Bipolar Disorder

The nature and severity of cognitive alterations can vary significantly between different mood disorders, according to Dr. Charles Cotrena and his associates.

The study of 205 Brazilians comprised patients with major depressive disorder (MDD), patients with bipolar disorder I (BDI) and II (BDII), and a healthy control group, all of whom took a battery of neurocognitive tests. MDD patients performed poorly in tests involving attention and timed tasks, compared with the control group, but had less motor inhibition than did patients with BDI. Patients with BDI tended to perform worse across all executive functions, compared with patients with MDD, BDII, and the control group; however, BDII patients were the only ones who performed worse on the Iowa Gambling Task than did the control group, and performed worse on the Stroop Color–Word Test than did BDI patients.

wildpixel/Thinkstock.com

While MDD patients had worse psychological quality of life (QOL) than that of controls, there was no difference in other QOL measures. MDD patients reported better physical health and lower disability rates than did BD patients. BDII patients had worse QOL than did control patients, but had lower disability rates than did BDI patients.

The investigators found that differences in cognitive function and quality of life still existed in patients with mood disorder, even after adjustment for mania and depressive symptoms.

“The importance of a detailed assessment of [executive function] and disability levels within each of these diagnostic categories, while controlling for demographic variables, was especially evident from the current results. Additionally, the comparison of impairment rates between groups – which is not a usual measure in the literature – provided important contributions to current knowledge regarding cognition and mood disorders,” the investigators noted.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.11.007).

[email protected]

The nature and severity of cognitive alterations can vary significantly between different mood disorders, according to Dr. Charles Cotrena and his associates.

The study of 205 Brazilians comprised patients with major depressive disorder (MDD), patients with bipolar disorder I (BDI) and II (BDII), and a healthy control group, all of whom took a battery of neurocognitive tests. MDD patients performed poorly in tests involving attention and timed tasks, compared with the control group, but had less motor inhibition than did patients with BDI. Patients with BDI tended to perform worse across all executive functions, compared with patients with MDD, BDII, and the control group; however, BDII patients were the only ones who performed worse on the Iowa Gambling Task than did the control group, and performed worse on the Stroop Color–Word Test than did BDI patients.

wildpixel/Thinkstock.com

While MDD patients had worse psychological quality of life (QOL) than that of controls, there was no difference in other QOL measures. MDD patients reported better physical health and lower disability rates than did BD patients. BDII patients had worse QOL than did control patients, but had lower disability rates than did BDI patients.

The investigators found that differences in cognitive function and quality of life still existed in patients with mood disorder, even after adjustment for mania and depressive symptoms.

“The importance of a detailed assessment of [executive function] and disability levels within each of these diagnostic categories, while controlling for demographic variables, was especially evident from the current results. Additionally, the comparison of impairment rates between groups – which is not a usual measure in the literature – provided important contributions to current knowledge regarding cognition and mood disorders,” the investigators noted.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.11.007).

[email protected]

The nature and severity of cognitive alterations can vary significantly between different mood disorders, according to Dr. Charles Cotrena and his associates.

The study of 205 Brazilians comprised patients with major depressive disorder (MDD), patients with bipolar disorder I (BDI) and II (BDII), and a healthy control group, all of whom took a battery of neurocognitive tests. MDD patients performed poorly in tests involving attention and timed tasks, compared with the control group, but had less motor inhibition than did patients with BDI. Patients with BDI tended to perform worse across all executive functions, compared with patients with MDD, BDII, and the control group; however, BDII patients were the only ones who performed worse on the Iowa Gambling Task than did the control group, and performed worse on the Stroop Color–Word Test than did BDI patients.

wildpixel/Thinkstock.com

While MDD patients had worse psychological quality of life (QOL) than that of controls, there was no difference in other QOL measures. MDD patients reported better physical health and lower disability rates than did BD patients. BDII patients had worse QOL than did control patients, but had lower disability rates than did BDI patients.

The investigators found that differences in cognitive function and quality of life still existed in patients with mood disorder, even after adjustment for mania and depressive symptoms.

“The importance of a detailed assessment of [executive function] and disability levels within each of these diagnostic categories, while controlling for demographic variables, was especially evident from the current results. Additionally, the comparison of impairment rates between groups – which is not a usual measure in the literature – provided important contributions to current knowledge regarding cognition and mood disorders,” the investigators noted.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.11.007).

[email protected]

One-third of patients with bipolar disorders abnormally metabolized glucose, in a study of outpatients from two university hospitals in Germany.

The study included 85 euthymic patients with bipolar disorders, who underwent an oral glucose tolerance test, laboratory screening, and clinical measurements.

©donskarpo/thinkstockphotos.com

Seven percent of the patients tested positive for diabetes mellitus, while 27% of the patients showed prediabetic abnormalities, including abnormalities in glucose metabolism. Patients in both of these groups had significantly lower quality of life and global functioning.

Additional study findings were that higher body mass index, leptin, triglycerides, and C-reactive protein levels significantly increased the likelihood of an individual having pre-diabetes abnormalities or diabetes.

Low sample size was a weakness of the study, according to Karolina Leopold and her colleagues.

Read the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.041).

[email protected]

One-third of patients with bipolar disorders abnormally metabolized glucose, in a study of outpatients from two university hospitals in Germany.

The study included 85 euthymic patients with bipolar disorders, who underwent an oral glucose tolerance test, laboratory screening, and clinical measurements.

©donskarpo/thinkstockphotos.com

Seven percent of the patients tested positive for diabetes mellitus, while 27% of the patients showed prediabetic abnormalities, including abnormalities in glucose metabolism. Patients in both of these groups had significantly lower quality of life and global functioning.

Additional study findings were that higher body mass index, leptin, triglycerides, and C-reactive protein levels significantly increased the likelihood of an individual having pre-diabetes abnormalities or diabetes.

Low sample size was a weakness of the study, according to Karolina Leopold and her colleagues.

Read the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.041).

[email protected]

One-third of patients with bipolar disorders abnormally metabolized glucose, in a study of outpatients from two university hospitals in Germany.

The study included 85 euthymic patients with bipolar disorders, who underwent an oral glucose tolerance test, laboratory screening, and clinical measurements.

©donskarpo/thinkstockphotos.com

Seven percent of the patients tested positive for diabetes mellitus, while 27% of the patients showed prediabetic abnormalities, including abnormalities in glucose metabolism. Patients in both of these groups had significantly lower quality of life and global functioning.

Additional study findings were that higher body mass index, leptin, triglycerides, and C-reactive protein levels significantly increased the likelihood of an individual having pre-diabetes abnormalities or diabetes.

Low sample size was a weakness of the study, according to Karolina Leopold and her colleagues.

Read the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.041).

[email protected]

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

People diagnosed with unipolar depression have a higher chance of developing mania or bipolar disorder if they’ve previously been treated with antidepressants, a new study shows (BMJ Open. 2015 Dec 15. doi: 10.1136/bmjopen-2015-008341).

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania,” Dr. Rashmi Patel of King’s College, London, and his associates reported in the study. Moreover, the association remains significant after adjusting for both age and gender, they wrote.

©g-stockstudio/thinkstockphotos.com

Dr. Patel and his associates conducted a retrospective cohort study on 21,012 individuals aged 16 to 65 years – all of whom were diagnosed with depression and had no previous diagnosis of mania or bipolar disorder between April 1, 2006, and March 31, 2013 – from the South London and Maudsley National Health Service Foundation Trust. Clinical data on subjects’ medical history, mental state examinations, diagnostic formulations, and management plans were collected. Subjects also were classified as having had “prior antidepressant therapy” if there was “documentation of antidepressant treatment prior to the date of diagnosis of depression.” Follow-ups occurred through March 31, 2014, and the primary outcome was a diagnosis of mania or bipolar disorder during that period.

Results showed an incidence rate of 10.9 per 1,000 person-years of mania or bipolar disorder across the entire study population. The lowest incidence, 8.3 per 1,000 person-years, was in the 56-65 years age cohort, while those in the 26-35 years age cohort had the highest incidence rate – 12.3 per 1,000 person-years (P = .004).

Subjects with prior antidepressant use saw significant increases in incidence rates of mania or bipolar disorder, depending on which antidepressant they were taking. Those on tricyclics (4.7% of subjects with previous antidepressant treatment) had a 13.1 per 1,000 person-years incidence rate, while those taking trazodone (0.8%) had a 19.1 per 1,000 person-years incidence rate (P = .09 and P = .03, respectively). The most commonly used antidepressants were selective serotonin reuptake inhibitors (35.5%), which yielded an incidence rate of 13.2 per 1,000 person-years.

“The association of antidepressant therapy with mania demonstrated in the present and previous studies highlights the importance of considering whether an individual who presents with depression could be at risk of future episodes of mania,” the authors concluded. They concluded that the findings reinforce the “ongoing need to develop better ways to predict future risk of mania in people with no prior history of bipolar disorder who present with an episode of depression.”

The study was supported by the U.K. Medical Research Council Clinical Research Training Fellowship. Neither Dr. Patel nor his associates reported relevant financial disclosures.

[email protected]

People diagnosed with unipolar depression have a higher chance of developing mania or bipolar disorder if they’ve previously been treated with antidepressants, a new study shows (BMJ Open. 2015 Dec 15. doi: 10.1136/bmjopen-2015-008341).

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania,” Dr. Rashmi Patel of King’s College, London, and his associates reported in the study. Moreover, the association remains significant after adjusting for both age and gender, they wrote.

©g-stockstudio/thinkstockphotos.com

Dr. Patel and his associates conducted a retrospective cohort study on 21,012 individuals aged 16 to 65 years – all of whom were diagnosed with depression and had no previous diagnosis of mania or bipolar disorder between April 1, 2006, and March 31, 2013 – from the South London and Maudsley National Health Service Foundation Trust. Clinical data on subjects’ medical history, mental state examinations, diagnostic formulations, and management plans were collected. Subjects also were classified as having had “prior antidepressant therapy” if there was “documentation of antidepressant treatment prior to the date of diagnosis of depression.” Follow-ups occurred through March 31, 2014, and the primary outcome was a diagnosis of mania or bipolar disorder during that period.

Results showed an incidence rate of 10.9 per 1,000 person-years of mania or bipolar disorder across the entire study population. The lowest incidence, 8.3 per 1,000 person-years, was in the 56-65 years age cohort, while those in the 26-35 years age cohort had the highest incidence rate – 12.3 per 1,000 person-years (P = .004).

Subjects with prior antidepressant use saw significant increases in incidence rates of mania or bipolar disorder, depending on which antidepressant they were taking. Those on tricyclics (4.7% of subjects with previous antidepressant treatment) had a 13.1 per 1,000 person-years incidence rate, while those taking trazodone (0.8%) had a 19.1 per 1,000 person-years incidence rate (P = .09 and P = .03, respectively). The most commonly used antidepressants were selective serotonin reuptake inhibitors (35.5%), which yielded an incidence rate of 13.2 per 1,000 person-years.

“The association of antidepressant therapy with mania demonstrated in the present and previous studies highlights the importance of considering whether an individual who presents with depression could be at risk of future episodes of mania,” the authors concluded. They concluded that the findings reinforce the “ongoing need to develop better ways to predict future risk of mania in people with no prior history of bipolar disorder who present with an episode of depression.”

The study was supported by the U.K. Medical Research Council Clinical Research Training Fellowship. Neither Dr. Patel nor his associates reported relevant financial disclosures.

[email protected]

People diagnosed with unipolar depression have a higher chance of developing mania or bipolar disorder if they’ve previously been treated with antidepressants, a new study shows (BMJ Open. 2015 Dec 15. doi: 10.1136/bmjopen-2015-008341).

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania,” Dr. Rashmi Patel of King’s College, London, and his associates reported in the study. Moreover, the association remains significant after adjusting for both age and gender, they wrote.

©g-stockstudio/thinkstockphotos.com

Dr. Patel and his associates conducted a retrospective cohort study on 21,012 individuals aged 16 to 65 years – all of whom were diagnosed with depression and had no previous diagnosis of mania or bipolar disorder between April 1, 2006, and March 31, 2013 – from the South London and Maudsley National Health Service Foundation Trust. Clinical data on subjects’ medical history, mental state examinations, diagnostic formulations, and management plans were collected. Subjects also were classified as having had “prior antidepressant therapy” if there was “documentation of antidepressant treatment prior to the date of diagnosis of depression.” Follow-ups occurred through March 31, 2014, and the primary outcome was a diagnosis of mania or bipolar disorder during that period.

Results showed an incidence rate of 10.9 per 1,000 person-years of mania or bipolar disorder across the entire study population. The lowest incidence, 8.3 per 1,000 person-years, was in the 56-65 years age cohort, while those in the 26-35 years age cohort had the highest incidence rate – 12.3 per 1,000 person-years (P = .004).

Subjects with prior antidepressant use saw significant increases in incidence rates of mania or bipolar disorder, depending on which antidepressant they were taking. Those on tricyclics (4.7% of subjects with previous antidepressant treatment) had a 13.1 per 1,000 person-years incidence rate, while those taking trazodone (0.8%) had a 19.1 per 1,000 person-years incidence rate (P = .09 and P = .03, respectively). The most commonly used antidepressants were selective serotonin reuptake inhibitors (35.5%), which yielded an incidence rate of 13.2 per 1,000 person-years.

“The association of antidepressant therapy with mania demonstrated in the present and previous studies highlights the importance of considering whether an individual who presents with depression could be at risk of future episodes of mania,” the authors concluded. They concluded that the findings reinforce the “ongoing need to develop better ways to predict future risk of mania in people with no prior history of bipolar disorder who present with an episode of depression.”

The study was supported by the U.K. Medical Research Council Clinical Research Training Fellowship. Neither Dr. Patel nor his associates reported relevant financial disclosures.

[email protected]

Three biotypes surpass traditional diagnostic categories when it comes to identifying subgroups of psychosis, a study showed.

“Classification and treatment of brain diseases subsumed by psychiatry rely on clinical phenomenology, despite the call for alternatives,” wrote Brett A. Clementz, Ph.D., of the University of Georgia, Athens, and his coinvestigators. “There is overlap in susceptibility genes and phenotypes across bipolar disorder with psychosis and schizophrenia, and considerable similarity between different psychotic disorders on symptoms, illness course, cognition, psychophysiology, and neurobiology [while] drug treatments for these conditions overlap extensively” (Am J Psychiatry. 2015. doi: 10.1176/appi.ajp.2015.14091200).

The researchers recruited 711 people from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium sites (probands). All subjects had diagnoses of schizophrenia, schizoaffective disorder, or bipolar disorder with psychosis, and underwent interviews and laboratory data collection at the time of enrollment. In addition, 883 first-degree relatives of the 711 initial enrollees also were clinically evaluated, along with a cohort of 278 people deemed “demographically comparable [and] healthy” by investigators.

Biotypes for all individuals enrolled in the study were determined through laboratory tasks designed to “assess brain function at the neurocogntive/perceptual level.” These tasks consisted of the Brief Assessment of Cognition in Schizophrenia (BACS), pro- and antisaccade tasks, stop signal tasks, auditory paired stimuli and oddball evoked brain responses, and MRI acquisition and voxel-based morphometry.

The Structured Clinical Interview for DSM-IV and the Structured Interview for DSM-IV Personality Disorders were used for interviewing enrollees. Data compiled from these tests underwent multivariate taxometric analyses to compare biomarker variance across the three cohorts, in order to determine what, if any, heterogeneity exists in psychosis biotypes.

According to the results, diagnoses made with the clinical DSM guidelines yielded a single-severity continuum showing schizophrenia to be the most severe, followed by schizoaffective disorder and bipolar psychosis. However, biotypes showed significant variation, with investigators noting that “the three biotypes had distinctive patterns of abnormality across biomarkers that were neither entirely nor efficiently captured by a severity continuum.”

Larger separations were seen in biotype cohorts than in the DSM, specifically among probands. Among probands, group separation from healthy subjects was –2.58, –1.94, and –0.35 for biotype 1, 2, and 3 respectively for the BACS. Separation was –0.99, –0.78, and –0.05 for the stop signal task, and 3.32, 1.90, and 1.19 for the antisaccade errors. On the other hand, DSM diagnostics revealed group differences of –1.01, –1.51, and –1.83 for bipolar disorder psychosis, schizoaffective disorders, and schizophrenia, respectively, for the BACS test. Separation was –0.41, –0.61, and –0.55 for the stop signal task, and 1.36, 1.66, and 2.45 for antisaccade errors.

“Each biotype included all DSM psychosis categories, but probands diagnosed with schizophrenia were more numerous in biotype 1 (although 20% had bipolar disorder with psychosis), and probands diagnosed with bipolar disorder with psychosis were more numerous in biotype 3 (although 32% had schizophrenia), respectively,” the investigators noted.

The authors added that “when considered across proband and relative data, the biotype subgroups were superior to DSM diagnostic classes in between-group separations on external validating measures, illustrating the former scheme’s superiority for capturing neurobiological distinctiveness.”

Investigators noted that their approach did not use social functioning, brain structure, and characteristics of biological relatives in the creation of biotypes, which could have led to stronger results. Also, trial participants were mostly already on medication, classified as chronically psychotic, and tested at least once previously. The trial also had no replication sample for this sample population.

The study was supported by grants from the National Institute of Mental Health. Dr. Clementz did not report any relevant financial disclosures. Dr. Matcheri S. Keshavan reported receiving a grant from Sunovion and serving as a consultant to Forum Pharmaceuticals. Dr. Carol A. Tamminga also reported potential conflicts.

[email protected]

Three biotypes surpass traditional diagnostic categories when it comes to identifying subgroups of psychosis, a study showed.

“Classification and treatment of brain diseases subsumed by psychiatry rely on clinical phenomenology, despite the call for alternatives,” wrote Brett A. Clementz, Ph.D., of the University of Georgia, Athens, and his coinvestigators. “There is overlap in susceptibility genes and phenotypes across bipolar disorder with psychosis and schizophrenia, and considerable similarity between different psychotic disorders on symptoms, illness course, cognition, psychophysiology, and neurobiology [while] drug treatments for these conditions overlap extensively” (Am J Psychiatry. 2015. doi: 10.1176/appi.ajp.2015.14091200).

The researchers recruited 711 people from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium sites (probands). All subjects had diagnoses of schizophrenia, schizoaffective disorder, or bipolar disorder with psychosis, and underwent interviews and laboratory data collection at the time of enrollment. In addition, 883 first-degree relatives of the 711 initial enrollees also were clinically evaluated, along with a cohort of 278 people deemed “demographically comparable [and] healthy” by investigators.

Biotypes for all individuals enrolled in the study were determined through laboratory tasks designed to “assess brain function at the neurocogntive/perceptual level.” These tasks consisted of the Brief Assessment of Cognition in Schizophrenia (BACS), pro- and antisaccade tasks, stop signal tasks, auditory paired stimuli and oddball evoked brain responses, and MRI acquisition and voxel-based morphometry.

The Structured Clinical Interview for DSM-IV and the Structured Interview for DSM-IV Personality Disorders were used for interviewing enrollees. Data compiled from these tests underwent multivariate taxometric analyses to compare biomarker variance across the three cohorts, in order to determine what, if any, heterogeneity exists in psychosis biotypes.

According to the results, diagnoses made with the clinical DSM guidelines yielded a single-severity continuum showing schizophrenia to be the most severe, followed by schizoaffective disorder and bipolar psychosis. However, biotypes showed significant variation, with investigators noting that “the three biotypes had distinctive patterns of abnormality across biomarkers that were neither entirely nor efficiently captured by a severity continuum.”

Larger separations were seen in biotype cohorts than in the DSM, specifically among probands. Among probands, group separation from healthy subjects was –2.58, –1.94, and –0.35 for biotype 1, 2, and 3 respectively for the BACS. Separation was –0.99, –0.78, and –0.05 for the stop signal task, and 3.32, 1.90, and 1.19 for the antisaccade errors. On the other hand, DSM diagnostics revealed group differences of –1.01, –1.51, and –1.83 for bipolar disorder psychosis, schizoaffective disorders, and schizophrenia, respectively, for the BACS test. Separation was –0.41, –0.61, and –0.55 for the stop signal task, and 1.36, 1.66, and 2.45 for antisaccade errors.

“Each biotype included all DSM psychosis categories, but probands diagnosed with schizophrenia were more numerous in biotype 1 (although 20% had bipolar disorder with psychosis), and probands diagnosed with bipolar disorder with psychosis were more numerous in biotype 3 (although 32% had schizophrenia), respectively,” the investigators noted.

The authors added that “when considered across proband and relative data, the biotype subgroups were superior to DSM diagnostic classes in between-group separations on external validating measures, illustrating the former scheme’s superiority for capturing neurobiological distinctiveness.”

Investigators noted that their approach did not use social functioning, brain structure, and characteristics of biological relatives in the creation of biotypes, which could have led to stronger results. Also, trial participants were mostly already on medication, classified as chronically psychotic, and tested at least once previously. The trial also had no replication sample for this sample population.

The study was supported by grants from the National Institute of Mental Health. Dr. Clementz did not report any relevant financial disclosures. Dr. Matcheri S. Keshavan reported receiving a grant from Sunovion and serving as a consultant to Forum Pharmaceuticals. Dr. Carol A. Tamminga also reported potential conflicts.

[email protected]

Three biotypes surpass traditional diagnostic categories when it comes to identifying subgroups of psychosis, a study showed.

“Classification and treatment of brain diseases subsumed by psychiatry rely on clinical phenomenology, despite the call for alternatives,” wrote Brett A. Clementz, Ph.D., of the University of Georgia, Athens, and his coinvestigators. “There is overlap in susceptibility genes and phenotypes across bipolar disorder with psychosis and schizophrenia, and considerable similarity between different psychotic disorders on symptoms, illness course, cognition, psychophysiology, and neurobiology [while] drug treatments for these conditions overlap extensively” (Am J Psychiatry. 2015. doi: 10.1176/appi.ajp.2015.14091200).

The researchers recruited 711 people from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium sites (probands). All subjects had diagnoses of schizophrenia, schizoaffective disorder, or bipolar disorder with psychosis, and underwent interviews and laboratory data collection at the time of enrollment. In addition, 883 first-degree relatives of the 711 initial enrollees also were clinically evaluated, along with a cohort of 278 people deemed “demographically comparable [and] healthy” by investigators.

Biotypes for all individuals enrolled in the study were determined through laboratory tasks designed to “assess brain function at the neurocogntive/perceptual level.” These tasks consisted of the Brief Assessment of Cognition in Schizophrenia (BACS), pro- and antisaccade tasks, stop signal tasks, auditory paired stimuli and oddball evoked brain responses, and MRI acquisition and voxel-based morphometry.

The Structured Clinical Interview for DSM-IV and the Structured Interview for DSM-IV Personality Disorders were used for interviewing enrollees. Data compiled from these tests underwent multivariate taxometric analyses to compare biomarker variance across the three cohorts, in order to determine what, if any, heterogeneity exists in psychosis biotypes.

According to the results, diagnoses made with the clinical DSM guidelines yielded a single-severity continuum showing schizophrenia to be the most severe, followed by schizoaffective disorder and bipolar psychosis. However, biotypes showed significant variation, with investigators noting that “the three biotypes had distinctive patterns of abnormality across biomarkers that were neither entirely nor efficiently captured by a severity continuum.”

Larger separations were seen in biotype cohorts than in the DSM, specifically among probands. Among probands, group separation from healthy subjects was –2.58, –1.94, and –0.35 for biotype 1, 2, and 3 respectively for the BACS. Separation was –0.99, –0.78, and –0.05 for the stop signal task, and 3.32, 1.90, and 1.19 for the antisaccade errors. On the other hand, DSM diagnostics revealed group differences of –1.01, –1.51, and –1.83 for bipolar disorder psychosis, schizoaffective disorders, and schizophrenia, respectively, for the BACS test. Separation was –0.41, –0.61, and –0.55 for the stop signal task, and 1.36, 1.66, and 2.45 for antisaccade errors.

“Each biotype included all DSM psychosis categories, but probands diagnosed with schizophrenia were more numerous in biotype 1 (although 20% had bipolar disorder with psychosis), and probands diagnosed with bipolar disorder with psychosis were more numerous in biotype 3 (although 32% had schizophrenia), respectively,” the investigators noted.

The authors added that “when considered across proband and relative data, the biotype subgroups were superior to DSM diagnostic classes in between-group separations on external validating measures, illustrating the former scheme’s superiority for capturing neurobiological distinctiveness.”

Investigators noted that their approach did not use social functioning, brain structure, and characteristics of biological relatives in the creation of biotypes, which could have led to stronger results. Also, trial participants were mostly already on medication, classified as chronically psychotic, and tested at least once previously. The trial also had no replication sample for this sample population.

The study was supported by grants from the National Institute of Mental Health. Dr. Clementz did not report any relevant financial disclosures. Dr. Matcheri S. Keshavan reported receiving a grant from Sunovion and serving as a consultant to Forum Pharmaceuticals. Dr. Carol A. Tamminga also reported potential conflicts.

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

Unaffected first-degree relatives of bipolar disorder patients show no differences in gray-matter volume compared with other healthy adults, Dr. Fabiano G. Nery of the University of São Paulo and colleagues reported.

Investigators took magnetic resonance images of the brains of 25 patients with bipolar disorder, 23 unaffected relatives, and 27 healthy controls recruited from outpatient facilities at the university and the local community. The total gray-matter volume from images was 646.64 mL plus or minus 71.87 among bipolar disorder patients, 645.97 mL plus or minus 48.20 in unaffected relatives, and 637.87 mL plus or minus 62.50 in healthy controls, indicating no significant differences. Bipolar disorder patients, however, had reduced gray-matter volumes in the bilateral thalamus, compared with healthy controls.

This finding was present after controlling for possible confounding effects of age and gender, suggesting that the thalamus “may be involved in the neurocircuitry responsible for the clinical manifestations of” bipolar disorder, they wrote.

“These results suggest that there is no structural endophenotype for [bipolar disorder] and support the role of the thalamus in the pathophysiology of” bipolar disorder, the authors noted.

Read the article in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.09.005).

Unaffected first-degree relatives of bipolar disorder patients show no differences in gray-matter volume compared with other healthy adults, Dr. Fabiano G. Nery of the University of São Paulo and colleagues reported.

Investigators took magnetic resonance images of the brains of 25 patients with bipolar disorder, 23 unaffected relatives, and 27 healthy controls recruited from outpatient facilities at the university and the local community. The total gray-matter volume from images was 646.64 mL plus or minus 71.87 among bipolar disorder patients, 645.97 mL plus or minus 48.20 in unaffected relatives, and 637.87 mL plus or minus 62.50 in healthy controls, indicating no significant differences. Bipolar disorder patients, however, had reduced gray-matter volumes in the bilateral thalamus, compared with healthy controls.

This finding was present after controlling for possible confounding effects of age and gender, suggesting that the thalamus “may be involved in the neurocircuitry responsible for the clinical manifestations of” bipolar disorder, they wrote.

“These results suggest that there is no structural endophenotype for [bipolar disorder] and support the role of the thalamus in the pathophysiology of” bipolar disorder, the authors noted.

Read the article in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.09.005).

Unaffected first-degree relatives of bipolar disorder patients show no differences in gray-matter volume compared with other healthy adults, Dr. Fabiano G. Nery of the University of São Paulo and colleagues reported.

Investigators took magnetic resonance images of the brains of 25 patients with bipolar disorder, 23 unaffected relatives, and 27 healthy controls recruited from outpatient facilities at the university and the local community. The total gray-matter volume from images was 646.64 mL plus or minus 71.87 among bipolar disorder patients, 645.97 mL plus or minus 48.20 in unaffected relatives, and 637.87 mL plus or minus 62.50 in healthy controls, indicating no significant differences. Bipolar disorder patients, however, had reduced gray-matter volumes in the bilateral thalamus, compared with healthy controls.

This finding was present after controlling for possible confounding effects of age and gender, suggesting that the thalamus “may be involved in the neurocircuitry responsible for the clinical manifestations of” bipolar disorder, they wrote.

“These results suggest that there is no structural endophenotype for [bipolar disorder] and support the role of the thalamus in the pathophysiology of” bipolar disorder, the authors noted.

Read the article in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.09.005).

Cerebellar soft signs are common symptoms in schizophrenia and bipolar disorder, a study suggests.

“While many authors used [neurological soft signs] scales to measure severity and progression of [schizophrenia ] and [bipolar disorder], we propose [cerebellar soft signs] scale as an accurate measure of cerebellar signs, which seems to co-occur in both diseases,” Adrian Andrzej Chrobak and his colleagues wrote.

The study included 30 patients with bipolar disorder, 30 patients with schizophrenia, and 28 individuals who had not been diagnosed with either bipolar or schizophrenia. The criteria for schizophrenia and bipolar disorder patient participation in the study included being in a state of symptomatic remission, as defined as scoring less than 3 on the Positive and Negative Syndrome Scale, and being treated with antipsychotic drugs from the dibenzoxazepine class (clozapine, quetiapine, and olanzapine). Schizophrenia and bipolar disorder patients treated with lithium or who had a history of alcohol or drug abuse; severe, acute or chronic neurologic and somatic diseases; and severe personality disorders were not allowed to participate in the study.

The researchers used the Neurological Evaluation Scale (NES) and the International Cooperative Ataxia Rating Scale (ICARS) to determine the presence and severity of neurological soft signs and cerebellar soft signs, respectively, in all of the study participants.

The average ICARS scores for the schizophrenia and groups were significantly higher than the mean ICARS score of the control group. No significant differences were found between the schizophrenia group and bipolar disorder group’s total ICARS and ICARS subscales scores. While the schizophrenia group scored significantly higher in all ICARS subscales than the control group, the bipolar disorder group only scored significantly higher than controls in the ICARS subscales of posture, gait disturbances, and oculomotor disorders.

The NES scores for the schizophrenia and bipolar groups also were significantly higher than that of the control group. No statistically significant differences between the schizophrenia group and bipolar group’s total NES and NES subscales were found.

“Our results suggest that there is no significant difference in both [neurological soft signs] and [cerebellar soft signs] scores between [bipolar disorder] and [schizophrenia] groups. This stays in tune with the theory of schizophrenia-bipolar disorder boundary and points to [the] cerebellum as a possible target for further research in this field,” according to the researchers.

Read the full study in Progress in Neuro-Psychopharmacology & Biological Psychiatry (doi: 10.1016/j.pnpbp.2015.07.009).

[email protected]

Cerebellar soft signs are common symptoms in schizophrenia and bipolar disorder, a study suggests.

“While many authors used [neurological soft signs] scales to measure severity and progression of [schizophrenia ] and [bipolar disorder], we propose [cerebellar soft signs] scale as an accurate measure of cerebellar signs, which seems to co-occur in both diseases,” Adrian Andrzej Chrobak and his colleagues wrote.

The study included 30 patients with bipolar disorder, 30 patients with schizophrenia, and 28 individuals who had not been diagnosed with either bipolar or schizophrenia. The criteria for schizophrenia and bipolar disorder patient participation in the study included being in a state of symptomatic remission, as defined as scoring less than 3 on the Positive and Negative Syndrome Scale, and being treated with antipsychotic drugs from the dibenzoxazepine class (clozapine, quetiapine, and olanzapine). Schizophrenia and bipolar disorder patients treated with lithium or who had a history of alcohol or drug abuse; severe, acute or chronic neurologic and somatic diseases; and severe personality disorders were not allowed to participate in the study.

The researchers used the Neurological Evaluation Scale (NES) and the International Cooperative Ataxia Rating Scale (ICARS) to determine the presence and severity of neurological soft signs and cerebellar soft signs, respectively, in all of the study participants.

The average ICARS scores for the schizophrenia and groups were significantly higher than the mean ICARS score of the control group. No significant differences were found between the schizophrenia group and bipolar disorder group’s total ICARS and ICARS subscales scores. While the schizophrenia group scored significantly higher in all ICARS subscales than the control group, the bipolar disorder group only scored significantly higher than controls in the ICARS subscales of posture, gait disturbances, and oculomotor disorders.

The NES scores for the schizophrenia and bipolar groups also were significantly higher than that of the control group. No statistically significant differences between the schizophrenia group and bipolar group’s total NES and NES subscales were found.

“Our results suggest that there is no significant difference in both [neurological soft signs] and [cerebellar soft signs] scores between [bipolar disorder] and [schizophrenia] groups. This stays in tune with the theory of schizophrenia-bipolar disorder boundary and points to [the] cerebellum as a possible target for further research in this field,” according to the researchers.

Read the full study in Progress in Neuro-Psychopharmacology & Biological Psychiatry (doi: 10.1016/j.pnpbp.2015.07.009).

[email protected]

Cerebellar soft signs are common symptoms in schizophrenia and bipolar disorder, a study suggests.

“While many authors used [neurological soft signs] scales to measure severity and progression of [schizophrenia ] and [bipolar disorder], we propose [cerebellar soft signs] scale as an accurate measure of cerebellar signs, which seems to co-occur in both diseases,” Adrian Andrzej Chrobak and his colleagues wrote.

The study included 30 patients with bipolar disorder, 30 patients with schizophrenia, and 28 individuals who had not been diagnosed with either bipolar or schizophrenia. The criteria for schizophrenia and bipolar disorder patient participation in the study included being in a state of symptomatic remission, as defined as scoring less than 3 on the Positive and Negative Syndrome Scale, and being treated with antipsychotic drugs from the dibenzoxazepine class (clozapine, quetiapine, and olanzapine). Schizophrenia and bipolar disorder patients treated with lithium or who had a history of alcohol or drug abuse; severe, acute or chronic neurologic and somatic diseases; and severe personality disorders were not allowed to participate in the study.

The researchers used the Neurological Evaluation Scale (NES) and the International Cooperative Ataxia Rating Scale (ICARS) to determine the presence and severity of neurological soft signs and cerebellar soft signs, respectively, in all of the study participants.

The average ICARS scores for the schizophrenia and groups were significantly higher than the mean ICARS score of the control group. No significant differences were found between the schizophrenia group and bipolar disorder group’s total ICARS and ICARS subscales scores. While the schizophrenia group scored significantly higher in all ICARS subscales than the control group, the bipolar disorder group only scored significantly higher than controls in the ICARS subscales of posture, gait disturbances, and oculomotor disorders.

The NES scores for the schizophrenia and bipolar groups also were significantly higher than that of the control group. No statistically significant differences between the schizophrenia group and bipolar group’s total NES and NES subscales were found.

“Our results suggest that there is no significant difference in both [neurological soft signs] and [cerebellar soft signs] scores between [bipolar disorder] and [schizophrenia] groups. This stays in tune with the theory of schizophrenia-bipolar disorder boundary and points to [the] cerebellum as a possible target for further research in this field,” according to the researchers.

Read the full study in Progress in Neuro-Psychopharmacology & Biological Psychiatry (doi: 10.1016/j.pnpbp.2015.07.009).

[email protected]

The prevalence of bipolar disorder might be higher among rheumatoid arthritis patients than in the general population, Dr. Adir Farhi of Sheba Medical Center in Tel-Hashomer, Israel, and colleagues reported in the Journal of Affective Disorders.

In a case-control study of nearly 70,000 members of Clalit Health Services, the largest health maintenance organization in Israel, the prevalence of bipolar disorder was found to be greater in patients with rheumatoid arthritis (RA) than in case-matched controls (0.6% vs 0.4%; odds ratio, 1.34; 95% confidence interval, 1.02-1.76; P less than .05). The study included 11,782 patients with RA and 57,973 subjects matched by age and sex.

When stratified by age, the association was significant only in the two extreme age groups: age younger than 19 years (P less than .005) and age older than 75 years (P less than .005). However, in a logistic regression model, RA showed a trend for positive association with bipolar disorder that was not statistically significant, and age had a weak but statistically significant association. Smoking was positively and independently associated with bipolar disorder (multivariate OR, 1.66; 95% CI, 1.31-2.11; P less than .001).

“Our data implied that patients with RA have a greater prevalence of bipolar disorder than matched controls,” the authors wrote. But because the association may have been confounded by smoking status, “further research is warranted before making inferences about this association.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10/1016/j.jad.2015.09.058).

The prevalence of bipolar disorder might be higher among rheumatoid arthritis patients than in the general population, Dr. Adir Farhi of Sheba Medical Center in Tel-Hashomer, Israel, and colleagues reported in the Journal of Affective Disorders.

In a case-control study of nearly 70,000 members of Clalit Health Services, the largest health maintenance organization in Israel, the prevalence of bipolar disorder was found to be greater in patients with rheumatoid arthritis (RA) than in case-matched controls (0.6% vs 0.4%; odds ratio, 1.34; 95% confidence interval, 1.02-1.76; P less than .05). The study included 11,782 patients with RA and 57,973 subjects matched by age and sex.

When stratified by age, the association was significant only in the two extreme age groups: age younger than 19 years (P less than .005) and age older than 75 years (P less than .005). However, in a logistic regression model, RA showed a trend for positive association with bipolar disorder that was not statistically significant, and age had a weak but statistically significant association. Smoking was positively and independently associated with bipolar disorder (multivariate OR, 1.66; 95% CI, 1.31-2.11; P less than .001).

“Our data implied that patients with RA have a greater prevalence of bipolar disorder than matched controls,” the authors wrote. But because the association may have been confounded by smoking status, “further research is warranted before making inferences about this association.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10/1016/j.jad.2015.09.058).

The prevalence of bipolar disorder might be higher among rheumatoid arthritis patients than in the general population, Dr. Adir Farhi of Sheba Medical Center in Tel-Hashomer, Israel, and colleagues reported in the Journal of Affective Disorders.

In a case-control study of nearly 70,000 members of Clalit Health Services, the largest health maintenance organization in Israel, the prevalence of bipolar disorder was found to be greater in patients with rheumatoid arthritis (RA) than in case-matched controls (0.6% vs 0.4%; odds ratio, 1.34; 95% confidence interval, 1.02-1.76; P less than .05). The study included 11,782 patients with RA and 57,973 subjects matched by age and sex.

When stratified by age, the association was significant only in the two extreme age groups: age younger than 19 years (P less than .005) and age older than 75 years (P less than .005). However, in a logistic regression model, RA showed a trend for positive association with bipolar disorder that was not statistically significant, and age had a weak but statistically significant association. Smoking was positively and independently associated with bipolar disorder (multivariate OR, 1.66; 95% CI, 1.31-2.11; P less than .001).

“Our data implied that patients with RA have a greater prevalence of bipolar disorder than matched controls,” the authors wrote. But because the association may have been confounded by smoking status, “further research is warranted before making inferences about this association.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10/1016/j.jad.2015.09.058).