I read a recent review last week which warned against the use of quetiapine for treating non-psychotic mood disorders.
Yet, I believe there are a number of reasons to consider quetiapine and similar medications for non-psychotic states:
1) there is a much lower risk of the medication causing mania or psychosis. With antidepressants, there is always the risk of mania induction. Quetiapine not only would not cause mania, it could protect against it.
2) the use of quetiapine could reduce the likelihood of other sedatives, such as benzodiazepines, being used as often. Benzodiazepine dependence is very common. Quetiapine is less "addictive."
3) the doses of quetiapine in non-psychotic states can often be very low (under 100 mg) causing a much lower risk of metabolic side-effects than full doses of 400-600 mg per day or more.
What about research evidence?
Mezhebovsky et al (2013) published results of a multi-centre study involving about 450 elderly patients, showing that quetiapine 50-300 mg (mean = 168 mg) daily for 11 weeks, led to significant improvements in generalized anxiety symptoms, compared to placebo.
( http://www.ncbi.nlm.nih.gov/pubmed/23070803 )
As with most effective treatments, the medication group had about twice as much improvement as the placebo group. It is true that sleep improvement could account for a significant proportion of the overall symptom score improvement, but there was also improvement in the other symptom domains. There were no major metabolic side effect problems in the quetiapine group. The most common side effect was somnolence (sleepiness).
A 2012 review by Sanford and Keating ( http://www.ncbi.nlm.nih.gov/pubmed/22519923 ) showed an abundance of evidence that quetiapine is beneficial for treating bipolar depression (typically at doses of 300 mg/day) and for preventing recurrences of any mood episode. For those who benefit acutely from quetiapine, there is evidence that it is a more effective mood stabilizer--on its own--than lithium.
In unipolar depression, quetiapine would be most commonly used when a standard treatment such as an antidepressant was not working well. In a study by El-Khalili et al (2010), quetiapine up to 300 mg per day was added as an adjunct to previous therapy for non-remitting depression:
( http://www.ncbi.nlm.nih.gov/pubmed/20175941). They showed a modest benefit of adding the quetiapine, particularly at a higher dose of 300 mg/d. A nice component of this article is the inclusion of symptom subtypes. Many critics would argue that quetiapine might simply be sedating, and improve sleep, leading to most of its benefit over placebo. These results confirm that quetiapine improves sleep symptoms. But there were also symptom improvements in other categories, such as pessimism, inner tension, and concentration impairment.
In conclusion, I think that quetiapine deserves to be considered as a medication option for non-psychotic conditions. In many cases, there are comorbidities or diagnostic uncertainties, in cases of depression. Many studies exclude patients who have comorbidities, or who do not neatly fit into diagnostic categories. Quetiapine is unlikely to worsen comorbid conditions, and may be beneficial for many. This makes it a safe option to think about if there is uncertainty or complexity in the diagnosis. Standard antidepressants in this situation may carry a higher risk of causing new problems, including agitation or a manic state.
The risks of metabolic side effects, etc. need to be watched for carefully, with consideration of stopping or changing the plan if problems of this type arise.
Monday, November 9, 2015
Duloxetine (Cymbalta)
Duloxetine (Cymbalta) is another newer antidepressant, approved in the US in 2004, and in Canada in 2007. It is a reuptake inhibitor of both serotonin and norepinephrine, and is most similar in this regard to venlafaxine (Effexor).
In a study of medication treatment options for severe depression, a switch to duloxetine was compared with a dose increase of escitalopram. The escitalopram group had better results, including a remission rate of 54% for escitalopram vs. 42% for duloxetine. ( http://www.ncbi.nlm.nih.gov/pubmed/22559255 )
Another similar comparative study also favoured escitalopram 10-20 mg daily over duloxetine 60 mg, both in terms of effectiveness and side effect profile. In this study 2% of the escitalopram group dropped out due to side effects, compared to 13% of the duloxetine group.
( http://www.ncbi.nlm.nih.gov/pubmed/17563128 )
In this well-done 2011 review by Schueler et al. comparing venlafaxine and duloxetine with SSRIs. They concluded the following:
1) Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs
2) Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine.
( http://www.ncbi.nlm.nih.gov/pubmed/20831742 )
Another study, done in 2006, also showing evidence that venlafaxine is superior to duloxetine: http://www.ncbi.nlm.nih.gov/pubmed/16867188
In one of the few well-designed comparative studies of venlafaxine vs. duloxetine, done by Perahia et al (2008), the two medications are found to have similar effectiveness, but with a higher dropout rate due to side effects in the duloxetine group. ( http://www.ncbi.nlm.nih.gov/pubmed/17445831 ) A look at graphs of symptom change show that the two medications appear identically effective. But duloxetine caused more side effects, especially nausea. It is true that discontinuing venlafaxine causes more side effects than discontinuing duloxetine, but this could be framed as a technical matter that just needs to be managed by very slow tapering.
This 2012 study (sponsored by the manufacturer!) by Martinez et al ( http://www.ncbi.nlm.nih.gov/pubmed/22027844 ) compares duloxetine with SSRI treatments for major depression, in a 12 week prospective trial. Duloxetine performed well, but on the primary outcome measure there was no significant difference in response or remission rates. On secondary measures there appeared to be some advantages for duloxetine, particularly for pain symptoms. But the study was not intended to be for treating pain syndromes! SSRIs are known to be ineffective for pain!
Duloxetine is often touted as a good treatment for neuropathic pain. And numerous studies do show that it can help. But how does it actually compare to other options? Specifically, how does it compare with a much cheaper and similar antidepressant, venlafaxine? Rudroju et al (2013) looked at comparative effectiveness of various medications for treating neuropathic pain. Many medications helped, including duloxetine. But in this study, gabapentin and venlafaxine had the best odds ratio of helping, followed by pregabalin. Duloxetine was farther down the list. With a benefit-risk analysis, which takes into account side effects and tolerability, gabapentin, pregabalin, and venlafaxine were once again at the top of the list of best agents, with duloxetine farther down.
( http://www.ncbi.nlm.nih.gov/pubmed/24284851)
Duloxetine (Cymbalta) costs about $4.23 for a 60 mg dose, compared to $0.38 for an equivalent 150 mg dose of Effexor XR. So it is about 10 times more expensive than an alternative which is shown to work as well if not better.
In conclusion, Cymbalta is yet another newer antidepressant which is not necessarily better than alternatives; in fact the alternatives such as Effexor XR are probably equally effective or more effective. It is marketed intensely as a treatment for neuropathic and other pain syndromes, but alternatives such as Effexor XR work better, with fewer side effects, at a lower cost. Therefore, just as with the other antidepressants mentioned in the previous posts, Cymbalta could be considered a third-line option, which might suit some people well if they have tried other things unsuccessfully.
In a study of medication treatment options for severe depression, a switch to duloxetine was compared with a dose increase of escitalopram. The escitalopram group had better results, including a remission rate of 54% for escitalopram vs. 42% for duloxetine. ( http://www.ncbi.nlm.nih.gov/pubmed/22559255 )
Another similar comparative study also favoured escitalopram 10-20 mg daily over duloxetine 60 mg, both in terms of effectiveness and side effect profile. In this study 2% of the escitalopram group dropped out due to side effects, compared to 13% of the duloxetine group.
( http://www.ncbi.nlm.nih.gov/pubmed/17563128 )
In this well-done 2011 review by Schueler et al. comparing venlafaxine and duloxetine with SSRIs. They concluded the following:
1) Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs
2) Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine.
( http://www.ncbi.nlm.nih.gov/pubmed/20831742 )
Another study, done in 2006, also showing evidence that venlafaxine is superior to duloxetine: http://www.ncbi.nlm.nih.gov/pubmed/16867188
In one of the few well-designed comparative studies of venlafaxine vs. duloxetine, done by Perahia et al (2008), the two medications are found to have similar effectiveness, but with a higher dropout rate due to side effects in the duloxetine group. ( http://www.ncbi.nlm.nih.gov/pubmed/17445831 ) A look at graphs of symptom change show that the two medications appear identically effective. But duloxetine caused more side effects, especially nausea. It is true that discontinuing venlafaxine causes more side effects than discontinuing duloxetine, but this could be framed as a technical matter that just needs to be managed by very slow tapering.
This 2012 study (sponsored by the manufacturer!) by Martinez et al ( http://www.ncbi.nlm.nih.gov/pubmed/22027844 ) compares duloxetine with SSRI treatments for major depression, in a 12 week prospective trial. Duloxetine performed well, but on the primary outcome measure there was no significant difference in response or remission rates. On secondary measures there appeared to be some advantages for duloxetine, particularly for pain symptoms. But the study was not intended to be for treating pain syndromes! SSRIs are known to be ineffective for pain!
Duloxetine is often touted as a good treatment for neuropathic pain. And numerous studies do show that it can help. But how does it actually compare to other options? Specifically, how does it compare with a much cheaper and similar antidepressant, venlafaxine? Rudroju et al (2013) looked at comparative effectiveness of various medications for treating neuropathic pain. Many medications helped, including duloxetine. But in this study, gabapentin and venlafaxine had the best odds ratio of helping, followed by pregabalin. Duloxetine was farther down the list. With a benefit-risk analysis, which takes into account side effects and tolerability, gabapentin, pregabalin, and venlafaxine were once again at the top of the list of best agents, with duloxetine farther down.
( http://www.ncbi.nlm.nih.gov/pubmed/24284851)
Duloxetine (Cymbalta) costs about $4.23 for a 60 mg dose, compared to $0.38 for an equivalent 150 mg dose of Effexor XR. So it is about 10 times more expensive than an alternative which is shown to work as well if not better.
In conclusion, Cymbalta is yet another newer antidepressant which is not necessarily better than alternatives; in fact the alternatives such as Effexor XR are probably equally effective or more effective. It is marketed intensely as a treatment for neuropathic and other pain syndromes, but alternatives such as Effexor XR work better, with fewer side effects, at a lower cost. Therefore, just as with the other antidepressants mentioned in the previous posts, Cymbalta could be considered a third-line option, which might suit some people well if they have tried other things unsuccessfully.
Vortioxetine
Vortioxetine is one of the newest antidepressants on the market, released in the U.S. in 2013. It has serotonin and norepinephrine reuptake inhibition effects, plus a variety of direct effects on serotonin receptors.
This is a negative study of vortioxetine, showing that it did not lead to any difference in rating scores compared to placebo, when used at doses of 10 mg or 15 mg daily, to treat depression for 8 weeks:
http://www.ncbi.nlm.nih.gov/pubmed/26035186
In another study, by Jacobson et al (2015), looking at doses of 10 mg or 20 mg daily, they found slight improvements in the vortioxetine groups compared to placebo, with "significant" differences in the MADRS score only for the 20 mg dose ( http://www.ncbi.nlm.nih.gov/pubmed/26035185 ). If you look at the symptom changes vs. placebo on a graph, the clinical relevance of the vortioxetine effect appears questionable. Yet, typically with papers of this type, despite the results being very unimpressive, the authors try to frame it in a very positive way, as though they had discovered a fantastically effective new treatment. Vortioxetine is supposed to be helpful for managing sexual side effects as well, but the measures of this done in the study once again do not show a spectacular benefit. For those who did not have sexual side effects previously, about half in the vortioxetine group developed sexual side effects, at a rate 10-20% greater than placebo. Here are the authors' final assertions at the end of their paper: "In conclusion, vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in adults with MDD. Overall, vortioxetine was well tolerated in this study." Perhaps a more fair conclusion could be "vortioxetine produced small differences compared to placebo in the MADRS score, but only at a dose of 20 mg daily. The degree of improvement does not compare favourably with similar studies using other antidepressants. Rates of side effects, including sexual side effects, were higher in the vortioxetine groups compared to the placebo groups."
A 2015 meta-analytic review paper by Rosenblat et al (http://www.ncbi.nlm.nih.gov/pubmed/26209859 ) showed in general that antidepressants appear to help with cognitive function when used to treat depression. But they conclude that "no statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs."
In this article by Llorca et al (2014), which is a "meta-regression analysis", it appears to favour vortioxetine as being better than other antidepressants. (https://www.ncbi.nlm.nih.gov/pubmed/25249164)This article is then quoted elsewhere, such as on Wikipedia, as supporting the claim that vortioxetine is a superior antidepressant. But the article shows indirect information only, there is no actual comparative study referred to at all. And the findings, even from this study, really only show that vortioxetine is in the "same ballpark" in terms of effects, compared to other agents-- it certainly doesn't show superiority.
It was hoped that vortioxetine might help with generalized anxiety, but after several negative studies (https://www.ncbi.nlm.nih.gov/pubmed/24424707,
https://www.ncbi.nlm.nih.gov/pubmed/24341301 ), the latter of which showing that it was significantly inferior to another antidepressant (duloxetine), it is no longer claimed by anyone that it is an appropriate treatment for GAD.
Vortioxetine costs about $3.25 for a 20 mg dose. This is about 10 times more than a 20 mg dose of citalopram.
In conclusion, vortioxetine is another new option for treating depression. It could be something to think about for treating anxious depression. But there is no evidence that it is superior to other options, and is probably inferior in many cases. There is no evidence of any specific benefit for treating anxiety disorders such as GAD. I would consider it to be a third-line alternative at this point.
This is a negative study of vortioxetine, showing that it did not lead to any difference in rating scores compared to placebo, when used at doses of 10 mg or 15 mg daily, to treat depression for 8 weeks:
http://www.ncbi.nlm.nih.gov/pubmed/26035186
In another study, by Jacobson et al (2015), looking at doses of 10 mg or 20 mg daily, they found slight improvements in the vortioxetine groups compared to placebo, with "significant" differences in the MADRS score only for the 20 mg dose ( http://www.ncbi.nlm.nih.gov/pubmed/26035185 ). If you look at the symptom changes vs. placebo on a graph, the clinical relevance of the vortioxetine effect appears questionable. Yet, typically with papers of this type, despite the results being very unimpressive, the authors try to frame it in a very positive way, as though they had discovered a fantastically effective new treatment. Vortioxetine is supposed to be helpful for managing sexual side effects as well, but the measures of this done in the study once again do not show a spectacular benefit. For those who did not have sexual side effects previously, about half in the vortioxetine group developed sexual side effects, at a rate 10-20% greater than placebo. Here are the authors' final assertions at the end of their paper: "In conclusion, vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in adults with MDD. Overall, vortioxetine was well tolerated in this study." Perhaps a more fair conclusion could be "vortioxetine produced small differences compared to placebo in the MADRS score, but only at a dose of 20 mg daily. The degree of improvement does not compare favourably with similar studies using other antidepressants. Rates of side effects, including sexual side effects, were higher in the vortioxetine groups compared to the placebo groups."
A 2015 meta-analytic review paper by Rosenblat et al (http://www.ncbi.nlm.nih.gov/pubmed/26209859 ) showed in general that antidepressants appear to help with cognitive function when used to treat depression. But they conclude that "no statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs."
In this article by Llorca et al (2014), which is a "meta-regression analysis", it appears to favour vortioxetine as being better than other antidepressants. (https://www.ncbi.nlm.nih.gov/pubmed/25249164)This article is then quoted elsewhere, such as on Wikipedia, as supporting the claim that vortioxetine is a superior antidepressant. But the article shows indirect information only, there is no actual comparative study referred to at all. And the findings, even from this study, really only show that vortioxetine is in the "same ballpark" in terms of effects, compared to other agents-- it certainly doesn't show superiority.
It was hoped that vortioxetine might help with generalized anxiety, but after several negative studies (https://www.ncbi.nlm.nih.gov/pubmed/24424707,
https://www.ncbi.nlm.nih.gov/pubmed/24341301 ), the latter of which showing that it was significantly inferior to another antidepressant (duloxetine), it is no longer claimed by anyone that it is an appropriate treatment for GAD.
Vortioxetine costs about $3.25 for a 20 mg dose. This is about 10 times more than a 20 mg dose of citalopram.
In conclusion, vortioxetine is another new option for treating depression. It could be something to think about for treating anxious depression. But there is no evidence that it is superior to other options, and is probably inferior in many cases. There is no evidence of any specific benefit for treating anxiety disorders such as GAD. I would consider it to be a third-line alternative at this point.
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