U.K. Guidelines: Sertraline First for Generalized Anxiety Disorder

TUCSON – New British guidelines on the management of generalized anxiety disorder advocate a stepped-care approach to this common psychiatric condition that one U.S. expert considers thoughtful and highly reasonable.

The U.K. National Institute for Health and Clinical Excellence (NICE) guidelines recommend as a first step in generalized anxiety disorder (GAD) simple, low-cost self-help and guided self-help educational and coaching interventions that can be provided in pamphlets or on the Internet.

"I like this a lot, because as we hope to get universal health coverage and yet not break the bank, online therapies that can be done essentially for free – you and your computer, sitting in your bedroom – can be a good first step in treating common conditions such as insomnia or anxiety," Dr. Alan J. Gelenberg said at the annual psychopharmacology review, sponsored by the University of Arizona.

Photo credit: ©absolut/Fotolia.com

The next step under the NICE guidelines is low-intensity group therapy. But if a patient continues to have marked functional impairment despite group sessions, it’s time to offer the choice of either pharmacotherapy or high-intensity, manual-based psychotherapy in the form of applied relaxation or cognitive-behavioral therapy.

The recently published guidelines (BMJ 2011;342 [doi:10.1135/bmj.c7460]) recommend selective serotonin reuptake inhibitors (SSRIs) as the first-line class of medications, with sertraline singled out as the drug of first choice. Interestingly, sertraline is not approved for treatment of GAD in the United Kingdom or the United States. The guideline writing group stated that, while NICE does not ordinarily recommend the use of a drug for an unlicensed application, an exception was made for sertraline, because the generic version is particularly cost effective.

"The NICE guidelines tend to be more cost conscious than other international guidelines in psychiatry," Dr. Gelenberg observed. "I prefer some of the off-patent generics as first line; I’ll go along with the Brits and the NICE guidelines."

There is persuasive published clinical trials evidence for sertraline’s effectiveness in GAD. Its manufacturer made a business decision not to pursue regulatory approval for the indication, because the drug was scheduled to lose its patent protection soon.

Although very few head-to-head clinical trials exist, all of the antidepressants in the various classes studied for GAD appear to have comparable efficacy. They are significantly more effective than placebo. However, there is a consistently large placebo effect in the studies, and the effect size of the medication compared to placebo is actually rather modest, according to Dr. Gelenberg, professor and chair of the department of psychiatry at Pennsylvania State University, Hershey.

One of the factors he likes best about the new NICE guidelines is the emphatic statement that benzodiazepines should not be offered in the treatment of GAD except short term during acute crises. This recommendation is at odds with current prescribing trends both in the United Kingdom and the United States, where benzodiazepines are prescribed for GAD more often than antidepressants, and the most frequently prescribed benzodiazepine is alprazolam (Xanax). This is a sore point for Dr. Gelenberg. He dislikes alprazolam, which he views as an often-abused drug with a "very nasty" withdrawal syndrome.

A consistent finding in numerous head-to-head studies of benzodiazepines vs. antidepressants over the past 2 decades is that the benzodiazepines bring faster improvement in the somatic symptoms of anxiety but, in the end, the antidepressant is always the clear winner in terms of efficacy. On this basis, a case can be made for a few weeks of concomitant therapy with a long-half-life benzodiazepine in selected patients as a lead in while waiting for the antidepressant to achieve full effect, he continued.

The NICE guidelines recommend that if sertraline is ineffective, offer another SSRI or a serotonin–norepinephrine reuptake inhibitor (SNRI). If the SSRIs and SNRIs are not tolerated, the guidelines recommend turning to pregabalin (Lyrica), which is approved for GAD in the United Kingdom but not in the United States. The clinical trials evidence shows pregabalin works as fast as alprazolam or lorazepam while achieving symptom improvement scores comparable with antidepressants, making it a particularly attractive back-up option in antidepressant nonresponders, Dr. Gelenberg said.

The Food and Drug Administration–approved drugs for GAD are the SNRIs venlafaxine and duloxetine, the SSRIs paroxetine and escitalopram, alprazolam, and buspirone. However, escitalopram and alprazolam are approved for acute treatment only, and buspirone is approved as maintenance therapy only. There is a widespread impression that buspirone is less effective than antidepressants in GAD, and most experts don’t use it much, he continued.

NICE advises against using antipsychotic agents for treatment of GAD in primary care, because the evidence of clinical efficacy is weak and the risk of serious side effects is well established.

In psychiatrists’ hands, however, Dr. Gelenberg considers second-generation antipsychotic agents a reasonable next step in treatment nonresponders. The evidence of efficacy for quetiapine (Seroquel) in GAD is "quite impressive," he said, citing a recent Cochrane analysis of four placebo-controlled clinical trials of quetiapine monotherapy for GAD totaling 2,265 patients. The Cochrane report concluded that quetiapine’s efficacy is comparable to that of antidepressants, although the dropout rate attributable to side effects – mostly sedation and weight gain – is higher (Cochrane Database Syst. Rev.;12:CD008120).

The NICE guidelines do not address the question of how long effective therapy should be continued. Dr. Gelenberg pointed to a recent enlightening study on this score by Dr. Karl E. Rickels and his colleagues at the University of Pennsylvania, Philadelphia, which concluded that treatment should continue for at least 12 months.

The study involved 268 GAD patients treated for 6 months with open-label extended-release venlafaxine. The 51% who were significantly improved at that point were then randomized double-blind to an additional 6 months of extended-release venlafaxine or placebo. Among patients still in the study at the 12-month mark, those on placebo were placed on another 6 months of placebo, while those on venlafaxine XR were randomized to a double-blind test for an additional 6 months of the drug or placebo.

During months 6-12, patients still on venlafaxine XR had a 10% relapse rate, compared with 54% in those switched to placebo. Among patients who’d been on venlafaxine XR during the first 12 months, those assigned to the antidepressant in months 12-18 had a 7% relapse rate during that final period, compared with 32% for those switched to placebo. Reassuringly, most patients who relapsed when taken off the antidepressant responded to a second course of therapy. The take-home message, according to the investigators, is that successful treatment should be maintained for at least a year (Arch. Gen. Psychiatry 2010;67:1274-81).

"GAD is a chronic disorder, and probably most patients need much longer therapy, but I don’t get as upset when a patient wants to stop as I do when it’s someone with severe major depressive disorder or bipolar disorder. I’m more inclined to say, ‘Try it. We’ll work together, and if you feel the anxiety start to return we’ll put you back on therapy,’ " Dr. Gelenberg said.

He disclosed that he serves as a consultant to Eli Lilly, Best Practice, AstraZeneca, Wyeth, GlaxoSmithKline, ZARS Pharma, Jazz Pharmaceuticals, H. Lundbeck A/S, Takeda, eResearch Technology, Dey Pharma, PGxHealth, and Myriad Genetics.

TUCSON – New British guidelines on the management of generalized anxiety disorder advocate a stepped-care approach to this common psychiatric condition that one U.S. expert considers thoughtful and highly reasonable.

The U.K. National Institute for Health and Clinical Excellence (NICE) guidelines recommend as a first step in generalized anxiety disorder (GAD) simple, low-cost self-help and guided self-help educational and coaching interventions that can be provided in pamphlets or on the Internet.

"I like this a lot, because as we hope to get universal health coverage and yet not break the bank, online therapies that can be done essentially for free – you and your computer, sitting in your bedroom – can be a good first step in treating common conditions such as insomnia or anxiety," Dr. Alan J. Gelenberg said at the annual psychopharmacology review, sponsored by the University of Arizona.

Photo credit: ©absolut/Fotolia.com

The next step under the NICE guidelines is low-intensity group therapy. But if a patient continues to have marked functional impairment despite group sessions, it’s time to offer the choice of either pharmacotherapy or high-intensity, manual-based psychotherapy in the form of applied relaxation or cognitive-behavioral therapy.

The recently published guidelines (BMJ 2011;342 [doi:10.1135/bmj.c7460]) recommend selective serotonin reuptake inhibitors (SSRIs) as the first-line class of medications, with sertraline singled out as the drug of first choice. Interestingly, sertraline is not approved for treatment of GAD in the United Kingdom or the United States. The guideline writing group stated that, while NICE does not ordinarily recommend the use of a drug for an unlicensed application, an exception was made for sertraline, because the generic version is particularly cost effective.

"The NICE guidelines tend to be more cost conscious than other international guidelines in psychiatry," Dr. Gelenberg observed. "I prefer some of the off-patent generics as first line; I’ll go along with the Brits and the NICE guidelines."

There is persuasive published clinical trials evidence for sertraline’s effectiveness in GAD. Its manufacturer made a business decision not to pursue regulatory approval for the indication, because the drug was scheduled to lose its patent protection soon.

Although very few head-to-head clinical trials exist, all of the antidepressants in the various classes studied for GAD appear to have comparable efficacy. They are significantly more effective than placebo. However, there is a consistently large placebo effect in the studies, and the effect size of the medication compared to placebo is actually rather modest, according to Dr. Gelenberg, professor and chair of the department of psychiatry at Pennsylvania State University, Hershey.

One of the factors he likes best about the new NICE guidelines is the emphatic statement that benzodiazepines should not be offered in the treatment of GAD except short term during acute crises. This recommendation is at odds with current prescribing trends both in the United Kingdom and the United States, where benzodiazepines are prescribed for GAD more often than antidepressants, and the most frequently prescribed benzodiazepine is alprazolam (Xanax). This is a sore point for Dr. Gelenberg. He dislikes alprazolam, which he views as an often-abused drug with a "very nasty" withdrawal syndrome.

A consistent finding in numerous head-to-head studies of benzodiazepines vs. antidepressants over the past 2 decades is that the benzodiazepines bring faster improvement in the somatic symptoms of anxiety but, in the end, the antidepressant is always the clear winner in terms of efficacy. On this basis, a case can be made for a few weeks of concomitant therapy with a long-half-life benzodiazepine in selected patients as a lead in while waiting for the antidepressant to achieve full effect, he continued.

The NICE guidelines recommend that if sertraline is ineffective, offer another SSRI or a serotonin–norepinephrine reuptake inhibitor (SNRI). If the SSRIs and SNRIs are not tolerated, the guidelines recommend turning to pregabalin (Lyrica), which is approved for GAD in the United Kingdom but not in the United States. The clinical trials evidence shows pregabalin works as fast as alprazolam or lorazepam while achieving symptom improvement scores comparable with antidepressants, making it a particularly attractive back-up option in antidepressant nonresponders, Dr. Gelenberg said.

The Food and Drug Administration–approved drugs for GAD are the SNRIs venlafaxine and duloxetine, the SSRIs paroxetine and escitalopram, alprazolam, and buspirone. However, escitalopram and alprazolam are approved for acute treatment only, and buspirone is approved as maintenance therapy only. There is a widespread impression that buspirone is less effective than antidepressants in GAD, and most experts don’t use it much, he continued.

NICE advises against using antipsychotic agents for treatment of GAD in primary care, because the evidence of clinical efficacy is weak and the risk of serious side effects is well established.

In psychiatrists’ hands, however, Dr. Gelenberg considers second-generation antipsychotic agents a reasonable next step in treatment nonresponders. The evidence of efficacy for quetiapine (Seroquel) in GAD is "quite impressive," he said, citing a recent Cochrane analysis of four placebo-controlled clinical trials of quetiapine monotherapy for GAD totaling 2,265 patients. The Cochrane report concluded that quetiapine’s efficacy is comparable to that of antidepressants, although the dropout rate attributable to side effects – mostly sedation and weight gain – is higher (Cochrane Database Syst. Rev.;12:CD008120).

The NICE guidelines do not address the question of how long effective therapy should be continued. Dr. Gelenberg pointed to a recent enlightening study on this score by Dr. Karl E. Rickels and his colleagues at the University of Pennsylvania, Philadelphia, which concluded that treatment should continue for at least 12 months.

The study involved 268 GAD patients treated for 6 months with open-label extended-release venlafaxine. The 51% who were significantly improved at that point were then randomized double-blind to an additional 6 months of extended-release venlafaxine or placebo. Among patients still in the study at the 12-month mark, those on placebo were placed on another 6 months of placebo, while those on venlafaxine XR were randomized to a double-blind test for an additional 6 months of the drug or placebo.

During months 6-12, patients still on venlafaxine XR had a 10% relapse rate, compared with 54% in those switched to placebo. Among patients who’d been on venlafaxine XR during the first 12 months, those assigned to the antidepressant in months 12-18 had a 7% relapse rate during that final period, compared with 32% for those switched to placebo. Reassuringly, most patients who relapsed when taken off the antidepressant responded to a second course of therapy. The take-home message, according to the investigators, is that successful treatment should be maintained for at least a year (Arch. Gen. Psychiatry 2010;67:1274-81).

"GAD is a chronic disorder, and probably most patients need much longer therapy, but I don’t get as upset when a patient wants to stop as I do when it’s someone with severe major depressive disorder or bipolar disorder. I’m more inclined to say, ‘Try it. We’ll work together, and if you feel the anxiety start to return we’ll put you back on therapy,’ " Dr. Gelenberg said.

He disclosed that he serves as a consultant to Eli Lilly, Best Practice, AstraZeneca, Wyeth, GlaxoSmithKline, ZARS Pharma, Jazz Pharmaceuticals, H. Lundbeck A/S, Takeda, eResearch Technology, Dey Pharma, PGxHealth, and Myriad Genetics.

TUCSON – New British guidelines on the management of generalized anxiety disorder advocate a stepped-care approach to this common psychiatric condition that one U.S. expert considers thoughtful and highly reasonable.

The U.K. National Institute for Health and Clinical Excellence (NICE) guidelines recommend as a first step in generalized anxiety disorder (GAD) simple, low-cost self-help and guided self-help educational and coaching interventions that can be provided in pamphlets or on the Internet.

"I like this a lot, because as we hope to get universal health coverage and yet not break the bank, online therapies that can be done essentially for free – you and your computer, sitting in your bedroom – can be a good first step in treating common conditions such as insomnia or anxiety," Dr. Alan J. Gelenberg said at the annual psychopharmacology review, sponsored by the University of Arizona.

Photo credit: ©absolut/Fotolia.com

The next step under the NICE guidelines is low-intensity group therapy. But if a patient continues to have marked functional impairment despite group sessions, it’s time to offer the choice of either pharmacotherapy or high-intensity, manual-based psychotherapy in the form of applied relaxation or cognitive-behavioral therapy.

The recently published guidelines (BMJ 2011;342 [doi:10.1135/bmj.c7460]) recommend selective serotonin reuptake inhibitors (SSRIs) as the first-line class of medications, with sertraline singled out as the drug of first choice. Interestingly, sertraline is not approved for treatment of GAD in the United Kingdom or the United States. The guideline writing group stated that, while NICE does not ordinarily recommend the use of a drug for an unlicensed application, an exception was made for sertraline, because the generic version is particularly cost effective.

"The NICE guidelines tend to be more cost conscious than other international guidelines in psychiatry," Dr. Gelenberg observed. "I prefer some of the off-patent generics as first line; I’ll go along with the Brits and the NICE guidelines."

There is persuasive published clinical trials evidence for sertraline’s effectiveness in GAD. Its manufacturer made a business decision not to pursue regulatory approval for the indication, because the drug was scheduled to lose its patent protection soon.

Although very few head-to-head clinical trials exist, all of the antidepressants in the various classes studied for GAD appear to have comparable efficacy. They are significantly more effective than placebo. However, there is a consistently large placebo effect in the studies, and the effect size of the medication compared to placebo is actually rather modest, according to Dr. Gelenberg, professor and chair of the department of psychiatry at Pennsylvania State University, Hershey.

One of the factors he likes best about the new NICE guidelines is the emphatic statement that benzodiazepines should not be offered in the treatment of GAD except short term during acute crises. This recommendation is at odds with current prescribing trends both in the United Kingdom and the United States, where benzodiazepines are prescribed for GAD more often than antidepressants, and the most frequently prescribed benzodiazepine is alprazolam (Xanax). This is a sore point for Dr. Gelenberg. He dislikes alprazolam, which he views as an often-abused drug with a "very nasty" withdrawal syndrome.

A consistent finding in numerous head-to-head studies of benzodiazepines vs. antidepressants over the past 2 decades is that the benzodiazepines bring faster improvement in the somatic symptoms of anxiety but, in the end, the antidepressant is always the clear winner in terms of efficacy. On this basis, a case can be made for a few weeks of concomitant therapy with a long-half-life benzodiazepine in selected patients as a lead in while waiting for the antidepressant to achieve full effect, he continued.

The NICE guidelines recommend that if sertraline is ineffective, offer another SSRI or a serotonin–norepinephrine reuptake inhibitor (SNRI). If the SSRIs and SNRIs are not tolerated, the guidelines recommend turning to pregabalin (Lyrica), which is approved for GAD in the United Kingdom but not in the United States. The clinical trials evidence shows pregabalin works as fast as alprazolam or lorazepam while achieving symptom improvement scores comparable with antidepressants, making it a particularly attractive back-up option in antidepressant nonresponders, Dr. Gelenberg said.

The Food and Drug Administration–approved drugs for GAD are the SNRIs venlafaxine and duloxetine, the SSRIs paroxetine and escitalopram, alprazolam, and buspirone. However, escitalopram and alprazolam are approved for acute treatment only, and buspirone is approved as maintenance therapy only. There is a widespread impression that buspirone is less effective than antidepressants in GAD, and most experts don’t use it much, he continued.

NICE advises against using antipsychotic agents for treatment of GAD in primary care, because the evidence of clinical efficacy is weak and the risk of serious side effects is well established.

In psychiatrists’ hands, however, Dr. Gelenberg considers second-generation antipsychotic agents a reasonable next step in treatment nonresponders. The evidence of efficacy for quetiapine (Seroquel) in GAD is "quite impressive," he said, citing a recent Cochrane analysis of four placebo-controlled clinical trials of quetiapine monotherapy for GAD totaling 2,265 patients. The Cochrane report concluded that quetiapine’s efficacy is comparable to that of antidepressants, although the dropout rate attributable to side effects – mostly sedation and weight gain – is higher (Cochrane Database Syst. Rev.;12:CD008120).

The NICE guidelines do not address the question of how long effective therapy should be continued. Dr. Gelenberg pointed to a recent enlightening study on this score by Dr. Karl E. Rickels and his colleagues at the University of Pennsylvania, Philadelphia, which concluded that treatment should continue for at least 12 months.

The study involved 268 GAD patients treated for 6 months with open-label extended-release venlafaxine. The 51% who were significantly improved at that point were then randomized double-blind to an additional 6 months of extended-release venlafaxine or placebo. Among patients still in the study at the 12-month mark, those on placebo were placed on another 6 months of placebo, while those on venlafaxine XR were randomized to a double-blind test for an additional 6 months of the drug or placebo.

During months 6-12, patients still on venlafaxine XR had a 10% relapse rate, compared with 54% in those switched to placebo. Among patients who’d been on venlafaxine XR during the first 12 months, those assigned to the antidepressant in months 12-18 had a 7% relapse rate during that final period, compared with 32% for those switched to placebo. Reassuringly, most patients who relapsed when taken off the antidepressant responded to a second course of therapy. The take-home message, according to the investigators, is that successful treatment should be maintained for at least a year (Arch. Gen. Psychiatry 2010;67:1274-81).

"GAD is a chronic disorder, and probably most patients need much longer therapy, but I don’t get as upset when a patient wants to stop as I do when it’s someone with severe major depressive disorder or bipolar disorder. I’m more inclined to say, ‘Try it. We’ll work together, and if you feel the anxiety start to return we’ll put you back on therapy,’ " Dr. Gelenberg said.

He disclosed that he serves as a consultant to Eli Lilly, Best Practice, AstraZeneca, Wyeth, GlaxoSmithKline, ZARS Pharma, Jazz Pharmaceuticals, H. Lundbeck A/S, Takeda, eResearch Technology, Dey Pharma, PGxHealth, and Myriad Genetics.