Inflammatory Cause of Bipolar Disorder Suggests New Treatments

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.