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Triple Reuptake Inhibitors For Depression: SNDRI Drugs Outlook

There is a newer class of antidepressant drugs called Triple Reuptake Inhibitors (TRI’s or SNDRI drugs) being developed that target all major neurotransmitters involved in depression: serotonin, norepinephrine, and dopamine. The thought process behind the creation of this new class of triple reuptake inhibitors is that they will target all three major neurotransmitters that are thought to contribute to a person’s depression.

Although SSRI’s are considered the most effective class of antidepressants, they are not perfect. In fact, many people get no relief from SSRI medications. This leads many people to try another class of drugs called SNRI’s – which affect both norepinephrine and serotonin. Since some people don’t respond well to SNRI’s, a doctor may suggest trying the NDRI class of drug which affects both norepinephrine and dopamine.

If we venture a little bit further down the rabbit hole of reuptake inhibition, we arrive at the Triple Reuptake Inhibitors, sometimes called SNDRI’s. These are known to affect serotonin, norepinephrine, and dopamine in equal proportions. Some would suggest that triple reuptake inhibition may be more beneficial as the dopamine and norepinephrine reuptake may eliminate some side effects including: weight gain, sexual dysfunction, and drowsiness.

Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701280/

Triple Reuptake Inhibitors: Past and Updated Research

Triple reuptake inhibitors have been hypothesized to work since the early 2000’s. Researchers began coming up with evidence to suggest that dopamine reuptake inhibition may be helpful to treat depression. So they came up with a compound that targeted: serotonin, norepinephrine, and dopamine and studied the effects in rodents in 2007.

  • Source: http://www.sciencedirect.com/science/article/pii/S001429990601140X

In 2009, some researchers hypothesized that dopamine reuptake inhibition may prove to be beneficial to those suffering from depression. There were already drugs that inhibited serotonin and norepinephrine reuptake at this time, so some suggested that dopamine should be added to the equation. This lead to a new class of drugs that inhibit all three neurotransmitters at the same time – prolonging duration of action at postsynaptic levels.

At this time, there was preclinical evidence suggesting that triple reuptake inhibitors would produce antidepressant effects in behavioral paradigms. It is thought that adding dopamine to the equation may help neurotrophic processes in the hippocampus. It is also thought that the combination of all three neurotransmitters may yield a quicker antidepressant response.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19702555

A paper published in 2012 evaluated a triple reuptake inhibitor that affects inhibition of the three neurotransmitters equally. This drug was called “GSK372475” and two randomized placebo-controlled, double blind studies were conducted in individuals from age 18 to 64. It was found that this triple reuptake inhibitor was not effective or well tolerated in people with major depression over the course of two 10-week studies. Both Effexor and Paxil were found to be more effective.

  • Source: http://jop.sagepub.com/content/26/5/653.short

In a study published in 2014, the triple reuptake inhibitor “LPM570065″ was investigated in rodents. This drug was administered over a 14-day period and a microdialysis revealed that 5-HT (serotonin), DA (dopamine), and NE (norepinephrine) levels were increased. Based on this evidence, results suggest that ” LPM570065″ has a relatively rapid-onset antidepressant effect and could prove therapeutic in depression treatment.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24614602

3 Major Neurotransmitters: Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors

Below I have outlined the three major neurotransmitters thought to influence depression: serotonin, norepinephrine, and dopamine. I briefly discuss drugs that prevent the reuptake of each of the specific neurotransmitters and what types of problems are associated with them.  Additionally I posted what each neurotransmitter regulates in regards to mood, energy, aggression, etc.

Serotonin Reuptake Inhibitors

Regulate: Impulsivity, aggression, sleep, anxiety, mood, eating, sex

Most antidepressants are in the SSRI class – they prevent the reuptake of serotonin. These result in reductions in anxiety and usually result in an antidepressant effect. In studies, these are the most effective type of treatment, which is why most people that take an antidepressant are on an SSRI. The major problem associated with this particular class of drugs is that of unfavorable side effects.

Side effects such as: loss of libido, inability to orgasm, weight gain, and poor motivation can make a person reconsider staying on the medication. Additionally these drugs typically carry a very taxing withdrawal period – with a person experiencing both physical and psychological withdrawal symptoms. Certain SSRI’s can carry a withdrawal lasting months – and in some cases, it is years before a person’s brain resets itself to “homeostasis” (e.g. activity pre-SSRI).

Due to the fact that people respond well to SSRI’s has lead many people to simply conclude that “low serotonin” causes depression. People are starting to smarten up though and realize that “low serotonin” doesn’t likely cause depression, rather treating depression with an SSRI is the most effective option on the market.

Norepinephrine Reuptake Inhibitors

Regulate: Psychomotor retardation, vigilance, attention, interest, anxiety, mood

Drugs like Strattera that strictly work as norepinephrine reuptake inhibitors (NRI’s), tend to provide more energy and vigilance than a standard SSRI. Some hypothesize that about 10% of people with depression may benefit more from a NRI as opposed to an SSRI. These drugs have been studied for depression and are not statistically effective.

With that being said, some people that have liberal psychiatrists and get to do a bit of experimentation find that they respond very well to Strattera for depression (which doesn’t affect serotonin). I wrote an article about the link between norepinephrine and depression. There is clear evidence that norepinephrine can often be an important neurotransmitter in cases of depression.

When a person takes a NRI for an extended period of time, the withdrawal symptoms tend to be pretty minimal. Of all three neurotransmitters, withdrawal from a medication like Strattera is considered relatively easy. Drugs that affect dopamine and serotonin can have very harsh withdrawal periods.

Dopamine Reuptake Inhibitors

Regulate: Motivation, pleasure, reward, attention, interest, sex, eating, mood

I already wrote an article addressing dopamine vs. serotonin in depression. Most clinical research has found that drugs affecting levels of serotonin are statistically “effective” in double blind, placebo trials. Medications that primarily affect dopamine do not typically yield a statistically significant response in regards to treating major depression.

Some have found that dopamine-altering agents such as psychostimulants can serve as a valid augmentation strategy. If we single out dopamine reuptake inhibitors (DRI), it is understood that these drugs can have a high abuse potential. Increasing dopamine levels can improve concentration, focus, mood and cognition.

When a person takes one of these drugs for an extended period of time, they may develop tolerance, addiction, and dependence. A person may become so accustomed to taking a DRI that they actually crave this type of drug.  Examples of illicit drugs that prevent the reuptake of dopamine include cocaine and methamphetamine.

Pros and Cons: Triple Reuptake Inhibitors

Below are some pros and cons associated with “triple reuptake inhibitors.” These are just hypothesized pros and cons based on preliminary evidence. There are currently no TRI’s on the market being prescribed. But there have been studies and trials conducted with them.

Pros: Benefits of SNDRI’s

  • Less sexual dysfunction – Likely due to the addition of both dopamine and norepinephrine.
  • Less weight gain – Mostly due to the dopamine, but norepinephrine can play a role.
  • Faster-acting – These are considered faster-acting because they affect three neurotransmitters at once. The dopamine reuptake can result in very quick feelings of pleasure and boost the mood.

Cons: Drawbacks of SNDRI’s

  • Possibly more overall side effects – There is the possibility that there are actually more total side effects than something like an SSRI. You are essentially making more changes in the reuptake of more neurotransmitters. In early studies, some of these TRI’s demonstrated too many side effects.
  • Not tolerated as well as other drugs – In some early studies, these were not tolerated as well as standard SSRI’s. If you combine the fact that the tolerability was worse than that for SSRI’s and there were more side effects, these drugs don’t appear to be too great.
  • Severe withdrawal – This could potentially be one of the most difficult drugs to withdraw from. If a person is on one of these for an extended period of time, it may result in low dopamine, serotonin, and norepinephrine. Take the key withdrawal symptoms associated with SSRI’s, DRI’s, and NRI’s and combine them.
  • Could possibly create a worsened imbalance – Just like SSRI’s can create an even greater chemical imbalance when you withdraw from them, these could create a more severe imbalance by comparison.  In the early days of SSRI withdrawal, doctors assumed that there were no major withdrawal symptoms.  Anyone that’s used one knows that early claims were complete BS.  Now the medical community has began realizing how long term the withdrawal can be – symptoms are likely from a “worsened” chemical imbalance.

Triple Reuptake Inhibitor Antidepressants: Should Be A Last Resort

Although these drugs are not out yet, they will be affecting multiple neurotransmitters simultaneously. When they come out, people are going to think they are the new “magic bullet” for depression.  The problem with triple reuptake inhibition is that they have potential to create an even greater chemical imbalance than SSRI’s due to the fact that they affect three major neurotransmitters.

Additionally I think that when you are changing levels of three neurotransmitters at once, you have potential to really create a (very potent) “artificial high” while these drugs are working. In theory, a practice that is already sometimes conducted is that of prescribing an SSRI (or SNRI) with a drug that affects dopamine levels such as Adderall. These two can be prescribed together and the Adderall can successfully augment the SSRI treatment.  (Read more about: Adderall for depression).

However, both drugs working at the same time has the potential to make some people feel a little bit too good. In the event that the serotonin reuptake is making people feel peaceful, the norepinephrine is giving people more energy, and the dopamine is giving people pleasure – this could induce a very “lucrative” emotional response from individuals that find these drugs effective.  This physiological response as a result of taking an SNDRI could prove to be extremely addicting.

Furthermore, when the person builds up tolerance and it comes time to withdraw from one of these drugs, they will not only be low on serotonin, they will also have to deal with imbalances in norepinephrine and dopamine. This could potentially create a very debilitating withdrawal or a discontinuation syndrome that is unparalleled in severity. These are all hypothetical assumptions of course, but after being on any drug for an extended period of time that affects neurotransmitters, your brain will adapt.

When you stop taking an SNDRI, your brain will likely become “chemically imbalanced” until it sorts things out. In other words a TRI has potential to create a “triple chemical imbalance” when used for an extended period.  In order to minimize the potential hazards associated with these drugs, it would be advised to use them at the lowest possible doses.  Most people do not need to tinker with multiple neurotransmitters to treat their depression.

The majority of research supports the use of SSRI’s to treat depression. For individuals that don’t respond well to that class of drugs, doctors usually throw some norepinephrine into the equation to see if it helps by prescribing an SNRI or NDRI. If a person responds to a drug that targets norepinephrine, we can conclude treatment with that individual may respond better to norepinephrine reuptake inhibition.

The idea that a person has deficiencies in serotonin, dopamine, and norepinephrine simultaneously is a bit farfetched. If all three neurotransmitters were “imbalanced” at the same time, it would likely only be as a result of a person quitting drugs that affected these neurotransmitters (e.g. the SNDRI’s).

The Future of Depression Treatment: Not in SNDRI’s

Despite the fact that most people with severe depression are chomping at the bit for the release of a new drug, most new drugs are not going to be the utopia that people think. So if you are waiting for the release of a new drug, don’t. I remember when Cymbalta was on the horizon of being released and I was very excited to give it a shot – it ended up being one of the most horrific experiences of my life.

I truly believe that for treating major depression, the future lies in taking a look at the person holistically including: environment, social life, diet, exercise, brain waves, and genetics. Many people with “major depression” are really suffering – in part because the medications on the market today actually create a chemical imbalance. Most people have no hope other than shovel down the drugs that a psychiatrist gives them.

I believe the future of depression treatment involves genetic engineering. Although some people would argue that this is essentially playing “God,” I think most people that have experienced major depression would really do anything it takes to get rid of their depression. Notice how certain people tend to have predispositions to good mood, making friends, etc.? Environment definitely plays a role, but so does genetics and genetic expression.

Triple Reuptake Inhibitors are a new “flashy” treatment that will likely work just as most current drugs do: be effective for awhile, the person will build up a tolerance, have to increase the dose or withdraw, and the person will go through a severe withdrawal. Any type of drug is usually not a long term solution to depression and will never be a cure as it merely patches the underlying problem. The question comes down to: how long will the new flashy triple reuptake inhibitor “patch” last?

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5 thoughts on “Triple Reuptake Inhibitors For Depression: SNDRI Drugs Outlook”

  1. I took Luvox for several years. This SSRI helped a little, taking me from depressed to merely feeling slightly less sh-tty all of the time. When it seemed to stop working, I switched to 150 mg of Effexor XR, which had a similar effect. For another several years I felt slightly less sh-tty, all of the time.

    Recently, my doctor increased my dose of Effexor XR to 225 and then 300 mg per day. It’s still too early to call it a success, but I do feel much improved. Perhaps some of us already have a chemical imbalance and any drug that affects all three neurotransmitters is not going to mess things up too much more, but might just have a beneficial “re-balancing” effect.

    I fully expect to be taking some form of antidepressant for the rest of my life, so I’m not too concerned about withdrawal.

  2. Thanks for your article. And I somewhat agree with Debbie. Also there is no reason that there cant be permanent benefits after 6 months of taking them. I’ve read that SSRI’s have been shown to cause actual brain growth. I think the problem with all the medicines is that they are abused — it isn’t something you take forever, just like ANY drug.

    I have experienced the ecstatic effect of antidepressants and I must say it was like being happy to just be alive for the first time in my life. Like, I was brimming with enthusiasm. I know we all put up a front, everyday — but that day I really felt it.

    I think these drugs have applications that are incredible as any drug. There are practical applications for methamphetamine, cannabinoids, even cocaine could be argued to have some practical applications. Opiates have proven their efficacy… The point is that we don’t abuse these things and we use them sparingly.

    Variety is the spice of life – perhaps people that have troubled childhood and complex genetics at the same time grow up to be more predisposed to this chemical imbalance. Maybe if you just have complex genetics, your environment growing up is enriching enough that the brain neurochemically adjusts by actually growing pathways that maintain these receptors and reinforce good levels of dopamine and all the others.

    Very interesting stuff.

  3. While I do agree more research is required on triple reuptake inhibitors – I do not agree that they may not be the answer for some individuals. This is why: You mention genetics as the future for mental health disorder treatments. I agree because I have my full genetic profile and have mutations at COMT and MAO A that cause a loss in the natural processing of dopamine and serotonin – respectively.

    This will always be the case and has manifested itself in mood disorders, depression, anxiety, addictions, and insomnia at different points in my life. Even at different points in the month because I’m female and neurotransmitters are affected by monthly hormonal changes. I have taken SSRIs with disastrous effects.

    Mainly because I don’t think I’m clinically depressed but suffer from an innate chemical imbalance that modern healthcare does not know how to solve. I have also taken MDMA and felt the best I ever have in life. Even ‘normal’ if there is such a state. Please read into Sasha Shulgin’s research from a medicinal standpoint and not a recreational standpoint.

    Because of feeling like a lab rat – I have not tinkered with my neurotransmitters in many years. I – instead – have tried to get the bottom of my individual chemical imbalance – beginning with my genetics. I’m undergoing very specific testing of neurotransmitters to find the true imbalance for myself. And I’m using your website to research what science has to offer in the here and now to counteract that imbalance.

    I just ask that you keep an open mind. Especially where ‘comprehensive’ treatments such as SNDRIs are concerned. It may just be the cure for those who are genetically compromised in all three areas of neurotransmission.


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