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COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
REPORTING FROM ECNP 2019