tictactoedias1908]

Will Prozac interact with thyroid meds 50mg . Thank you 🙏

[@PsychiatrySimplified]

There is no interaction. Thyroxine combined with SSRI such as Prozac is an established augmentation strategy to treat depression. Thyroid hormone is known to enhance receptor sensitivity.

[@jocs8824]

You didn't cover Trazodone on the chart for tolerability and efficacy. Is that med awful?

[@PsychiatrySimplified]

I don't mention it. It is useful and used in US - but didn't because not routinely used or available in Aus. Similar to mirtazapine In some aspects with some differences.

[@goygoy8441]

hello ... can we take 5htp with bupropion _? thank you

[@PsychiatrySimplified]

Theoretically yes but this has to be an individualised decision. Which means one should discuss this with the pharmacist / doctor. Bupropion is a CYP2D6 inhibitor and can increase levels of other medications - this aspect should be considered. Ps not advice

[@loriholman1459]

THANK YOU DR.

[@PsychiatrySimplified]

Most welcome!

[@teenaakhir9105]

Brilliant ❤

[@garysimone4977]

How do reply to all the studies that are coming out that SSRI are no better then placebo

[@PsychiatrySimplified]

Very important to delve into the details of the studies. Depression is an heterogenous entity. Here is from the latest study - “Patients with depression are likely to improve substantially from acute treatment of their depression with drug or placebo. Although the mean effect of antidepressants is only a small improvement over placebo, the effect of active drug seems to increase the probability that any patient will benefit substantially from treatment by about 15%. Further research is needed to identify the subset of patients who are likely to require antidepressants for substantial improvement. “ this 15% is a number needed to Treat of 7 which is good. Important to recognise however that patients with more severe forms of depressions - melancholic / psychotic are excluded from many of these trials ; these are patients where the response is even higher. Therefore it’s important to recognise and target appropriate Rx to the different types of depressions. Some may not need or have minimal response to medications and may need psychological Rx over medication. Hope this makes sense. Thanks for your question.

[@garysimone4977]

@@PsychiatrySimplified makes sense, as per Dr David Burns just very small % are helped..thank you, ooo no ssri ever been tested past 14 months ..

[@PsychiatrySimplified]

@@garysimone4977 antidepressant development has moved on to looking beyond serotonin and involving other mechanisms - NA , DA , glutamate. So overall many more choices for clinicians with better tolerability.

[@garysimone4977]

@@PsychiatrySimplified ba the studies coming out are they are no better then olcebo...a medical fact

[@PsychiatrySimplified]

@@garysimone4977 placebo responses have increased over time. So it's very difficult to ‘beat’ a placebo by a high margin now. Most importantly though one has to recognise that more severe ends of spectrum are not included in placebo controlled studies. So they are not real world. Covered some reasons here psychscenehub.com/psychinsights/efficacy-acceptability-antidepressants-network-meta-analysis/

[@sorianasor9730]

why stimulation of serotonin receptor a2 lead to depression

[@PsychiatrySimplified]

Stimulation of 5HT2A does not lead to depression - it can be associated with some emotional blunting. Other effects of activation are increased anxiety , akathisia, insomnia but these subside with sensitisation of the receptor. Some side effects can persist.

[@sorianasor9730]

@@PsychiatrySimplified thanks 🌹❤

[@knowledgeos]

your knowldge better than textbooks..

[@stevensicherman4101]

Is hypersecretion of cortisol, the real culprit in depression and anxiety?

[@PsychiatrySimplified]

it is a possible part of the mechanism but not in isolation.

[@stevensicherman4101]

Thank you

[@pacifiquebusiness]

Thank You ❤

[@PsychiatrySimplified]

You are welcome

[@Haiderali-be7bs]

Impressive,thx

[@stevensicherman4101]

What can be done with a rapid metabolizer of tricyclics where we need to use a tricyclic for melancholic depression?

[@libbywakefield6202]

I call Trazadone Spazadone for my experience, my horrible experience with this drug. YUK

[@paulgianni]

Thank you for this video. "[S]ome of the mechanisms of action, WE DON'T EVEN KNOW HOW THEY WORK." Why do doctors prescribe medicine if nobody knows how it works? Is this why it's called a "practice," doctors "practice medicine?"

[@PsychiatrySimplified]

It's not unique to psychiatry. Most drug discoveries have been serendipitous. Viagra was initially developed for cardiovascular issues. Recently the trkb receptor was discovered which likely mediates downstream effects of ADs. Fluvoxamine for example has shown anti infective / immunomodulatory properties in Covid. So there is a lot we don't know. Fair to say we gave theories based on evidence but the exact mechanisms may be unknown. And that is also because the precise mechanism of disorders like depression are unknown.

[@paulgianni]

@@PsychiatrySimplified Thank you for clarifying.

[@laughingxmermaid]

@@paulgianni Also, for SSRIs, in particular, they're sort of a happy accident. Invented in the 1970s, they were used when medicine believed that serotonin deficiency was the sole cause of depression in the brain and they worked to alleviate symptoms in many patients so there was little reason to doubt that belief. However, as we learned more about both the causes of depression itself as well as the way SSRIs interact with the brain, we started to notice inconsistencies. For example, while serotonin levels increased in many cases 1 hour after the first dose, patients did not start to see real improvement until after using the drugs for about 4 weeks. Obviously, if the efficacy of the drugs were solely dependent on increasing seratonin levels, we'd see results much sooner. The drugs were still working but we began to realize that the increased serotonin was only a piece of the puzzle as to why. I hope that example helps. :)

[@sywakit]

.

[@dogc333]

bad explaining

[@evaeight]

very interesting. been on many different meds and by far the most helpful one was Fluoxetine. still very depressed tho. before that I was on Milnacipran and many others but none seem to really work except Temgicoluril to help with anxiety and Fluoxetine.

[@piotrppp2339]

Thank you for the next post. I wanted to get advise from you, because doctors are still prescribing new drugs that work differently. I mainly treat anxiety disorders and am addicted to Zolpidem. { can take 400mg/ day] By now the anxiety had been successfully reduced by Duloxetine, but it had awakened me at night. The doctor prescribed me Brintellix, I’d like to ask your opinion that this drug can reduce the arousal and anxiety, as duloxetine did. should l Try to stay with Brintellix? doktor suggestet added Agometaline, to help resolve my problems with sleep. Please give me advise with in what direction to go. Many thanks. Peter

[@PsychiatrySimplified]

We can’t provide specific medical advice. However in this video we have covered both brintellix ( vortioxetine) and agomelatine both agents which are evidence based for treating anxiety and have good tolerability profiles. We wish you well.