This interview took place on September 24, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Perkins is a consultant to Dainippon Sumitomo Pharma Co., Ltd; is on the speaker’s bureaus of AstraZeneca and Eli Lilly; and receives grant support from Janssen.


 

Dr. Perkins is professor of psychiatry in the Department of Psychiatry at the University of North Carolina (UNC) School of Medicine in Chapel Hill. She is medical director of Outreach and Support Intervention Services at UNC Hospitals and the UNC-Chapel Hill School of Medicine. Dr. Perkins’ research emphasizes treatment of the prodromal period and early intervention of the first episode of schizophrenia. Currently investigating pharmacologic and psychotherapeutic treatments for psychosis, she focuses on managing side effects of atypical antipsychotics and the weight gain mechanism in patients taking psychotropic medications. In addition, Dr. Perkins is investigating the genetic basis of schizophrenia.

 

How has the pathogenesis of schizophrenia evolved in the last century?

It is known that both gene and environment contribute to schizophrenia risk. For example. when an identical twin has schizophrenia, his or her counterpart has a 50% chance of having schizophrenia as well.1 This compares to the population risk of .01%. It is also likely that genetic or environmental risk factors act by changing when and how much protein is made.2

In addition, some forms of schizophrenia are likely neurodevelopmental disorders, meaning that the brains of some people who developed schizophrenia may have developed differently from those unaffected with schizophrenia. It may also be that an environmental event is needed to trigger the disorder in an at-risk person.3 There is also strong evidence that neurocircuits involving the front of the brain, especially the prefrontal cortex, are involved in schizophrenia. Much work needs to be conducted, however, to determine the underlying causes of schizophrenia.

It has been found that schizophrenia is a heterogeneous disorder similar to pneumonia; it is likely that there are hundreds of independent causes to schizophrenia. Such heterogeneity makes it challenging to further decipher the pathogenesis of schizophrenia.

How do parents influence their children having schizophrenia?

One epidemiologic finding is that schizophrenia risk is associated with higher paternal age at the time of conception.  We do not know the reason for this association, but I could speculate that perhaps it is because men make sperm throughout their life, and as they age genetic mistakes may accumulate in the germ line, including variations in the number of copies of genomic regions as well as point mutations. New evidence suggests that the genetic risk of schizophrenia may be due to de novo mutations in the patient.4,5 This may explain why approximately 70% of people who develop schizophrenia do not have a relative with the disorder.6

Is there anything specific about viruses implicated in early development that might be associated with schizophrenia?

There is a wealth of epidemiologic research showing increased risk in individuals who had certain prenatal environmental exposures. An example is maternal starvation where the risk of schizophrenia in offspring doubles.7 While data show most people whose mothers starved did not develop schizophrenia, there is still a small group that may have a biologic vulnerability. Some leading hypotheses suggest it is micro nutrium, meaning some critical nutrients (eg, vitamins D or B) were not received in utero. The second epidemiologic observation involves the fetus’ exposure to an infectious disease process in utero. As a result of this exposure, risk of schizophrenia in adulthood increases by 2–3 fold. Research on that relationship has tried to determine whether it is brain infection with the virus or the maternal immune response that affects brain development, increasing later risk of schizophrenia. Numerous animal models point to the immune maternal response. For example, if there is an infection or something provoking the maternal immune response, then antibodies, cytokines, or other aspects of the immune system response cross the placenta, enter the fetus, and affect brain development. Epidemiologic studies also find that maternal exposure to a traumatic event during pregnancy is associated with an increased risk of schizophrenia. One mechanistic theory involves stress hormones affecting brain development in utero, making a person vulnerable to schizophrenia in adulthood.

There have been studies investigating viral exposures in childhood  and later risk of schizophrenia. For example,  one recent population-based epidemiologic study8 found that childhood cytomegalovirus in the central nervous system was associated with a 16-fold increase in schizophrenia risk.

Is there a connection with gene expression?

One percent of a genome codes for a protein. Until recently, the remaining 99% was considered “junk deoxyribonucleic acid (DNA).” There was no explanation for its function; junk DNA was considered an evolutionary relic. However, in the past 5 years, it has been found that ≥50% of DNA is transcribed into ribonucleic acid (RNA), but this RNA is not translated into protein. Instead, this RNA regulates when and how much of the protein-coding genes are expressed. Numerous post-mortem studies of schizophrenia find altered levels of specific RNAs or proteins, suggesting that some process regulating the expression of a protein is impaired. There is no firm evidence of what regulatory processes might be altered, but research is now focusing on the variety of factors that impact protein expression.

Is there evidence that antipsychotics used earlier are neuroprotective?

Eighty-five percent of patients with schizophrenia will report prodromal symptoms; for example, they may report having weird ideas, illusions, or transient hallucinations (eg, hearing clicking noises, someone calling their name when no one was around). In the prodromal stage of psychosis, people may also complain of increased distractability, problems in school, and social problems. Researchers have been looking at the kinds of symptoms that can help distinguish people at highest increased vulnerability to schizophrenia. The best predictors of psychosis risk appear to be altered thought process (eg, ideas of reference) and abnormal perceptions (eg, illusions or brief hallucinations) that also interfere with social or vocational function.

Current estimates are that approximately 35% to 40% of people experiencing these “clinical high-risk” symptoms will develop a psychotic disorder within 2 years.9 Note that most people who are experiencing these “psychosis-like” symptoms do not go on to develop a psychotic disorder. Some (approximately 20%) will remit; here the symptoms may have been the result of a rough time or a glitch in adolescent brain development that self-corrected. Other times the person was experiencing early symptoms of anxiety disorders, depression, or a personality disorder, but not schizophrenia.

There is great interest in improving the ability to predict risk. One factor that has emerged is functional impairment. The more severe the symptoms, the more they significantly interfere with function. Environmental factors, such as marijuana use or severe stress may further increase psychosis vulnerability. However, more research is required to appropriately identify symptoms before prevention is possible. Studies10-12 examined people experiencing prodromal symptoms who have investigated an antipsychotic, an antipsychotic plus psychotherapy, or psychotherapy alone. In these studies, all interventions were equally successful in preventing psychosis, meaning both pharmacologic and psychotherapeutic interventions could benefit patients.

When the clinician is faced with an adolescent or young adult having clinical high risk symptoms and also struggling in school, treatment decisions are complicated by the fact that most (>50%) will not develop a psychotic illness. While preventative antipsychotic treatment may benefit the approximately 40% who are truly in the earliest stages of illness, antipsychotics are not appropriate for the other 60% of patients. These patients would be unnecessarily exposed to the risks of antipsychotics, such as metabolic or neurologic side effects. In addition, the clinical trials find that patients who are clinically at risk for psychosis are only protected from psychosis while they are taking the antipsychotic. When the antipsychotic is discontinued, the patients continue to be at high risk, and eventually 35% to 40% will develop a psychotic disorder. I think treating clinical high-risk symptoms with an antipsychotic is premature and should only be used when a patient is suffering severe functional impairment. Psychotherapy, however, is a relatively benign and effective treatment. Clinicians should consider some form of psychotherapy, especially a cognitive-behavioral type to help people cope with symptoms, manage stress, and deal with life issues conducive to stress.

Do atypical antipsychotics cause less risk of tardive dyskinesia than the older treatments?

Despite the ongoing debate on this issue, I think they do. In the early part of my career, only typical antipsychotics were available. Tardive dyskinesia was not at all unusual. In my clinical practice tardive dyskinesia is unusual.  Many medical or nursing students rotating through inpatient and outpatient settings will not see a single case of tardive dyskinesia.

Studies on tardive dyskinesia risk are difficult to conduct. Unmedicated people with schizophrenia will develop dyskinetic movements that are indistinguishable from tardive dyskinesia. While dyskinetic movements are not necessarily caused by antipsychotics, there is clear evidence showing antipsychotics increase the risk of developing those movements. In order to understand the difference between the two treatments, patients may have to be followed for several years. Unfortunately, studies of that length are almost impossible to conduct. The reinterpretation of short-term clinical studies suggest that tardive dyskinesia happens less often  with patients treated with atypical antipsychotics. Tardive dyskinesia can certainly emerge in people treated with atypical antipsychotics, but it appears less likely than in patients treated with typical antipsychotics.

Why do antipsychotics tend to cause weight gain and metabolic syndrome?

These adverse effects are seen mostly with newer antipsychotics. For example, patients taking quetiapine, olanzapine, or risperidone have increased risk of weight gain while aripiprazole or ziprasidone might not cause weight gain (at least in adults). In children, there is some increased risk of weight gain and metabolic syndrome with ziprasidone.

There are three possible mechanisms that could explain weight gain and metabolic syndrome in antipsychotic treatment patients. First, the patient’s appetite might increase once starting the antipsychotic. Second, patients using sedative drugs experience increased sleep time, resulting in a decrease in the amount of calories spent in a 24-hour period. Decreased activity is conducive to weight gain. Third, there may be changes in metabolism—for example, how readily a person may tap into fat stores.

I advise patients to exercise regularly and go on a low carbohydrate diet such as the American Diabetic Association diet or the Atkins diet. I have had patients who were able to follow that kind of diet and lose weight associated with antipsychotics. However, weight loss and behavioral change is a difficult task to accomplish, even for people who have schizophrenia. In addition to lifestyle changes, there is emerging evidence from clinical trials13 that metformin may attenuate or even reverse antipsychotic-related weight gain. In addition, there are clinical trials13 suggesting similar benefits from topirimate and amantadine.

Are there developing treatments that may benefit people who are not being treated effectively?

We are learning more about how to best use available treatments. Most clinical trials with antipsychotics were conducted by pharmaceutical industries. As the studies are highly regulated, the data are valid. However, the problem with industry-sponsored studies is that they are initially designed in favor of the company’s drugs. For example, if there is a drug that could cause weight gain, the researchers might not weigh people in the study. There is a fundamental problem with depending on the people who may profit from the drug conducting all of the studies with that drug.

The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study14 involved the atypical antipsychotics that were FDA approved at the time, namely risperidone, quetiapine, and olanzapine. Ziprasidone was added once it was approved by the Food and Drug Administration. Perphenazine was chosen as a typical antipsychotic comparator because the researchers wanted a drug that was unfamiliar and not used. The outcome measure in the CATIE study was all-cause treatment discontinuation. This was picked because it was thought to reflect both clinicians’ and patients’ judgment on how well a medication was working. If a patient experiences enough benefit from a medication and the side effects are not too troublesome, he or she is willing to continue using it. However, if the benefits seem negligible or the side effects are too much relative to the benefit, the patient will stop taking that medication. This was a novel outcome measure that is still somewhat controversial, but it was chosen as a measure of overall effectiveness. The study was large; it randomized 1,400 patients from the United States. Unlike most pharmaceutical industry studies, the CATIE study did not restrict inclusion to those patients who are very healthy, who do not use street drugs, and/or who do not require treatment with other medications, making the findings generalizable to routine clinical practice.

Overall, the study found that 74% of patients discontinued treatment prior to the end of the 18-month study. The time to discontinuation was significantly longer for olanzapine compared to risperidone and quetiapine, and was longer at a trend level compared to perphenazine- and ziprasidone-treated patients. However, olanzapine-treated patients were more likely to gain weight and have lipid abnormalities, so that the improved effectiveness came at the price of more severe side effects. One of the surprising findings of the CATIE study was how well the typical antipsychotic perphenzine peformed compared to the other antipsychotics, especially since other studies had shown that other typical antipsychotics, like haloperidol and chlorpromazine, were not as efficacious as the atypical antipsychotics. Perphenazine prescribing has increased since the publication of the CATIE study.

 What can also be concluded from the CATIE study is that none of the study drugs are optimal, and that treatment discontinuation rates overall are very high. There are now efforts to develop better strategies to improve medication treatment adherence, both with schizophrenia as well as other chronic diseases. Only approximately 50% of patients being treated for chronic illness are compliant with that treatment by 1 year,15 and the reasons for poor adherence are similar in schizophrenia and other chronic disease. We know that there will be a low rate of treatment adherence if a clinician simply writes a prescription and hands that prescription to the patient. A different kind of therapeutic model is needed.

There is growing evidence of a “concordance” model of care, where the patient’s experience of the illness and how treatment affects his or her life is taken into consideration. The clinician may engage in a negotiation with the patient until both agree with the treatment plan. However, it is important to note that even the best-intended patient will likely have difficulties in complying long term. It is difficult to remember to take a medication every day. To be successful, patients usually need to actively work on medication adherence, and the clinician can help. For example, the clinician can keep the medication regimin as simple as possible and also encourage the use of “cognitive adaptive strategies,” where patients develop environmental cues, like pill boxes or alarms to help with adherence.16 The lessons from the CATIE study reveal more than just the need for a new drug. Better ways to use available medication and optimize treatment are needed as well.

There may be breakthrough drugs on the horizon, however. There is a recent clinical trial of a drug that is a selective agonist at certain glutamate receptors (mGluR2 and mGluR3), but that does not affect dopamine receptors. The first published clinical trial17 is promising, and this new drug, at this point called “LY2140023,” may open up a new strategy for treating schizophrenia. Other promising areas include drugs targeting nicotinic receptors. PP

References

1.    Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait—evidence from a meta-analysis of twin studies. Arch Gen Psych. 2003;60(12):1187-1192.
2.    Perkins et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27.
3.    Lewis DA, González-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008;33(1):141-165.
4.    Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455(7210):232-236.
5.    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237-241.
6.    Mortensen PB, Pedersen CB, Westergaard T, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340(8):603-608.
7.    Penner JD, Brown AS. Prenatal infectious and nutritional factors and risk of adult schizophrenia. Expert Rev Neurother. 2007;7(7):797-805.
8.    Dalman C, Allebeck P, Gunnell D, et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008;165(1):59-65.
9.    Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65(1):28-37.
10.    Morrison AP, French P, Parker S, et al. Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk. Schizophr Bull. 2007;33(3):682-687.
11.    Phillips LJ, McGorry PD, Yuen HP, et al. Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis. Schizophr Res. 2007;96(1-3):25-33.
12.    McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-799.
13.    Baptista T, ElFakih Y, Uzcátegui E, et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs. 2008;22(6):477-495.
14.    Lieberman JA, Stroup TS, McEvoy JP, al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
15.    Adherence to Long Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
16.    Velligan DI, Diamond PM, Mintz J, et al. The use of individually tailored environmental supports to improve medication adherence and outcomes in schizophrenia. Schizophr Bull. 2008;34(3):483-493.
17. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13(9):1102-1107.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

This column continues a series reviewing the interface between dermatology and psychiatry. Dermatologists and primary care physicians frequently encounter important psychiatric issues affecting diagnosis and management of patients with dermatologic complaints. Psychological factors affect many dermatologic conditions, including atopic dermatitis, psoriasis, alopecia areata, urticaria and angioedema, and acne vulgaris. Some dermatologic conditions are best considered as idiopathic functional disorders, such as idiopathic pruritus, which can be generalized or focal (eg, pruritus ani, vulvae, and scroti). Some primary psychiatric disorders present with primarily physical symptoms to dermatologists, including body dysmorphic disorder (BDD) and delusional disorder, somatic type (eg, delusions of parasitosis, delusions of a foul body odor). Indeed, most patients with delusions of parasitosis or BDD avoid seeing psychiatrists or other mental health professionals, and resist referral. Dermatologists also see patients with compulsive behaviors that may be part of obsessive-compulsive disorder, or that stand alone, eg, trichotillomania, psychogenic excoriation, and onychophagia. Factitious skin disorders include factitious dermatitis (also called dermatitis artefacta) and psychogenic purpura. Another important aspect of the interface between psychiatry and dermatology is the range of dermatologic adverse reactions to psychotropic drugs. More detailed coverage of these topics can be found elsewhere.1,2 The first part of the series focused on atopic dermatitis and psoriasis,3 and the second reviewed alopecia areata, urticaria, and angioedema.4 This third installment reviews acne vulgaris and chronic idiopathic pruritus.

Acne Vulgaris

Acne vulgaris, a common skin disease affecting sebaceous glands with sebum blocking hair follicles, is characterized by a variety of lesions, including comedones, inflammatory papules, pustules, and nodules. The face and upper neck are the most common sites, but the chest, back, and shoulders may also be involved. Most cases of acne vulgaris develop in early adolescence, affecting 85% of teenagers, and it frequently continues into adulthood. During adolescence, the frequency of acne increases with age and pubertal development. In girls, the commencement of menstruation is associated with increased frequency of acne. Perhaps this explains why adolescent girls may be more vulnerable than boys to the negative psychological effects of acne.5 The course of acne vulgaris is usually self-limited, with gradual improvement and spontaneous disappearance after several years, but it may persist into the thirties and forties. Possible complications include development of pitted or hypertrophic scars as well as psychological adverse effects, discussed below. Although women are more likely than men to have persistent acne, it tends to be more severe in men.1,2

Although the cause of acne vulgaris is unknown, many factors are probably involved in its pathogenesis, including genetics, inflammation, skin flora, hormonal activity, and stress. The relationship with stress has long been observed, but there are few prospective studies. One study6 reported that patients with acne may experience worsening of the disease during academic examinations. While there is a significant association between psychological stress and severity of acne, it does not appear to be mediated by increased sebum production.7 A variety of neuroendocrine mediators may be involved in the precipitation or aggravation of acne by stress, including adrenal steroids, corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y, insulin-like growth factor, and calcitonin gene-related peptide.1,2,8 It has also been long recognized that lithium can cause or aggravate acne,9 and there have been case reports of acne resulting from aripiprazole,10 lamotrogine,11 valproate,12 and other anticonvulsants, as well as the atypical tricyclic antidepressant amineptine13 (not available in the United States).

Severe acne is associated with increased depression, anxiety, poor self-image, and poor self-esteem.1,2 Not surprisingly, psychiatric symptoms are more common in more severe acne and in the later stages of puberty.14 A cross-sectional study15 of approximately 10,000 teenagers in New Zealand found that “problem acne” was associated with an increased risk of depressive symptoms (odds ratio 2.04), anxiety (odds ratio 2.3), and suicide attempts (odds ratio 1.83). The association of acne with suicide attempts remained after controlling for depressive symptoms and anxiety (odds ratio 1.5). One study16 has estimated the incidence of suicidal ideation in patients with acne as 7.1%. However, psychiatric comorbidity may even occur with milder acne. A Turkish study17 found that patients with acne were at increased risk for anxiety and depression compared to the normal population, irrespective of the degree of severity.

Acne can substantially interfere with social and occupational functioning and result in impairment in quality of life (QOL). There are numerous available rating scales for quantifying QOL in patients with acne.18 Acne negatively affects quality of life, and there is not always a correlation between the severity of acne and its impact on QOL. The magnitude of anxiety and depression is proportional to degree of impairment of QOL due to acne.17 Acne patients with greater social sensitivity experience poorer QOL compared to other patients with the same severity of acne.19 Anger, similarly, is associated with poorer QOL and less satisfaction with treatment, independent of other variables.20

Successful treatment of acne with isotretinoin leads to reduction in anxiety and depression and significant improvement in self-image.1,2 However, patients’ perceptions of the results of treatment for acne can differ from their physician’s judgment, with more pessimistic self-assessment in those with emotional distress.21

Anecdotal reports of depression, suicidal ideation, suicide attempts, and suicide with the use of isotretinoin for treatment of acne vulgaris were widely reported in the media and led the US Food and Drug Administration to expand the label warning to include that “accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.”22 However, a recent systematic review23 of nine controlled trials found that rates of depression among isotretinoin users were similar to the rates in oral antibiotic control groups, ranging from 1% to 11%. Trials that compared depression before and after isotretinoin treatment did not show a statistically significant increase in depression symptoms or diagnoses. Some even found a trend toward reduction in depressive symptoms after isotretinoin therapy, particularly in patients with higher pretreatment depression scores. Similar reductions have been reported in uncontrolled trials.24 Another recent study25 in Canada using a retrospective case-crossover design found that, the relative risk for those exposed to isotretinoin of developing a depression diagnosis was 2.68 (95% CI=1.10–6.48), after adjusting for confounders. In contrast, another Canadian group26 recently reported a prospective controlled cohort study that concluded that isotretinoin does not appear to be associated with the development of depression. The literature to date has not proven a causative association between isotretinoin use and depression or suicidal behavior. Interpretation of the literature is complicated both by important methodologic limitations in many of the studies and by the association of acne itself with depression, anxiety, and possibly suicidal behavior.

The FDA and isotretinoin’s manufacturer subsequently added a warning regarding the possible development of aggressive and/or violent behavior to the psychiatric disorder warning section of the package insert previously focused on depression and suicidality. While there have been reports of several cases of manic psychosis in association with isotretinoin treatment,27 large population-based cohort studies have found no evidence that use of isotretinoin is associated with an increased risk for psychosis.28

One may ask how clinicians should proceed, given the FDA’s black box warning and the case reports suggesting an association between isotretinoin and depression and suicide, yet an overall lack of support for these associations in the more rigorous observational and epidemiologic studies. It is prudent to continue to prescribe isotretinoin to treat severe acne, while at the same time educating patients (and the parents of minor patients) of the importance of actively monitoring for depressive symptoms; if symptoms appear, referral to a psychiatrist and discontinuation of isotretinoin should be considered. In addition, patients should be cautioned not to self-medicate for depression with St. John’s Wort both because it is ineffective and because its metabolic interaction with hormonal contraceptives may reduce their effectiveness.

Numerous reports attest to the benefits of a wide variety of psychiatric and psychological treatments for acne, including paroxetine,29 olanzapine,30 relaxation techniques, hypnosis, cognitive-behavioral therapy, and biofeedback,31,32 but no controlled clinical trials except for one.33

Chronic Idiopathic Pruritus

Pruritus, or itchiness, is a common symptom of dermatologic diseases, several systemic diseases (eg, hepatic or renal failure, HIV), and advanced age,1,2 but the cause in chronic pruritus is often not identifiable. Such idiopathic pruritus is typically experienced on a daily basis, especially at night and in the evening, resulting in mostly having difficulty falling asleep. Generalized idiopathic pruritus mainly involves the legs, arms, and back. The most common focal presentations of idiopathic pruritus are pruritus ani, vulvae, and scroti. Idiopathic pruritus may be described as crawling, tickling, stinging, or burning.34,35 In one study,34 idiopathic pruritus patients described the itching as unbearable (73%), bothersome (72%), annoying (67%) and/or worrisome (45%). The pathophysiology of pruritus is not well understood, and it is unclear why it is worse at night.36 While psychiatric symptoms are common in idiopathic pruritus, and idiopathic pruritus is common in psychiatric patients, idiopathic pruritus should be considered as a functional disorder rather than a psychogenic one. New onset of unexplained pruritus should lead to evaluation for occult medical disease before considering it to be idiopathic pruritus.

Recent stressful life events, and degree of anxiety and/or depressive symptoms have been correlated with an increased ability to experience itching.1,2 In a study37 of 100 psychiatric inpatients, idiopathic pruritus was reported by 42% of the subjects, 34% of the men, and 58% of the women, with increased prevalence in those without adequate social support and in those without regular employment. It is not surprising that depression is common in patients with idiopathic pruritus, especially given the chronicity and sleep disturbance.38

For focal idiopathic pruritus (eg, pruritus ani, vulvae, and scroti), topical treatments are used. For both generalized and focal idiopathic pruritus, the most commonly prescribed oral medications are antihistamines, which usually provide some short-term relief. Tricyclic antidepressants, especially doxepin, can relieve chronic idiopathic pruritus. Paroxetine has also been reported to be helpful.39 Opiate receptor antagonists and anticonvulsants (gabapentin, pregabalin, carbamazepine) have also been suggested as possible remedies.40 Behavioral treatment, such as habit-reversal training and cognitive-behavioral therapy, may also be helpful in interrupting the itch-scratch cycle,1,2 and there is one case report of the benefits of hypnosis.41 PP

 

References

1. Arnold L. Dermatology. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:629-646.
2. Arnold L. Dermatology. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:629-646.
3. Levenson JL. Psychiatric issues in dermatology, part 1: atopic dermatitis and psoriasis. Primary Psychiatry. 2008;15(7):35-38.
4. Levenson JL. Psychiatric issues in dermatology, part 2: alopecia areata, urticaria and angioedema. Primary Psychiatry. 2008;15(9):31-34.
5. Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne vulgaris in adolescents. Int J Dermatol. 2000;39(5):354-357.
6. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol. 2003;139(7):897-900.
7. Yosipovitch G, Tang M, Dawn AG, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol. 2007;87(2):135-139.
8. Zouboulis CC, Böhm M. Neuroendocrine regulation of sebocytes—a pathogenetic link between stress and acne. Exp Dermatol. 2004;13(suppl 4):31-35.
9. Yeung CK, Chan HH. Cutaneous adverse effects of lithium: epidemiology and management. Am J Clin Dermatol. 2004;5(1):3-8.
10. Mishra B, Praharaj SK, Prakash R, Sinha VK. Aripiprazole-induced acneiform eruption. Gen Hosp Psychiatry. 2008;30(5):479-481
11. Nielsen JN, Licht RW, Fogh K. Two cases of acneiform eruption associated with lamotrigine. J Clin Psychiatry. 2004;65(12):1720-1722.
12. de Vries L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia. 2007;48(3):470-477.
13. De Gálvez Aranda MV, Sánchez PS, Alonso Corral MJ, Bosch García RJ, Gallardo MA, Herrera Ceballos E. Acneiform eruption caused by amineptine. A case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15(4):337-339.
14. Kilkenny M, Stathakis V, Hibbert ME, Patton G, Caust J, Bowes G. Acne in Victorian adolescents: associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health. 1997;33(5):430-433.
15. Purvis D, Robinson E, Merry S, Watson P. Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students. J Paediatr Child Health. 2006;42(12):793-796.
16. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54(3):420-426.
17. Yazici K, Baz K, Yazici AE, et al. Disease-specific quality of life is associated with anxiety and depression in patients with acne. J Eur Acad Dermatol Venereol. 2004;18(4):435-439.
18. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006;7(2):99-106.
19. Krejci-Manwaring J, Kerchner K, Feldman SR, Rapp DA, Rapp SR. Social sensitivity and acne: the role of personality in negative social consequences and quality of life. Int J Psychiatry Med. 2006;36(1):121-130.
20. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol. 2004;151(1):183-189.
21. Jones-Caballero M, Pedrosa E, Peñas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309-314.
22. FDA Approved Drug Products. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed September 24, 2008.
23. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2007;26(4):210-220.
24. Kaymak Y, Kalay M, Ilter N, Taner E. Incidence of depression related to isotretinoin treatment in 100 acne vulgaris patients. Psychol Rep. 2006;99(3):897-906.
25. Azoulay L, Blais L, Koren G, LeLorier J, Bérard A. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry. 2008;69(4):526-532.
26. Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol. 2007;14(2):e227-e233.
27. Barak Y, Wohl Y, Greenberg Y, et al. Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol. 2005;20(1):39-41. Erratum in: Int Clin Psychopharmacol. 2005;20(3):182.
28. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136(10):1231-1236.
29. Moussavian H. Improvement of acne in depressed patients treated with paroxetine. J Am Acad Child Adolesc Psychiatry. 2001;40(5):505-506.
30. Gupta MA, Gupta AK. Olanzapine may be an effective adjunctive therapy in the management of acne excoriée: a case report. J Cutan Med Surg. 2001;5(1):25-27.
31. Shenefelt PD. Using hypnosis to facilitate resolution of psychogenic excoriations in acne excoriée. Am J Clin Hypn. 2004;46(3):239-245.
32. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther. 2003;16(2):114-122.
33. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of acne vulgaris by biofeedback relaxation and cognitive imagery. J Psychosom Res. 1983;27(3):185-191.
34. T-J Goon A, Yosipovitch G, Chan YH, Goh CL. Clinical characteristics of generalized idiopathic pruritus in patients from a tertiary referral center in Singapore. Int J Dermatol. 2007;46(10):1023-1026.
35. Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147(1):32-36.
36. Patel T, Ishiuji Y, Yosipovitch G. Nocturnal itch: why do we itch at night? Acta Derm Venereol. 2007;87(4):295-298.
37. Kretzmer GE, Gelkopf M, Kretzmer G, Melamed Y. Idiopathic pruritus in psychiatric inpatients: an explorative study. Gen Hosp Psychiatry. 2008;30(4):344-348.
38. Sheehan-Dare RA, Henderson MJ, Cotterill JA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol. 1990;123(6):769-774.
39. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage. 2003;26(6):1105-1112.
40. Lynde CB, Kraft JN, Lynde CW. Novel agents for intractable itch. Skin Therapy Lett. 2008;13(1):6-9.
41. Rucklidge JJ, Saunders D. Hypnosis in a case of long-standing idiopathic itch. Psychosom Med. 1999;61(3):355-358.

 

Dr. Ying is director of New York University (NYU) Behavioral Health Programs and clinical assistant professor at NYU School of Medicine in New York City.

Disclosure: Dr. Ying reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the following unapproved medications for depression or bipolar disorder: aprepitant, ketamine, memantine, mifepristone, paliperidone, and riluzole.

Please direct all correspondence to: Patrick Ying, MD, Director, NYU Behavioral Health Programs, Clinical Assistant Professor, NYU School of Medicine, Faculty Practice Tower, 530 First Ave, #7D, New York, NY 10016; Tel: 212-774-1459; Fax: 212-263-7460; E-mail: yingp02@med.nyu.edu.


 

Focus Points

• In the last few years, the only medications approved for mood disorders are existing medications or derivatives of them.
• New medications for mood disorders rely on both the existing monoaminergic and novel mechanisms of action.
• Medications that work on tachykinins, glutamate, and the hypothalamic-pituitary-adrenal axis are being investigated.
• Newer mechanisms of action may allow for improved efficacy, tolerability, and speed of response.

 

Abstract

There remains a significant need for new treatments for mood disorders. In the last 2 years, only one new drug has been approved for the treatment of major depressive disorder, desvenlafaxine; during this time, the other medications approved for the treatment of depression or bipolar disorder have been atypical antipsychotics that have already been approved for the treatment of schizophrenia. There are, however, numerous medications in development for the treatment of mood disorders. Agomelatine is an agonist at melatonin (MT)1 and MT2 receptors and a serotonin (5-HT)2C antagonist in Phase III trials. Vilazodone, which is undergoing a Phase III clinical trial, is a selective serotonin reuptake inhibitor which also has 5-HT1A agonist properties. Triple reuptake inhibitors which selectively inhibit reuptake of serotonin, norepinephrine, and dopamine are also being developed. There are also medications in development whose mechanism of action does not depend on directly affecting monoaminergic function. Glucocorticoid receptor antagonists and corticotropin releasing factor-1 antagonists, which seek to modulate the hypothalamic-pituitary-adrenal axis, are being explored for efficacy in the treatment of unipolar depression. Agents that modify the glutamatergic system, such as riluzole and ketamine, are being explored for treatment of bipolar and unipolar depression. This article reviews the rationale and evidence for these proposed agents in the treatment of mood disorders.

Introduction

There remains an acute need for new, effective treatments for mood disorders. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study1 reported a cumulative 67% remission rate after four treatment steps. However, not only did approximately 33% of patients not achieve remission, but patients who went into remission during the third or fourth treatment step had relapse rates of 41% to 50%.1 Likewise, the Systematic Treatment Enhancement Program for Bipolar Disorder2 indicated that only 58.5% of patients experiencing a manic, mixed, or depressive episode achieved symptom-free recovery in up to 2 years of follow up, and of those who did, 48.5% of these individuals experienced recurrences.2 These two National Institute of Mental Health (NIMH)-funded studies, which sought to deliver “best practice” care to “real world” patients, provide an effective snapshot of effectiveness of current medications for mood disorders.

Some authors suggest that there has been no truly revolutionary drug for the treatment of mood disorders for numerous decades. Recent Food and Drug Administration approvals for bipolar disorder and unipolar depression have been for compounds that have already been approved for other disorders or reformulations or metabolites of already available medications. However, the pharmacologic treatment of mood disorders remains an area of intense and exciting research. Multiple approaches that appear promising are being investigated, some of which hold the promise of extending existing paradigms of mood disorder psychopharmacology.3-5

Atypical Antipsychotics

Atypical antipsychotics continue to expand their indications for bipolar disorder. Quetiapine has received approval for maintenance treatment of bipolar disorder as an adjunct to lithium or divalproex. Applications have been made to the FDA for the extended-release version quetiapine for treatment indications for manic and depressed episodes of bipolar disorder, and for unipolar depression. (The steps for FDA approval are defined in the Table.6) Aripiprazole has received expanded indications for the acute treatment of manic or mixed episodes in pediatric patients. Perhaps the most notable FDA indication is the approval of aripiprazole as an augmentation agent for the treatment of unipolar depression. This represents the first indication of an atypical antipsychotic for unipolar depression. Curiously, two large studies7 were unable to demonstrate aripiprazole’s effectiveness as monotherapy for bipolar depression.

 

Two large randomized placebo-controlled trials8,9 demonstrated aripiprazole’s efficacy as augmentation treatment in unipolar depression. Both studies started with a screening phase, where patients were determined to be in a major depressive episode for at least 8 weeks, had between 1–3 adequate antidepressant trials for which they had a <50% response, and had a Hamilton Rating Scale for Depression (HAM-D)17 score of >18. If patients met these criteria, they entered an 8-week prospective treatment phase. Patients received single-blind treatment; escitalopram, paroxetine, sertraline, fluoxetine, or venlafaxine; and an adjunctive placebo. Antidepressant choice was based on the investigator’s clinical assessement. After 8 weeks, if patients did not respond, they entered a randomized double-blind study phase where they received aripiprazole or a placebo in addition to the antidepressant selected by the investigator. Doses started at 5 mg, were increased to 10 mg if tolerated, and could be lowered to 2 mg if not tolerated. Investigators could also increase the dose by 5 mg/week to 20 mg/week if there was no response. Patients in both studies had significant drops in the Montgomery Åsberg Depression Rating Scale (MADRS) total score, the primary outcome measure. Separation from placebo began at week 2 in both studies. Remission rate at 6 weeks was statistically significant for both studies at 25.4% to 26.0% versus 15.2% to 15.7% for placebo. The average dose of aripiprazole was 11.1–11.8 mg, somewhat below the dose for bipolar disorder and schizophrenia.8,9

Desvenlafaxine

Desvenlafaxine was approved in 2008 for treatment of major depressive disorder (MDD). It is the major active metabolite of venlafaxine, and like venlafaxine is a serotonin norepinephrine reuptake inhibitor. Desvenlafaxine has a greater effect on norepinephrine reuptake relative to its effect on serotonin reuptake compared to venlafaxine, although it is similar to venlafaxine in that it continues to have a greater effect on serotonin reuptake than norepinephrine reuptake overall. Desvenlafaxine is not predominately metabolized by the cytochrome P450 (CYP) system and is eliminated primarily by phase II metabolism; as a result, it has lower potential for drug interactions, especially with the CYP 2D6 pathway. It is suggested that a potential advantage of desvenlafaxine over venlafaxine is greater predictability with regard to the ratio of inhibition of norepinephrine reuptake to serotonin reuptake. Since venlafaxine is converted to desvenlafaxine by CYP 2D6, patients who are taking 2D6 inhibitors or who are genetically poor metabolizers will have a greater ratio of venlafaxine to desvenlafaxine and, therefore, comparatively less norepinephrine reuptake compared to serotonin reuptake.10

Efficacy has been demonstrated by four fixed-dose double-blind placebo controlled studies.11-14 Two studies11,12 examined 50 mg and 100 mg doses, while one study13 examined 100 mg, 200 mg, and 400 mg doses. The last study14 examined 200 mg and 400 mg doses. Desvenlafaxine demonstrated superiority over placebo in all four studies in terms of decrease in HAM-D17 scores, although in one study did not separate from placebo at the 100 mg dose. Overall, there was no statistically significant  improvement in efficacy at doses >50 mg and these higher doses were associated with higher dropout rates and more adverse events; as a result, the recommended dose is 50 mg.15 In one published study11 with the recommended 50-mg dose, the remission rate was 34%, significantly greater than for placebo group, 24%; in the other study,12 while the response rate at 50 mg dose was significantly greater than placebo, 65% to 50%, the remission rate did not significantly separate from placebo, 37% to 29%.

Desvenlafaxine appears to be well tolerated. The most common adverse events leading to discontinuation are nausea (4%), dizziness (2%), headache (2%), and vomiting (2%). Nausea was reported by 22% of patients taking 50 mg, and this increases in dose dependent fashion to where 41% of patients taking 400 mg report nausea.15 As with the other serotonergic antidepressants, the caveats regarding the risk of combination with monoamine oxidase inhibitors (MAOIs) apply. Serotonergic antidepressants are frequently associated with weight gain and sexual dysfunction. In premarketing studies,15 decreased libido, delayed ejaculation, and erectile dysfunction were noted in men, especially at higher doses, whereas in women only anorgasmia was notable at the 400 mg dose. However, with regard to weight gain, patients lost an average 0.4–1.1 kg in short-term studies,15 In one long-term study,15 there was no difference in mean weight change between patients who were on desvenlafaxine or placebo for 6 months. Like venlafaxine, desvenlafaxine is associated with sustained elevations in blood pressure. Venlafaxine is associated with elevations at higher doses; however, desvenlafaxine is associated with sustained diastolic hypertension at all doses. Curiously, there is no clear dose response relationship. The incidence of sustained hypertension is 1.3% at a dose of 50 mg of desvenlafaxine, 0.7% at 100 mg, 1.1% at 200 mg, 2.3% at 400 mg, and 0.5% for placebo. Venlafaxine is known to have significant discontinuation syndrome related to its short half-life and serotonergic action. Desvenlafaxine’s half-life is approximately 11 hours, and it is also associated with a discontinuation syndrome. Since desvenlafaxine comes in an extended-release tablet that is not recommended to be cut or split, the recommendation is to taper the medication by increasing the interval between doses.15

The clinical utility of desvenlafaxine over its parent compound remains an open question. The decrease in potential drug-drug interaction is an incremental benefit. However, it is not clear that desvenlafaxine’s greater ratio of norepinephrine to serotonin reuptake inhibition compared to venlafaxine is clinically meaningful with regards to efficacy or tolerability.

With the relative dearth of novel agents for mood disorders, it is worth surveying drugs that are in development. There are >50 drugs in phases I, II, or III clinical trials for depression and bipolar disorder.16 What follows is not a comprehensive survey, but rather an overview of compounds that may be close to an approval decision or have a novel mechanism of action.

New Atypical Antipsychotics

The success of atypical antipsychotics in mood disorders will lead to newer atypical antipsychotics to be tried in mood disorders as well. Paliperidone, the active metabolite of risperidone and recently approved for schizophrenia, is in phase III trials for the treatment of manic and mixed episodes. Asenapine, a serotonin (5-HT2)/dopamine-2 antagonist, has been submitted to the FDA for approval for both mania and schizophrenia. Bifreprunox, a dopamine partial agonist, which received a non-approvable letter for a schizophrenia indication, is in phase III trials for bipolar depression.16

Agomelatine

Agomelatine, a melatonergic agonist at melatonin (MT)1 and MT2 receptors and a 5-HT2C antagonist, is in phase III clinical trials in the United States for the treatment of MDD. Blockade of 5-HT2C receptors on gamma-aminobutyric acid interneurons is thought to result in the increase of norepinephrine and dopamine in the prefrontal cortex. In addition, its activity at the MT1 and MT2 receptors is thought to have positive effects on sleep promotion and the regulation of circadian rhythms.17 Efficacy of agomelatine in MDD was demonstrated in three published double-blind, placebo controlled trials.18-20 The first trial18 involved 711 depressed patients with either MDD or bipolar type II, comparing 1 mg, 5 mg, and 25 mg of agomelatine to 20 mg of paroxetine and placebo. Both the 25 mg agomelatine group and the paroxetine group showed statistically significant decreases in HAM-D scores. Both groups had significantly more remitters than the placebo group—30.5% for 25 mg agomelatine and 25.7% for the paroxetine group—compared to 15.7% for placebo.18 Two additional trials,19,20 which featured flexible dosing starting at 25 mg and going to 50 mg after 2 weeks of nonresponse, also showed significant improvement in HAM-D scores and response rates after 6 weeks. All three trials performed subanalyses that showed significant improvement in severely depressed patients with HAM-D scores >25.21

Agomelatine appears to be well tolerated. In all three studies18-20 mentioned above, agomelatine did not have significantly more adverse events than placebo. Separate studies found that agomelatine compares favorably to venlafaxine with regards to sexual dysfunction22 and was also not associated with discontinuation symptoms.23 Notably, in a 24-week relapse prevention study,6 patients on agomelatine did not have significant changes in sexual functioning, weight, cardiovascular effects, or laboratory studies.

Agomelatine has initially been rejected by regulatory agencies in the European Union on efficacy grounds, particularly in long-term studies, although efforts to gain approval continue in Europe and the US. Although not appearing to have significant efficacy advantages, agomelatine would appear to have significant advantages in tolerability, especially with regards to weight gain and sexual dysfunction.

Vilazodone

Vilazodone, a selective serotonin reuptake inhibitor (SSRI), also has partial agonist properties at the 5-HT1 receptor. It is undergoing a Phase III clinical trial for the treatment of depression. Partial agonism at 5-HT1 is thought to enhance the action of SSRIs, perhaps by accelerating the desensitization of somatodendritic autoreceptors. This has been borne out clinically by studies indicating the effectiveness of buspirone, a 5-HT1 partial agonist, in the augmentation of SSRI treatment, most notably in the STAR*D trial. In addition, there is thought that activity at the 5-HT1 receptor can mitigate sexual side effects of SSRIs. There is also some evidence that buspirone is effective in treating sexual dysfunction brought on by SSRIs, although it is somewhat equivocal. In one 8-week, double-blind, placebo-controlled study24 of 410 patients, vilazodone had significant decreases in HAM-D and MADRS scores beginning at week 1. Vilazodone also had a significantly higher percentage of responders and remitters. Principal adverse events include diarrhea, nausea, and somnolence. Sexual dysfunction was examined using the Arizona Sexual Experiences Scale, and no significant differences were noted between treatment and placebo group. Furthermore, the investigators identified a genetic biomarker which identifies patients that had significantly more improvement after 8 weeks of vilazodone treatment. Patients with the biomarker and treated with vilazodone had significantly more improvement compared to patients without the biomarker and treated with vilazodone as well as patients treated with placebo regardless if they had the biomarker.24

Triple Reuptake Inhibitors

The monoaminergic hypothesis of depression underlies existing antidepressants and the preceding compounds. All existing antidepressants are thought to modify mood based on effects on serotonin, norepinephrine, or dopamine. However, the majority of antidepressants only have significant effects on serotonin and norepinephrine. Substantial evidence exists linking the importance of dopaminergic pathways to depression. In particular, anhedonia and lack of motivation are thought to be connected to dopaminergic deficits. Of existing antidepressants, bupropion is thought to work by increasing levels of dopamine and norepinephrine; only the MAOIs, which carry significant drug interactions and have tolerability issues, are thought to increase all three neurotransmitters. Triple reuptake inhibitors, compounds that add blockade of the dopamine transporter to actions blocking serotonin and norepinephrine, seek to increase level of all three neurotransmitters while maintaining the tolerability found in SSRIs or serotonin norepinephrine reuptake inhibitors.25

Triple reuptake inhibitors have been referred to as “broad spectrum,” being able to target a wide range of symptoms that have been associated with either serotonergic, noradrenergic, or dopaminergic deficits. Theoretically, such an agent might have a more rapid onset of action and higher remission rates. There are proposed tolerability advantages as well. Dopaminergic activity might serve to attenuate serotonergic-mediated sexual dysfunction and weight gain.26 However, dopaminergic agents, with their effects on reward pathways, may have abuse liability. Dopamine transporter drugs that produced >50% dopamine transporter blockade within 15 minutes were reinforcing.27

Numerous triple reuptake inhibitors have shown promise in animal models of depression and have progressed to clinical trials. DOV 21,947 has completed eight Phase I trials and is now recruiting for Phase II clinical trials for the treatment of MDD. DOV 21,947 is an enantiomer of DOV 216,303 which has also been developed as a triple reuptake inhibitor, although patent life concerns have halted development. Results of a double-blind Phase I study with DOV 216,303 showed significant decreases in HAM-D scores after 2 weeks of treatment. The study was limited by the lack of a placebo arm and the short time frame. The length of the study was limited by the amount of safety data at the time. Instead of a placebo arm, there was an active comparator arm using citalopram 20 mg BID, which also showed significant decrease in HAM-D scores in the same time period.28 Another triple reuptake inhibitor, GSK 372475, is also in phase II trials for depression. A third, SEP 225289, has started phase I clinical trials.15 Conceptually, triple reuptake inhibitors are quite appealing and are the natural extension of the monoaminergic hypothesis of depression, although questions remain about what the most effective balance of neurotransmitter action would be.

Novel Mechanisms of Action: Beyond Monoamines

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in patients with mood disorders have been explored since the 1950s. Under normal circumstances, in response to stress, the hypothalamus releases corticotrophin releasing factor which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH) which, in turn, stimulates the adrenal glands to produce cortisol. High levels of cortisol produce negative feedback on corticotropin releasing factor (CRF) which ultimately leads to cortisol levels returning to normal. However, in depressed patients, this regulatory mechanism does not function properly. Depressed patients are found to have elevated cortisol levels, exaggerated adrenal responses to ACTH, and fail to suppress cortisol secretion when given the synthetic glucocorticoid dexamethasone. Chronic high levels of cortisol are thought to contribute to hippocampal volume loss and possibly neurocognitive symptoms of depression. Furthermore, successful treatment of depression leads to normalization of cortisol levels and regulation of the HPA axis. It is hypothesized that modulating the HPA axis and correcting cortisol levels will result in improvement of depressive symptoms and improved neurocognitive function.29

Numerous strategies have been employed to regulate the HPA axis in the treatment of depression. Steroid synthesis inhibitors such as ketoconazole, metyrapone, or aminogluthemide have been studied with mixed results.30 In particular, two approaches are being actively pursued as treatments for mood disorders, namely, glucocorticoid receptor antagonists and CRF-1 receptor antagonists.

Mifepristone is a glucocorticoid receptor-2 antagonist and progesterone receptor, which is approved by the FDA for termination of early pregnancy. There have been multiple published studies examining it’s efficacy in depression with psychosis. Early open-label studies demonstrated rapid and durable responses in patients after only 4–6 days of treatment with mifepristone 600 mg.31 In a large double-blind, placebo-controlled study32 of >200 patients, 58.1% of patients receiving mifepristone 600 mg achieved at 50% reduction in the Brief Psychiatric Rating Scale-Positive Symptoms Subscale in 1 week and maintained it until the fourth week compared to 38.1% in the placebo arm. However, there were no significant differences in HAM-D scores between the mifepristone and placebo group. Although three Phase III clinical trials for mifepristone have failed to demonstrate efficacy versus placebo for depression with psychosis, trials continue to examine higher doses of 1,200 mg. Two other glucocorticoid receptor-2 antagonists are in phase II trials, ORG 34517 and ORG 34850.15

Numerous CRF-1 receptor antagonists have been developed for depression and anxiety disorders. In an open-label study of 20 patients, patients who received R121919 40–80 mg had significant decreases in HAM-D and Beck Depression inventory scores over 30 days. Sleep electroencephalogram studies indicated reversal of sleep architecture changes associated with depression. However, development was halted when drug-induced reversible increases in liver enzymes were detected in a safety study, although this was thought to be unrelated to its principal method of action.33 Despite this setback, the exploration of CRF-1 receptor antagonists for the treatment of depression and anxiety disorders remains extremely active. Pexacerfont is currently in Phase III clinical trials and three other compounds are in phase I or phase II clinical trials.15,16

Tachykinins

Substance P, neurokinin A, and neurokinin B are the three most common tachykinins. Tachykinins are short 11–13 amino acid-long peptide neurotransmitters sharing a common C-terminal sequence. Tachykinins exert their effect through G-protein-mediated receptors called neurokinin (NK)1, NK2, and NK3.34 Substance P preferentially binds NK1, neurokinin A preferentially binds NK2, and neurokinin B prefererentially binds NK3, although all three have agonist effects at all three receptors. Tachykinins—especially substance P—became of interest as targets for potential psychiatric medications, as these neuropeptides and their receptors are found in areas of the brain involved in stress, fear, and emotional response (amygdala, hippocampus, hypothalamus and frontal cortex) and closely overlap serotonergic and noradrenergic neurons.35

Antagonists to NK1 and NK2 receptors have been found to have antidepressant effects in animal models and have progressed to clinical trials. In particular, NK1 antagonists have been explored as potential treatments for depression for a number of years.  However, results with numerous compounds have been disappointing.35

Aprepitant (MK-836) had shown promise in two early studies.36,37 In the first,37 MK-836 showed superior efficacy to placebo and equal efficacy to paroxetine with improved tolerability, and had been hailed as a potential breakthrough drug. Only somnolence was found to be a more common adverse event than placebo; weight gain, sexual dysfunction, nausea or vomiting were not significant problems.37  In an another study36 in which both aprepitant and fluoxetine failed to separate from placebo, a post hoc analysis indicated the antidepressant efficacy of aprepitant in a subgroup of severely depressed patients. However, an analysis38 of five clinical trials representing over 750 patients failed to show efficacy versus placebo. Furthermore, using paroxetine 20 mg as an active comparator, investigators were able to replicate paroxetine’s efficacy versus placebo in the same studies.38  Finally, positron emission tomography studies indicate that the doses used in these clinical studies would result in 95% occupancy of NK1 receptors.38

A similar compound, with higher brain penetration and oral bioavailability, L-759274 was also studied. A double-blind placebo-controlled study39 of >162 patients demonstrated superiority to placebo in patients with depression with melancholic features, although a dose-finding trial40 has failed to show separation from placebo. Development on these two compounds for mood disorders has been halted, although aprepitant has been approved for the adjunctive treatment of chemotherapy-induced emesis. Nevertheless, many NK-1 antagonists are still being developed for depression and anxiety.16

Saredutant is a NK-2 receptor antagonist that had progressed to the point that an application for approval for depression seemed to be forthcoming. However, efficacy results were also somewhat equivocal. Of four unpublished phase III studies only two demonstrated statistically significant results compared to placebo.3 Subsequently, a long-term study.41 which compared the ability of saredutant to prevent relapse in patients who had already responded to saredutant for 3 months failed to show superiority to placebo. As a result, approval application will rest on the results of studies currently running on saredutant in combination with  citalopram and paroxetine.

Glutamate and Mood Disorders

Glutamate is the principal excitatory neurotransmitter in the brain. A growing body of research implicates abnormal glutamatergic function with an important role in the pathophysiology of mood disorders. A proposed mechanism for the mood stabilizing and antidepressant effects of lamotrigine is the inhibition of glutamate release through its effect on sodium channels. A number of compounds that modulate the glutamatergic system have been examined for the treatment of mood disorders.42

Riluzole is the only FDA-approved medication for amyotropic lateral sclerosis. It has multiple mechanisms of action which include inhibition of glutamate release through sodium channels, similar to that of lamotrigine, and the enhancement of glutamate reuptake.43 Two open-label studies44,45 have been performed in unipolar depression, and one open-label study46 in bipolar depression. The first study44 used riluzole 100–200 mg as monotherapy for unipolar depression for 19 patients. All patients had to be unresponsive to one medication trial and 53% were unresponsive to at least two trials from two different classes; 68% of the patients completed the 6-week trial. Response rates on the MADRS were 32% for all patients and 46% for completers. Remission rates were 21% for all patients and 31% for completers. In another study,45 riluzole 100 mg was used as an augmentation strategy in unipolar depression for patients who had a HAM-D24 score >21 despite being on a stable dose of medication for at least 6 weeks. After 6 weeks, the average HAM-D score was reduced 36%; significant decreases were noted in week 1. Forty percent of the 10 patients who completed the 6 weeks had responded and 30% were in remission. Patients who responded seemed to respond rapidly in the first week and held durable responses for months. Another open-label study46 looked at riluzole in addition to lithium for bipolar depression. The response and remission rate at week 8 was 50%. Notably, four patients who had remitted had failed to respond to lamotrigine in the past. Two of these patients remitted, while one had a partial response and one had no response. The NIMH is sponsoring a Phase II trial in unipolar and bipolar depression. Riluzole, while available, can cost upwards of $1,000/month. It has an extended patent due to orphan drug status, which expires in 2013.

The N-methyl-D-aspartate excitotoxic amino acid (NMDA) receptor is a subtype of glutamate receptor and has been the subject of investigation regarding depression. Ketamine, a general anesthetic which is also known as a “club drug,” is an NMDA receptor antagonist. Two randomized, double-blind, crossover studies47,48 have been published. In both studies, patients were randomized to receive either a single subanesthetic (0.5 mg/kg) infusion of ketamine over 40 minutes or a saline solution. At least 1 week later, the patient would receive the infusion that they did not receive the first time. Significant decreases in depression occurred within 110 minutes after infusion, which persisted for 1 week. In one study,48 71% of patients receiving ketamine were responders after 1 day and 35% were responders after 1 week. No patients in the placebo group showed a response at any time.47,48

The ketamine studies are notable if only for the speed of response and proof of concept. However, the need for intravenous infusion and ketamine’s notoriety as a potential drug of abuse may limit its ultimate utility as an antidepressant. Memantine is a low-affinty NMDA antagonist used for the treatment of Alzheimer’s disease. Compared to ketamine, it does not have psychotomimetic properties, is well tolerated, and is orally bioavailable. However, double-blind placebo-controlled study49 of 32 subjects with bipolar depression showed no treatment effect at doses of memantine 20 mg/day.

Conclusion

The need for new treatments in the pharmacotherapy of mood disorders remains. New medications, some of which continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine and some of which employ novel mechanisms of action hold the potential to improve the treatment of patients. Novel mechanisms of action include modifying the HPA axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy. PP

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14.    Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-347.
15.    Pristiq [package insert]. Madison, NJ: Wyeth-Ayerst. September 2008.
16.    Future treatments for depression, anxiety, sleep disorders, psychosis, and ADHD. Available at: www.neurotransmitter.net/newdrugs.html. Accessed October 24, 2008.
17.    San L, Arranz B. Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry. 2008;23(6):396-402.
18.    Lôo H, Hale A, D’haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239-247.
19.    Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16(2):93-100.
20.    Olié JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10(5):661-673.
21.    Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol. 2007;22(5):283-291.
22.    Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28(3):329-333.
23. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol. 2004;19(5):271-280.
24.    Rickels K, Athanasiou M, Robinson, D, Gibertini, M, Whalen H, Reed CR. Vilazodone: evidence for efficacy and tolerability in the treatment of major depressive disorder. Poster presented at: the Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington, DC.
25.    Liang Y, Richelson E. Triple reuptake inhibitors: next-generation antidepressants. Primary Psychiatry. 2008;15(4):50-56.
26.    Skolnick P, Basile AS. Triple reuptake inhibitors (“broad spectrum” antidepressants). CNS Neurol Disord Drug Targets. 2007;6(2):141-149.
27.    Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005;57(6):640-646.
28.    Skolnick P, Krieter P, Tizzano J, et al. Preclinical and clinical pharmacology of DOV 216,303, a “triple” reuptake inhibitor. CNS Drug Rev. 2006;12(2):123-134.
29.    Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008;(1):CD005168.
30.    Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis. Neurochem Res. 2008;33(4):691-707.
31.    Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychotic [corrected] disorders. Eur J Pharmacol. 2008;583(2-3):358-364.
32.    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60(12):1343-1349.
33.    Ising M, Holsboer F. CRH-sub-1 receptor antagonists for the treatment of depression and anxiety. Exp Clin Psychopharmacol. 2007;15(6):519-528.
34.    Rupniak NM, Kramer MS. Substance P and related tachykinins. In: Davis K, Charney D, Coyle J, Nemeroff C, Neuropsychopharmacology, the 5th Generation of Progress. New York, NY: Lippincott, Williams and Wilkins; 2002:169-176.
35.    Hafizi S, Chandra P, Cowen J. Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations. Br J Psychiatry. 2007;191:282-284.
36.    Herpfer I, Lieb K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs. 2005;19(4):275-293.
37.    Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281(5383):1640-1645.
38.    Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59(3):216-223.
39.    Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology. 2004;29(2):385-392.
40.    Krishnan KR. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry. 2002;63(suppl 11):25-29.
41.    sanofi-aventis press release, July 31, 2008. Available at: http://en.sanofi-aventis.com/press/press_releases/2008/ppc_20376.asp  Accessed November 6, 2008.
42.    Kugaya A, Sanacora G. Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 2005;10(10):808-819.
43.    Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761-786.
44.    Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
45.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
46.    Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430-432.
47.    Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
48.    Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
49.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.

 

Needs Assessment: “Online Cancer Support Groups” discusses a compelling issue in cancer support that has heretofore not received enough focus, the needs of patients with limited English proficiency. It also demonstrates how innovative online methodologies can effectively reach this often neglected segment of the cancer patient community.

Learning Objectives:
• Give examples of barriers faced by immigrant women with breast cancer in accessing psychological support.
• List four scales to study the effectiveness of psychosocial interventions targeting cancer patients.
• Describe the potential benefits of online support groups for cancer patients.


Target Audience:
Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: August 21, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by October 1, 2010 to be eligible for credit. Release date: October 1, 2008. Termination date: October 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Primary Psychiatry. 2008;15(10):55-62

 

Dr. Changrani is assistant professor in the Department of Medicine and associate director of the Center for Immigrant Health at New York University (NYU) School of Medicine in New York City. Dr. Lieberman is professor emeritus at the University of California, San Francisco. Dr. Golant is senior vice president of Research & Training at The Wellness Community in Los Angeles, California. Dr. Rios is program director at The Wellness Community-Greater Miami in Florida. Ms. Damman is medical student at the University of California Davis School of Medicine. Dr. Gany is associate professor in the Department of Medicine and director of the Center for Immigrant Health at NYU School of Medicine.

Disclosures: The Virtual Community for Immigrants with Cancer, was supported by the Langeloth Foundation during the study period (the research for which this financial support was granted, which was used for this article, officially ended in 2005). Additional support was received from the Lance Armstrong Foundation (the research for which this financial support was granted, which was used for this article, officially ended in 2006).

Please direct all correspondence to: Jyotsna Changrani, MD, MPH, Center for Immigrant Health, New York University School of Medicine, 550 First Ave, BCD-D-402, New York, NY 10016; Tel: 212-263-8783; Fax: 212-263-8234; E-mail: Jyotsna@med.nyu.edu.


Abstract

Online support groups (OSGs) may be a particularly promising option for immigrants. They can be a cost-effective method that easily addresses geographic isolation and immigrants’ needs for privacy. This article examines the viability of OSGs for Hispanic immigrants with breast cancer and the effectiveness of OSGs for the participants. The authors hypothesized that OSGs are a feasible mechanism for delivering support to Latina women with breast cancer, as immigrant Latinas with breast cancer in OSGs showed significant improvement compared to a control group on depression, in coping with pain, in quality of life, and personal growth. Of 85 potential participants approached, 68 Spanish-dominant speaking immigrant women with breast cancer were recruited into the Virtual Community for Immigrants with Cancer (VCIC). Forty-eight were randomly assigned to OSGs and 20 were assigned to a usual care control group. VCIC participants were grouped into OSGs with eight participants in each. Each group met for 90 minutes once a week for 30 weeks. The groups were facilitated by trained bilingual facilitators and issues of interest to the group were discussed, such as managing symptoms and side effects from medications, family concerns, and alienation. The dropout rate from the groups was 13%. The VCIC experiences suggest that OSGs are acceptable to and feasible for immigrant minorities, including those with limited English proficiency. While none of the outcome measures showed statistically significant change pre-post compared to the control group, statistical trends were noted suggesting beneficial impact on outcomes. When compared to the controls, the experimentals had increases in seeing new possibilities (F=2.81, P=.09) and increased feelings of strength (F=3.59, P=.06).

Introduction

In 2000, the United States was home to 31.1 million immigrants.1 Over 21 million immigrants in the US, including 25% of New York City residents, have limited English proficiency.2,3 The diagnosis of cancer in immigrants is often the cause for much fear and can lead to isolation from family and community.4,5 Immigrants are frequently marginalized from institutional, social, and psychological support, including cancer care.5

The value of cancer support groups is widely accepted. The National Cancer Institute advises that support groups can help people affected by cancer feel less alone and can improve their ability to deal with the uncertainties and challenges that cancer brings.6 A meta-analysis by Rehse and Pulkrop7 summarized the results of 37 published, controlled studies investigating the effectiveness of non-Internet psychosocial interventions on the quality of life (QOL) of adult cancer patients. They found an overall effect size of 0.31 for psychosocial interventions.7 The most important moderating variable identified was the duration of psychosocial intervention, with interventions lasting >12 weeks being significantly more effective than those of shorter duration. Support groups for cancer patients have led to improvement in QOL, reduction of psychological symptoms;,improvement in coping responses, and reduction in pain.8-11

A few studies have examined ethnicity and support groups. Miano and colleagues12 reported that the traditional support group model has not been effective in reaching the Hispanic population. Instead, they developed a program facilitated by Spanish-speaking social workers using other professionals within the institution to promote a multidisciplinary approach to provide support services. They reported that participants experienced an increased sense of social and emotional well being, expanded their knowledge of health-related information, and became aware of other services and benefits available to them. A second study involving cancer patients in Texas13 examined the role of informal and formal social support networks in mitigating barriers to cancer treatment among whites, African Americans, and Hispanics. Minorities were more apt to report that the formal support groups helped patients to continue treatment. In addition, informal social support networks, such as extended families and civic clubs, were seen as more helpful for African-Americans and Hispanics as compared with whites. Finally, Alferi and colleagues14 examined predictors of use of complementary therapies by African American, Hispanic, and non-Hispanic white patients with early-stage breast cancer who also received standard medical treatment. Most patients used ≥1 complementary therapy, most commonly psychotherapy, support groups, meditation, and spiritual healing.

The Internet has enabled non-immigrant patients to help one another through the emotional turmoil of cancer.15 It is estimated that one out of three cancer patients in the developed world is online.16,17 A virtual community is one of the most powerful uses of the Internet, as people can meet, interact, share interests, and exchange social support via online support groups (OSG).

Fifteen million Internet users in the US have visited OSGs.18 Furthermore, when asked whether they visited an OSG on the previous day, 1.6 million responded in the affirmative. Results from a 2007 Harris poll indicated that 160 million US adults searched for health information online.19 In an analysis of a recent National Cancer Institute public data set,20 approximately 50% of the cancer sample comprised of both men and women used the Internet to locate information about cancer and approximately 5% of men and 8% of women had participated in an Internet cancer support group. However, there are few outcomes studies on OSGs. Klemm and colleages21 identified 10 non-controlled, descriptive research studies on cancer OSGs. Nine of the 10 studies concluded that OSGs help people to cope more effectively, but none of them used randomization to groups or a control group. Eysenbach22 conducted a comprehensive, systematic review of online, peer-led OSGs that included efficacy data and found few studies (n=38). Three studies23-25 focused on the effects of OSGs for breast cancer patients. OSGs for breast cancer patients may reduce depression, cancer-related trauma, and perceived stress.23-25 A study26 of The Wellness Community (TWC)-facilitated chat groups for women with breast cancer found that participation in 16 weekly groups significantly reduced depressive symptoms and negative reactions to pain and showed a trend toward increased posttraumatic growth. Sixty-seven percent of patients found the groups beneficial. Several studies examined the processes associated with benefit. They found that greater expression of anger in OSGs for women with breast cancer was associated with higher QOL and lower depression in previous studies, while the expression of fear and anxiety was associated with lower QOL and higher depression.27 Insightful disclosure played a crucial and significant role.28

OSGs may be a particularly promising option for immigrants. One in three Spanish-dominant Hispanics in the US uses the Internet.29 OSGs can be a cost-effective method of intervention with minimal, if any, transportation requirements. OSGs also easily address geographic isolation as well as needs for privacy, both of which may be heightened among immigrants. However, OSGs for immigrants with cancer are sorely lacking. In fact, no previous studies of Latina women with breast cancer and OSGs are available.

This study examines the viability of OSGs for Hispanic immigrants with breast cancer and attempts to bridge the digital divide with a culturally relevant online intervention. The authors test the feasibility of providing professionally led Internet groups for Spanish-speaking immigrant women with breast cancer and attempt to determine if Spanish-speaking immigrant women with breast cancer can be recruited and retained for OSGs. In addition, the authors wanted to gather pilot data on effectiveness of OSGs for the participants. The leadership model and measures used in the current study are similar to the model employed in a previous study reporting statistically significant pre-post changes in depression, reactions to pain and a trend towards increased growth.22

Specifically, the authors tested three central hypotheses. First, OSGs are a feasible mechanism for delivering support to Latina women with breast cancer. Second, immigrant Latina women with a breast cancer diagnosis in online, professionally facilitated support groups will show significant improvement compared to a control group (ie, usual care) on depression, coping with pain, QOL, and personal growth. Last, women with breast cancer who start the group with high levels of distress will show significantly greater improvement than those with lower levels of distress.

Method

In 2001, the Virtual Community for Immigrants with Cancer (VCIC) was launched to bridge the immigrant Internet support group divide. VCIC was developed to advance immigrants’ ability to cope with cancer and to increase their confidence in accessing treatment options. VCIC provides informational, emotional, and social network support to Spanish-speaking women with breast cancer  through an OSG. The study was a replica of a previous study23 of non-Hispanic whites with breast cancer. Both the intervention as well as the outcome measures were identical except that in the present study, the language of intervention and measures was Spanish.

At the program’s inception, three focus groups were conducted with Spanish-speaking breast cancer survivors, including women who had attended face-to-face support groups. The focus groups provided direction to the content and design structure for VCIC’s Web site30 and OSGs in addition to informing topics for chat sessions. A team of web-designers and public health professionals worked together to design a site with culturally appropriate visuals and content, navigable by those with little or no familiarity with the Internet and computer technology.

The authors of this article did not want to restrict VCIC to Internet-savvy participants or those who had computers or Internet access at home. Several participants had never used a computer prior to joining VCIC. The auhtors secured refurbished computers and provided them to the participants, along with dial-up Internet connections. Staff provided one-on-one, at-home, half- to full-day training to the participants on using computers, the Internet, and the VCIC OSG, as needed.

VCIC participants were grouped into OSGs with eight participants in each. Each time eight people enrolled, a new group would begin. Each group met for 90 minutes once a week for 30 weeks. The groups were facilitated by trained bilingual facilitators and issues of interest to the group were discussed, such as managing symptoms and side-effects from medications, family concerns, and alienation.

Sample

Within a 2-year period, the authors identified and approached 85 potential participants. Seventeen declined participation, and 68 Spanish-dominant-speaking immigrant women with breast cancer were recruited into VCIC. Forty-eight were randomly assigned to the OSGs and 20 were assigned to a usual care control group. Of those in the intervention, 42 participated fully and 6 dropped out. Key stakeholders in the community, including volunteer survivors, aided with the recruitment. Sample characteristics of the intervention and control groups are shown in Table 1.

 

 

 

 

Measures

Depression was measured by the Center for Epidemiological Studies Depression Scale Spanish language (CES-D).31 The CES-D scale is a 20-item self-report measure designed to assess depressive symptoms in the general population. It has been found to have high internal consistency (a=.89) with cancer patients and adequate test-retest reliability. The instrument permits comparison with other cancer studies using this measure, is sensitive to intervention effects, and is easily administered.32

 Personal growth was measured by the authors’ translation of the Posttraumatic Growth Inventory (PTGI).33,34 The PTGI was developed to assess positive changes experienced by traumatized individuals. The 21-item scale yields a total score and five subscale scores, namely new possibilities, relating to others, personal strength, spiritual change, and appreciation of life. Items are rated on a 6-point Likert scale, ranging from “I did not experience this change as a result of my crisis” (0) to “I experienced this change to a very great degree as a result of my crisis” (5). While internal consistency of the total score was .95 in a previous sample of cancer survivors, the translated version has never been tested for internal consistency.

QOL was measured by translation of the functional analysis of cancer therapy (FACT-B). The FACT-B measures multidimensional QOL in patients with cancer. The a coefficient total score is a=.90, with subscale a coefficients ranging from .63–.86.35

The authors translated three subscales8 to assess pain, First, pain intensity-Likert scale ranges from 0 (none) to 10 (excruciating). Second, pain interference during household chores, yard work, or shopping; socialization with friends; recreation and hobbies; sexual relations; and physical exercise. Last, reactions to pain (ie, agonizing, intolerable, unbearable, awful, distressing, unpleasant, distracting, uncomfortable, tolerable, bearable, and none).

To score the transcript interaction the authors used the Linguistic Inquiry and Word Count (LIWC).36 The dictionary provides a method for studying the various emotional, cognitive, structural, and process components present in written speech. The dictionary includes 17 standard linguistic dimensions (eg, word count, percentage of pronouns, articles), 25 categories tapping psychological constructs (eg, affect, cognition), 10 dimensions related to “relativity” (time, space, motion), and 19 personal/content concern categories (eg, work, home, leisure activities). This procedure has been extensively utilized in studies examining the beneficial effects of writing about traumatic life events. Two scales were assessed, namely emotional (anger) and cognitive (insight) dimensions. The transcripts of the meetings were first translated in English and then scored using the LIWC scales. All scores are corrected for number of words.

Statistical Analysis

To test improvement compared to a control group (usual care) on depression, coping with pain, QOL, and personal growth over time, a repeated measures multivariate analysis of variance (MANOVA) was used. Four outcome measures wre used, including CES-D, total pain, sum of the FACT-B, and PTGI scales, were used. Three control variables were used as covariates, namely length in the US (proxy for acculturation),  cancer stage, and level of education. A bonferonni correction was used to control for the inter-correlation of the three measures. Because the use of a summed score for both the FACT-B and PTGI may mask some of the possible changes, a separate repeated measures MANOVA with the covariates was used for the subcales of the PTGI and FACT-B.

To test whether women with breast cancer who start the group with high levels of distress will show significantly greater improvement than those with lower levels of distress, the authors used an analysis of variance. Distress was assessed by Time 1 CES-D scores, dividing the sample into those who at Time 1 did not show clinical depression (score of ≤17) and those defined by the CES-D as clinically depressed (score of >17). The dependent variable was CES-D at Time 2. The independent variables were experimental/control and high or low depression at Time 1. Covariates were the three cited in the previous paragraph.

Results

The mean participant age for VCIC was 46.8 years, with a range of 22–84 years of age. The participants hailed from 12 Latin American countries. The top two countries of origin were the Dominican Republic (25.5%) and Colombia (18.2%). The mean age in the United States was 16.7 years, with a range of 0.25–43 years. Forty-point-seven percent of the participants had not completed high school, and 32.7% of the participants were employed outside their home. Eleven-point-three percent of participants did not have health insurance.

Eighty percent of potential participants approached enrolled into VCIC. Reasons for declining included not having a stable place to live, not having a telephone at home to dial in for Internet access, becoming nervous around computers, and family issues such as family member death and illness.

The themes of the chat sessions were varied. They included faith; family as well as lack of family in the US; relationships; financial and insurance issues, including what insurance covers and how they could procure free wigs; and breast reconstruction, sharing personal experiences and concerns. The women expressed fears and provided emotional support. Pain was often discussed, with participants seeking and offering suggestions to decrease symptoms.

The dropout rate from the groups was 13%. Reasons for dropout included participants’ death, eviction from apartment, disconnection of telephone, feeling too tired after work to participate, changes in work schedule, and returning to home country.

Outcomes

Table 2 shows both the repeat measure multivariate analysis of covariance of the summary measures (ie, CES-D, Total Pain, FACT-B, and PTGI) and the repeat measure multivariate analysis of covariance for the subscales of the PTGI and the FACTB. Length of time in the US and previous support group was used as a covariate because of the difference between the experimental and control group. Table 3 shows the adjusted means for all the outcome measures.

 

 

 

 

 

Overall, none of the outcome measures showed statistically significant change pre-post compared to the control group. However, some PTGI subscales, when analyzed separately, showed a statistical trend. A multivariate analysis of the five PTGI scales, using the three covariates described in the main analysis and a bonferroni correction, found an overall trend (F=2.13, P=.07).5 Univariate analysis showed a statistical trend in two of the scales. The experimentals compared to the controls had increases in seeing new possibilities (F=2.81, P=.09) and increased feelings of strength (F=3.59, P=.06). The means of that analysis are also shown in Table 3 for comparison purposes. The significant items on the PTG included: “I am more likely to try to change things which need changing,” “An appreciation for the value of my own life. A feeling of self-reliance,” “A willingness to express my emotions. Being able to accept the way things work out,” “Appreciating each day. Having compassion for others,” “I am able to do better things with my life,” “New opportunities are available which would not have been otherwise,” “Putting effort into my relationships,” “I developed new interests,” and “I established a new path for my life.”

Level of Distress

For this analysis, the authors of this article used 21 controls; 12 were low distress and 11 were high distress. The experimental sample of 40 women was divided; 22 were in low distress and 18 were in high distress. As expected, there was a difference between all the subjects, the high-low yielded an F=25.7, P=.000, indicating that people with high distress in both experimental and control groups show lower (better) scores over time regardless of the experimental conditions.

The authors’ previous research on OSGs with breast cancer patients found that two mechanisms measured by Pennebaker’s LIWC showed significant effects on outcomes. Women who expressed more negative emotions and more insightful behaviors in the groups showed more positive changes. A similar analysis comparing the Latino sample to the non-hispanic whites27,28 found that the critical group characteristics identified (ie, group’s participant expression of negative emotions and insightful disclosure)27 using the Pennebaker text analysis software were significantly linked to positive change. The Latina support groups were significantly lower in these dimensions, as were the facilitators in encouraging this behavior. Mean scores for the expression of anger were .22 (.16) for non-Latina sample, .17 (.11); insight 1.9 (.77) and 1.4 (.85). T-test anger scores were t=4.57, P=.05; insight t=6.95, P=.00.37

Discussion

The VCIC experiences suggest that OSGs are acceptable to and feasible for immigrant minorities, including those with limited English proficiency. The participant feedback has been overwhelmingly encouraging. Participants have commented that VCIC has allowed them “desahogo,” or to “undrown” themselves. They have commented often that they had not been able to talk with anyone about their situation prior to VCIC. Participants have consistently expressed their immense gratitude.

Several obstacles were encountered in setting up this study related to the living situations of the population recruited. These need to be taken into account when implementing OSGs in similar immigrant communities. Space at the participants’ homes was an issue. Several apartments were cramped, and the refurbished computers occupied a large amount of space. The computers purchased after the first batch were considered for their size. Dial-up Internet access was provided free of cost to the participants. However, the authors of this article did not take into account the participants’ limited landline phone access. A few participants had very restricted plans. By dialing up once a week for 90 minutes, they exceeded their monthly telephone minute allowance. This resulted in a higher bill and, for one participant, a reluctance to dial up. Remedial measures were taken to augment the participants’ phone plans, allowing them to continue to participate.

Because of their unfamiliarity with the Internet, participants were provided with the project coordinator’s telephone number for assistance. However, this was limiting. Most participants did not have a second phone, to call the coordinator once they were online. They would have to log off the Internet to place a call, compromising their ability to describe the problem, and the potential for the coordinator to assist them. This would result in missed chat sessions.

Since completing this pilot study, the Wellness Community has been experimenting with providing online support groups through the Virtual Wellness Community-Spanish website.38 It has been learned anecdotally that patients prefer to start their online support group experience with cancer-related specific information (ie, managing side effects from treatment, preparing for chemotherapy). In this model, the first half of the online support group is education and the second half is support. It is easier and more comfortable for Spanish-speaking participants to express emotions in the context of the information presented. It is as if the information provides a safe distraction for participants to express emotions that would otherwise be burdensome on the rest of the group members without the initial focus on education. This insight and practical methodology should be explored in future studies. However, it should be noted that no outcome data is available from the Virtual Wellness Community-Spanish Web site. It is not known if this experiment would yield more robust outcomes.

The Latina women’s change in attitudes towards the future and their feelings of empowerment suggest potential impact of the groups. However, the scales used to measure difference were not transcreated but merely translated, potentially limiting their utility severely. Future studies should consider the use of specifically created and/or validated scales for this population. Additionally, reflections of effectiveness (eg, empowerment in decision making, completion of treatment) were potentially not measured. Unfortunately, there is little guidance from previous studies of both face-to-face and OSGs to provide a context for these findings. There are no studies comparing Latina and non-Latina women in support groups. Alternatively, it may be that women of color have sufficient interpersonal support in their own communities and do not need the extra support offered by these computer-mediated groups, while the Caucasian women are using the group so much for everyday life exchanges because they do not have similarly rich and effective support from their friends or families. Moreover, what they did while they used discussion group was different. Their comments were much less likely to be about day-to-day events than were those of Caucasian women, suggesting that women of color used the discussion group to focus very tightly on breast cancer. Another possible clue to the differences in the Wellness Community studies of breast cancer support groups,31,32 and this study with Latina immigrant women may be found in the quality of the groups themselves. In previous studies on online breast cancer support groups, three critical group and leader characteristics were isolated using the Pennebaker text analysis software that were significantly linked to positive change of the participants the group’s cohesiveness, participant expression of negative emotions, and insightful disclosure.27 The Latina support groups were significantly lower in these dimensions, as were the facilitators in encouraging this behavior. Thus, the absence of significant change in depression, QOL and addressing physical pain may in part have been contributed to by more inexperienced leadership and the low experienced cohesiveness, expression of negative emotions, and insightful disclosure.

Another possible explanation lies in the cultural characteristics of the Latina women. Here the possibilities are broad and varied and obviously do not rise above the level of speculation. That the women in the study emigrated from 12 countries, each with its own special culture, makes an explanation based on culture even more suspect. These individuals represent diverse nationalities, sociopolitical histories, races, ethnicities, and cultures.

Many researchers of Latino culture have attempted to describe some general characteristics of their culture despite the above cited differences.37,39-42 For example, traditional Western values stress the desirability of individualism, autonomy, and competition, whereas Hispanic cultural traditions emphasize the importance of collectivism, interdependence, and cooperation. The data available to the investigators in this study does not provide a source of empirical information on the effects of culture on their attitudes and behavior for OSGs. The following is offered as a speculation on why the effectiveness of OSGs for Latina breast cancer patients was limited.

“Familismo” (ie, family values and the value of family) has been described an allocentric cultural value that stresses attachments, reciprocity, and loyalty to family members beyond the boundaries of the nuclear family.41,42 Allocentrism is a cultural value by which people understand themselves through others, emphasizing social relationships and highlighting group goals rather than individual ones. “Personalismo” refers to a preference for relating on a personal, rather than formal or institutional, level.43 Irrespective of gender, physical touch is used more liberally by Hispanics than Euro-Americans, and the appropriate conversational distance for Hispanics is much closer.44 “Marianismo,” which is rooted in the Roman Catholic reverence for the Mother Mary, refers to some traditional cultural prescriptives assigned to women. With motherhood, women achieve an elevated status of spiritual superiority to men and consequently enjoy a certain amount of power.37 However, in keeping with reverence for the Madonna, mothers are expected to embody the virtues of selflessness and to endure suffering with dignity.39 Though collectivist ideals are consistent with the self-sacrifice of all individuals, because women are considered to be more virtuous than men, they are deemed capable of greater sacrifice. Religion and Spirituality. Faith, rooted in Roman Catholicism, is generally the cornerstone of Hispanic life in many communities.45 The belief that God is the author of one’s destiny is prevalent across the Spanish-speaking world and is evident in widespread references to God’s will.46

How could these common cultural touchstones impact on the study’s intervention? There are no definitive answers. Perhaps the emphasis on closeness and touching influenced their experience of the relative “coolness” of Internet communication. Perhaps the propensity to endure suffering may have limited the women’s willingness to speak of the burdens associated with their breast cancer diagnosis. Perhaps even more important was the use of tools that were not validated in these communities and may not have accurately measured the intervention’s impact.

Threats to the Study’s Validity

Numerous problems mitigate the authors’ conclusions. The randomization protocol was compromised by selecting patients serially as they registered, signed the human subjects forms, and completed the measures. The first eight people were placed in a group, then the next eight people formed the next group, and so on until 48 people were enrolled into 6 groups. Finally, the control group was formed from the last 20 who registered. Reliance on merely translated Spanish versions of the measures raises the question of differences in language usage and cultural norms. The computer analysis of the interaction may be problematic because the translations of the transcripts and the language usage and cultural norms may have a major effect on the authors’ conclusions. Words describing abstract concepts (eg, emotions) are not as readily interpreted.47 The findings from previous studies on the effect of emotional expression and cognitive processes are based on non-Hispanic Caucasians. The authors provide no evidence suggesting that these are critical for the immigrant Latina sample studied.

Conclusion

Virtual communities hold tremendous promise for cancer support. Despite the issues noted, underserved communities, including immigrants, can and must be included. Participants eagerly joined and remained in the groups, expressing much gratitude for their existence. Upon deployment and demonstration of the effectiveness of “e-health” interventions such as VCIC, these interventions will likely present cost-effective alternatives to traditional health interventions for underserved populations. However, sufficient resources need to be devoted to ensure their smooth functioning for communities without prior computer and/or Internet experience. A replication of “e-health” interventions that have been effective in mainstream communities must be carefully tailored to the cultural context of immigrant communities. Further research is important into the content and the processes of online support interventions for immigrants with cancer. PP

References

1.    Larsen LJ. US Bureau of the Census. The foreign-born population in the United States: 2003. Current Population Reports [serial online]. 2004;P20-551:1–9. U.S. Bureau of the Census. Washington, DC. Available at: www.census.gov/prod/2. Accessed September 3, 2008.
2.    United States Census 200. Summary tables on language use and english ability: 2000 (PHC-T-20). Available at: www.census.gov/population/www/cen2000/briefs/phc-t20/index.html. Accessed September 11, 2008.
3.    Newest New Yorkers 2000: Immigrant New York in the new millennium. New York City Department of City Planning. January 2005. Available at: www.nyc.gov/html/dcp/html/census/nny.shtml. Accessed September 3, 2008.
4.    Perez TE. Health and civil rights. Cancer. 2001;91(1 suppl):217-220.
5.    Women’s Information Network Against Breast Cancer. Breast Buddy Program for Indigent and Underserved. Available at: www.winabc.org/programs/breast-buddy-underserved.htm. Accessed August 25, 2008.
6.    Facing forward: life after cancer treatment. National Cancer Institute: U.S. National Institute of Health. Available at  www.cancer.gov/cancertopics/life-after-treatment/allpages#e6. Accessed August 25, 2008.
7.    Rehse B, Pukrop R. Effects of psychosocial interventions on quality of life in adult cancer patients: meta analysis of 37 published controlled outcome studies. Patient Educ Couns. 2003;50(2):179-186.
8.    Spiegel D, Bloom JR. Group therapy and hypnosis reduce metastatic breast carcinoma pain. Psychosom Med. 1983;45(4):333-339.
9.    Cain EN, Kohorn EI, Quinlan DM, Latimer K, Schwartz PE. Psychosocial benefits of a cancer support group. Cancer. 1986;57(1):183-189.
10.    Taylor SE, Falke RL, Shoptaw SJ, Lichtman RR. Social support, support groups, and the cancer patient. J Consult Clin Psychol. 1986;54(5):608-615.
11.    Fawzy FI. Malignant melanoma: effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry. 1993;50(9):681-689.
12.    Miano LY, Rojas MS, Trujillo M. “Platicas y merienda”: reaching Spanish-speaking patients in an oncology setting. Cancer Pract. 1996;4(4):199-203.
13.    Guidry JJ, Aday LA, Zhang D, Winn RJ. The role of informal and formal social support networks for patients with cancer. Cancer Pract. 1997;5(4):241-246.
14.    Alferi SM, Antoni MH, Ironson G, Kilbourn KM, Carver CS. Factors predicting the use of complementary therapies in a multi-ethnic sample of early-stage breast cancer patients. J Am Med Womens Assoc. 2001;56(3):120-123,126.
15.    National Cancer Institute. CIS research agenda: overview of relevant research U.S. Department of Health and Human Services, National Institutes of Health 2005. Available at: http://cis.nci.nih.gov/research/agenda_overview.pdf. Accessed August 25, 2008.
16.    Fukui S, Kugaya A, Okamura H, et al. A psychosocial group intervention for Japanese women with primary breast carcinoma. Cancer. 2000;89(5):1026-1036.
17.    van Wegberg B, Lienhard A, Andrey. Does a psychosocial group intervention program alter the quality of life of cancer patients? Schweiz Med Wochenschr. 2000;130(6):177-185.
18.    Spooner T, Rainie L. Hispanics and the Internet. Pew/Internet: Pew Internet & American Project for Life. Available at: www.pewinternet.org/reports/toc.asp?report=38. Accessed August 25, 2008.
19.    Harris Poll shows number of “cyberchondriacs” – adults who have ever gone online for health information– increases to an estimated 160 million nationwide. Harris Interactive. Available at: www.harrisinteractive.com/harris_poll/index.asp?PID=792. Accessed August 25, 2008.
20.    Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI). SEER Data, 1973-2005. Available at: http://seer.cancer.gov/data/. Accessed September 3, 2008.
21.    Klemm P, Bunnell D, Cullen M, Soneji R, Gibbons P, Holecek A. Online cancer support groups: a review of the research literature. Comput Inform Nurs. 2003;21(3):136-142.
22.    Eysenbach G. The impact of the Internet on cancer outcomes. CA Cancer J Clin. 2003;53(6):356-371.
23.    Wellman B. An electronic group is virtually a social network. In: Kiesler S, ed. Culture of the Internet. 1st ed. Mahwah, NJ: Lawrence Erlbaum; 1997:170-205.
24.    Lieberman M, Golant M, Giese-Davis J, et al. Electronic support groups for breast carcinoma: a clinical trial of effectiveness. Cancer. 2003;97(4):920-925.
25.    Winzelberg AJ, Classen C, Alpers GW, et al. Evaluation of an internet support group for women with primary breast cancer. Cancer. 2003;97:1164–1173.
26.    Lieberman MA, Golant M, Giese-Davis J, et al. Electronic support groups for breast cancer: a pilot study of effectiveness. Cancer. 2003;97(4):920-925.
27.    Lieberman MA, Goldstein BA. Not all negative emotions are equal: the role of emotional expression in online support groups for women with breast cancer. Psychooncology. 2006;15(2):160-168.
28.    Lieberman M. The role of insightful disclosure in outcomes for women in peer-directed breast cancer groups: a replication study. Psychooncology. 2007;16(10):961-964.
29.    Pew Hispanic Center and Pew Internet Project. Latinos Online. March 14, 2007. Washington, DC. Available at: www.pewinternet.org/pdfs/Latinos_Online_March_14_2007.pdf. Accessed September 3, 2008.
30.    CAVIC. Available at: www.cavic.org. Accessed September 3, 2008.
31.    Cho MJ, Moscicki EK, Narrow WE, Rae DS, Locke BZ, Regier DA. Concordance between two measures of depression in the Hispanic Health and Nutrition Examination Survey. Soc Psychiatry Psychiatr Epidemiol. 1993;28(4):156-163.
32.    Hann D, Winter K, Jacobsen P. Measurement of depressive symptoms in cancer patients: evaluation of the Center for Epidemiological Studies Depression Scale (CES-D). J Psychosom Res. 1999;46(5):437-443.
33.    Tedeschi RG, Calhoun LG. The Posttraumatic Growth Inventory: measuring the positive legacy of trauma. J Trauma Stress. 1996;9(3):455-471.
34.    Tedeschi RG, Calhoun LG. Trauma and Transformation: Growing in the Aftermath of Suffering. 1995. Thousand Oaks: Sage; 1995.
35.    Cella DF, Tulsky DS, Gray G. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570-579.
36.    Lawrence Erlbaum Associates, Linguistic Inquiry and Word Count. Revised. Mahwah, NJ; 2000.
37.    Comas-Diaz L. Culturally relevant issues and treatment implications for Latinos. In: DR Koslow, Pathy E, eds. Crossing Cultures in Mental Health. Washington, DC: SIETAR International; 1989:31-48.
38.    The Wellness Community. Available at: http://espanol.thewellnesscommunity.org. Accessed September 3, 2008.
39.    Stevens EP. Machismo and marianismo. Society. 1973;10(4):57-63.
40.    Sue DW. Multidimensional facets of cultural competence. Couns Psychol. 2001;29(6):790-821.
41.    La Roche MJ. Psychotherapeutic considerations in treating Latinos. Harv Rev Psychiatry. 2002;10(2):115-122.
42.    La Roche MJ, Turner C. Self-orientation and depression level among Dominicans in the United States. Hisp J Behav Sci. 1997;19:479-488.
43.    Delgado M, Humm-Delgado D. Natural support systems: a source of strength in Hispanic communities. Social Work. 1982;27:83-89.
44.    Hall ET. The silent language. In: O’Brien RW, ed. Readings in General Sociology. 4th ed. Boston, MA: Houghton Mifflin; 1969.
45.    Nava Y. It’s All in the Frijoles: 100 Famous Latinos Share Real-life Stories, Time-tested Dichos, Favorite Folktales, and Inspiring Words of Wisdom. New York, NY: Diane Publishing Company; 2000.
46.    Falicov CJ. The cultural meanings of money: the case of Latinos and Anglo-Americans. Am Behav Sci. 2001;45(2):313-328.
47.    Bond MH, Lai TM. Embarrassment and code-switching into a second language. J Soc Psychol. 1986;126(1):179-186.

To the Editor:              

We read with interest the article describing horticultural therapy by Fried and Wichrowski.1  Although they and others2 describe the therapeutic benefits of gardening activities with children, we have been conducting a “gardening group” each summer for the past several years at a state-operated psychiatric facility for adults. The garden itself is located in the fenced-in courtyards adjacent to the day rooms of a specialized clinical research unit jointly operated by Rockland Psychiatric Center and the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York.3 Patients under the guidance of clinical and research staff participate in the selection of which vegetables and flowers to grow, preparing the earth, planting, irrigation, weeding, and harvesting. The edible plants get eaten (waiting until they are ripe and ready for a salad is encouraged but not always successful), and the flowers get sold in the autumn to facility staff. Over time, the gardening group has become one of the most popular voluntary groups on the research unit.

We have observed multiple benefits the gardening group provides to our patients. First and foremost, the garden increases patients’ understanding and appreciation of the natural world. Many of our patients were raised in New York City and have never had the opportunity to see their food grow or work in a garden before. Ideas that the rest of us may take for granted, such as the fact that tomatoes ripen from green to orange to red, can really engage the interest of someone who has never seen this before. The relaxed structure of the group also allows patients with an interest or desire to be more involved to take on leadership roles. For each of the past three summers one or two patients have self-selected into the role of “master gardener,” taking responsibility to watch over the garden on a daily basis and to water and weed on the weekends when the usual staff is unavailable. Harvesting the garden is not only enjoyable and tasty; it also allows staff the opportunity to teach the patients some basic cooking skills. We hope that by having the patients prepare salads, cook vegetables such as green beans and eggplant, and even bake zucchini bread, some will be able to remember and use these lessons in the future.

We highly recommend such “gardening groups” for other intermediate and long-term psychiatric units.

Sincerely,

Rachel T. Ziwich, BS, Charlene Olang, Henry Epstein, LCSW, and Leslie Citrome, MD, MPH

Ms. Ziwich is a research coordinator at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York. Ms. Olang is a rehabilitation assistant and Mr. Epstein is a unit chief at the Rockland Psychiatric Center in Orangeburg, New York. Dr. Citrome is a professor in the Department of Psychiatry at New York University School of Medicine in New York City and the director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

References

1.  Fried GG, Wichrowski MJ. Horticultural therapy: a psychosocial treatment option at the Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders. Primary Psychiatry. 2008;15(7):73-77.
2.  Levin A. Members in the news: psychiatrists sow seeds of good mental health. Psychiatr News. 2007;42(16):14.
3.  Citrome L, Epstein H, Nolan KA, Tremeau F, Elin C, Roy B, Levine J. Integrating state psychiatric hospital treatment and clinical research. Psychiatr Serv. 2008;59(9):958-960.

Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; E-mail: ns@mblcommunications.com.

 

Ms. Kornreich is research associate at New York University (NYU) Department of Social Work in New York City. Ms. Mannheim is manager of Supportive Services at NYU Cancer Institute. Dr. Axelrod is associate professor in the Department of Surgery at NYU School of Medicine and director of Clinical Breast Programs and Breast Surgery at the NYU Cancer Institute.

Disclosures: Ms. Kornreich and Ms. Mannheim report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Axelrod is on the board of trustees for Self-help for Women with Breast and Ovarian Cancer; and is on the medical advisory boards of People Living with Cancer at the American Society of Cancer Oncology and the Young Survival Coalition.

Please direct all correspondence to: Deborah Axelrod, MD, FACS, New York University Cancer Institute, 160 E 34th St, New York, NY 10016; Tel: 212-731-5366; Fax: 212-731-6051; E-mail: deborah.axelrod@nyumc.org.


 

Focus Points

• Children’s understanding of illness and possible reactions vary with age and the individual.
• Parents can ease their children’s distress through a host of mechanisms.
• Coordination of service delivery by the multi-disciplinary team can work to reduce stressors in children whose parents have cancer.
 

Abstract

A parental diagnosis of cancer can have a powerful psychological effect on a child. Although responses vary significantly with age and the individual, children often react with uncertainty, fear, guilt and anxiety. It is up to the parents and the healthcare team to maintain awareness of this growing issue and respond accordingly. Parents can minimize their child’s distress by maintaining open communication throughout the diagnosis, treatment, and recovery processes. Furthermore, an informative, timely, and supportive response from a multidisciplinary healthcare team can successfully reduce stressors and guide the child through the experience. As cancer becomes a more chronic issue, it is becoming imperative that medical physicians address its psychological impacts on the patient and family in order to both improve the quality of life during illness and reduce the long-term negative consequences for years after.

Introduction

According to the National Cancer Institute, one in two men and women will get cancer in their lifetime, and 22.2% of cancer diagnoses will occur between 20–54 years of age.1 While the number of cancer cases is no longer rising, the American Cancer Society estimates that there will be 1,437,180 new cancer cases in the United States in 2008 alone.2 Although cancer predominately appears in an older population (the median age at diagnosis from 2000–2004 for cancer of all types was 67 years old), both men and women have an approximately 1 in 10 chance of developing cancer before age 60.1,2 Cancer has a unique impact on this younger population, in part because the disease not only affects the patient, but also impacts on the patient’s immediate family (including spouses, domestic partners, and oftentimes young children).3 According to the Centers for Disease Control, women increasingly postpone having children until their thirties or forties, and, therefore, have an increased risk of developing cancer while there is still a young child or adolescent living at home.4 A parental cancer diagnosis impinges on a child’s life by changing family routines, altering parent-child interactions, giving the child additional responsibilities, eliciting a fear of potential parental death and increased vulnerability, and adding to already difficult developmental issues.5-7 Children respond differently to the stressors associated with parental illness, and it is important for physicians and parents to understand possible responses in order to anticipate their child’s needs.

Recognition has been slow to address the needs of the family when a parent becomes ill. Despite advances in cancer treatment, even the most sophisticated cancer treatments often bring debilitating physical and emotional side effects. Ensuring quality of life takes many forms. In order to cover the entire landscape—not only addressing the physical but also the emotional, and spiritual aspects of illness—the medical team must include psychiatrists, psychologists, psycho-oncologists, and social workers. The emergence of psycho-oncology is only now being recognized as a crucial part of patient care. As Holland8 stated in an interview in which she describes the slowness to build psycho-social support: “You’ve got to look at the way society has viewed the disease over the years and how it has impacted on people’s responses to the disease.”

It has been difficult in society for adults (let alone children and family) to discuss cancer. During the crisis of parental cancer, childhood behavioral and psychological changes often go unnoticed.6 Perhaps due to this factor, the psychological consequences of parental cancer on a child have rarely been analyzed or acknowledged, and many of the studies that have been performed on the subject show conflicting results. These disparities stem from the fact that researchers used various means of collecting data, methodology, and informant perspectives.9 Because of the inconsistent results, it is difficult to know the exact effect that cancer in a parent will have on a child; however, parental cancer does appear to sometimes elicit numerous negative reactions in a child such as mood and self-esteem changes, academic changes, social and interpersonal alterations, and somatic symptoms.10 Parents can minimize their child’s distress during the diagnosis, treatment, and recovery processes through a host of mechanisms.

Most of the studies that have been performed looked at the effects of maternal breast cancer on children, particularly focusing on the effects of said cancer on adolescent girls.7 It is unclear whether the results of these studies can be applied to children of a broader age group or males. The effects of parental cancer on children do appear to vary based on the age and sex of the child, the sex of the affected parent, the family setting, and the complications associated with the illness.11 Depending on these variables (and existing developmental problems), children and adolescents cope with cancer differently, sometimes in ways that can be psychologically detrimental.

Although cancer remains a major killer of young men and women, overall cancer death rates have gone down considerably in the last 15 years, causing the disease to become a chronic rather than acute illness.1 Thus, childhood psychological distress pertaining to parental care and treatment is becoming more of an issue. In an effort to deal with this growing situation, numerous intervention programs have been developed and standard models have been proposed.9 Many community organizations have developed child support programs with play and “talk” therapy, acknowledging the impact of cancer on children and adolescents. However, these programs are not enough. Physicians must increase their own awareness of the problem by taking not only a full medical history, but a social history as well in order to learn about their patient and their patient’s children. It is up to the parents, teachers, medical team, and social workers to address the issues at hand and provide the proper education and support for children and adolescents throughout the difficult and emotional process of parental diagnosis, surgery, treatment, and recovery.

This article reviews the literature describing possible effects of parental cancer on latency-aged children as well as adolescents and offers examples of pediatric responses from the authors’ personal clinical experiences. Children are divided into two age groups along these lines because a literature search revealed that most studies on pediatric responses to parental cancer separated children into these approximate categories.3,6,11-14 The authors describe what parents can do to minimize the deleterious effects of cancer on their child and conclude that the medical team must act concurrently with social workers and psycho-oncologists in an effort to recognize and reduce the psychological impact of the disease.

Latency-Aged Children (Ages 4–11)

Diagnosis

Despite what many parents believe, a parental cancer diagnosis will affect a young child whether or not the child is informed outright of their parent’s condition. Children can detect the anxiety that will infiltrate their parents’ actions and conversations, and oftentimes cancer will disrupt family routines, affecting a child’s life.12,13,15 Studies show that anxiety levels in children uninformed of their parent’s condition are much greater than anxiety levels in informed children.10,16 Experientially, children worry more when secrets are kept from them than when they know the truth, and it is always worse to overhear bad news than to hear it. When one patient’s 12-year-old son heard about his father’s cancer from a friend, the child confronted his parents, visibly upset that they had not told him first. The family had intended on telling their son after they had elicited the help of family and friends and had “everything in place;” however, it proved too long a wait. A 10-year-old girl discovered that her father’s lung cancer was at end stage when she entered a room full of nervous family members and the conversation stopped. Because the parents were unaware of their daughter’s knowledge, they could not support her when she needed their help. In order to prevent exacerbating an already distressful situation, parents must tell their children of their condition soon after diagnosis.

Latency age children (defined as preschoolers and school-age children) operate in a concrete mind-frame; they can talk about what is happening to them and can express their feelings and thoughts simply, but they are only partially able to use symbolic and abstract language.14 A young child will not be able to grasp many details associated with the disease; therefore, the American Cancer Society recommends that a parent only tell children basic information such as the name of the cancer, the part of the body affected by the cancer, the treatment regiment, and how the child’s life will be affected.15 After informing the child of these basic facts, it is important to anticipate thoughts and concerns the child might have. Children of this age group will care about issues such as parental death and who will care for them; however, they will oftentimes be unable to express these fears.13 On hearing of his mother’s diagnosis, a 6-year-old boy replied “Will I have to move? Will I have to change my room?” Young children will apply abstract concepts to concrete ideas, such as their room and friends, and express their fears through these more concrete thoughts.

Children may also display irrational anxiety concerning their role in their parent’s illness or the nature of the disease itself, believing that they caused the disease or that cancer is contagious.13,15 It is important for parents and health professionals to address these concerns as such fears can lead to severe anxiety which can debilitate a child behaviorally and emotionally.13,16 Healthcare providers should make sure that the child knows that everything possible is being done to help his or her parent, but providers should let the parents judge how much information their child can take in and understand, as parents know their child best. The amount of information given will vary based on each child’s abilities; it is up to parents, healthcare professionals, and social workers to acknowledge this individualism and respect the child’s instincts and worst fears. If a family is religious, the presence of a spiritual leader during this discussion might be useful in order to calm both the parents and children. Parents can attempt to alleviate their child’s fears by reassuring the child that concrete details will not change (such as the child’s room or friends) or by taking the child to the doctor’s office for a casual visit (demonstrating that the doctor’s office is not a scary place). Parents might also want to enlist the help of a friend who has gone through a cancer diagnosis to talk with their child, as the friend can serve as an image of survival. In general, parents should remember that they need to communicate to their children the basics, even if children do not respond with questions; details are unnecessary. Children do not have to know that their mother’s tumor is estrogen receptor positive or that their father is trying a new vascular endothelial growth factor inhibitor.

Coping

Preschoolers and school-aged children are affected by the diagnosis differently than adolescents or adults. Following diagnosis, children are oftentimes unable to verbally express their concerns or fears, and instead they might react by changing their behavior. Children who never cry might cry more often, or children might become more clingy, distractible, or aggressive.13,16 Furthermore, children may demonstrate psychosomatic symptoms or be unable to concentrate in school.16,17

According to a study performed by Compas and colleagues, preadolescents as well as adolescents perceived little control over their parents’ illness. However, the preadolescents used fewer coping strategies than adolescents or young adults.4 Another study demonstrated that children 7–12 years of age cope with the illness by going “in and out” of the situation literally and emotionally. Children in the study were more anxious than their peers, although this anxiety often appeared to be caused by stressors unrelated to their parent’s illness. These children dealt with their anxiety by separating their lives into two spheres, or zones, namely, the zone dominated by cancer, and the “free zone” where they could forget about the disease and escape from the illness. Through this method, children could recreate a balance in their lives and eventually re-establish a routine that would only be disrupted when the disease developed or changed dramatically.16 In general, parents must try to keep routines as much as possible, and “mind the minutia” in order to achieve this goal, ie, ask about the commonplace, specific things in a child’s life, such as the soccer score, or how the child played in a particular game.

School-aged children’s ability to cope depends in part on their family setting. One study that analyzed how sociodemographic and family characteristics affected child functioning in families with parental cancer demonstrated that children have more trouble coping with the illness in single-parent households, when the parents are from smaller families, and when the ill parent is younger. Furthermore, the number of children and the position of the child within the family appeared to be important, as children with siblings had less trouble coping than an only child, and eldest children had more trouble coping than their younger siblings. While no study has looked at the effects of socioeconomic status on children with parental cancer, studies on the general population demonstrate that a lower socioeconomic status is linked to an increased risk of problems in children.11 Because there is limited research looking at how social, economic, and demographic factors will effect these children, it is difficult to know the validity of the results from this study. What does appear to be important is the family’s support during this experience through a strong network of friends, fellow religious congregants, and so forth. Ultimately, the impact that cancer will have on a family will relate to how the family functioned before the illness. If communication and support were present before the cancer came, then it is more likely that it will continue after.

Treatment and Recovery

Diagnosis is not the only time to be concerned about children’s psychological responses to parental cancer. In fact, latency-aged children displayed the most stress-related symptoms when confronted with physical signs of parental illness (oftentimes seen during treatment) such as vomiting and hair loss, as well as during complications and emergency hospitalizations that disrupt a normal routine.9,14 Even before long-term treatment is initiated, a parent might need in-patient hospitalization and surgery. The recovery following surgery can pose a particular threat to young children as many hospitals do not allow children under 14–18 years of age (ie, the minimum age varies with hospital guidelines) on patient floors. These rules are even more stringent when the treatment involves a compromised immune system, such as a bone marrow transplant. Even if these rules are not in effect, there should always be consultation between the medical staff and the family about the possibility of visitation.

The physical separation enforced by hospitalization can be stressful for a child. In order to minimize this separation, ill parents should attempt to maintain communication with their children. Aside from the conventional phone calls, creative communication can include cards, faxes, and even refrigerator magnet postings, and children should be reminded that their parent is thinking about them. In school, teachers, guidance counselors, social workers, and school nurses should all encourage children to engage in creative activities in order to express his or her emotions, and at home parents should attempt throughout treatment to maintain a child’s normal routine and constantly remind the child that the parent has not forgotten about him or her and will be coming back home.13 Physicians should advise parents to give their child an item to hold that the child associates with the parent, such as a set of keys, an eyeglass case, or a coffee mug. This action allows a child to feel as though he or she is protecting their parent’s domain, awaiting their inevitable return. Post-surgery, as cancer becomes more chronic, it might be useful for children to meet with a social worker or establish a strong network of friends and relatives who can be there for them consistently over time. This continuity of building a familial or extended support network can ease both parental and child stressors.

The American Cancer Society offers a list of books geared toward children in this age group which can offer additional information on parental cancer.15 There are also many intervention programs for children in this situation, such as Quest, “For Kids Only,” The Komen Kids, and “Kids Can Cope.”10 These programs aim to improve the mood, quality of life, coping skills, and stress management of these children. Most of the programs that are currently underway involve three components: education, normalization (creating a safe environment), and building on their strengths to help them cope.10 Other community-based organizations throughout the country have children’s programs, such as Noogieland at Gilda’s Club and CancerCare for Kids. Some of these have telephone groups, play therapy, and social events to ease the isolation children are often facing. By utilizing these programs as well as parental communication, school resources, and books, it is possible to minimize a child’s anxiety throughout the diagnosis and treatment process.

Adolescence (Ages 12–18)

Diagnosis

Adolescents (ie, teenagers) are at a very different mental and emotional state than latency-aged children as they maintain greater cognitive abilities and the potential for abstract and symbolic thought.16,18 They are also more aware of their parent’s pain during treatment and the potential loss of a parent that can accompany cancer.17 Studies demonstrate that adolescents respond best when given detailed information at a level they can comprehend soon after parental diagnosis.19 By being better informed, adolescents reported that they found it easier to talk to friends and family about the illness, thereby creating an outlet to discuss their feelings or get their mind off the problems at hand.7 Information should include facts about the cancer, potential treatment side effects, and the seriousness of the disease. Many adolescents expressed a desire not only to be informed second hand about their parent’s illness, but also to be present at appointments and updated on advancements or alterations in their parent’s condition.19 Studies also demonstrate that the emotions expressed by parents when they inform their children of the diagnosis is important; when parents were upset during the initial discussion, children became more upset as well.7 Thus, it is imperative that parents try to remain as composed as possible when informing their adolescents (or younger children) about their diagnosis. Children should be informed in a familiar setting and when they will not be distracted by their phone or friends. The atmosphere is important and helping the child get comfortable may affect the child’s reaction. It can also sometimes be helpful for parents to validate the child’s feelings by expressing their own fears while reassuring the child that they are doing everything they can to eradicate the disease.

A diagnosis of cancer is difficult for an adolescent child in part because it brings on numerous conflicting feelings. Adolescents by nature want to separate from their families and establish an independent identity. However, adolescents in this position realize the potential of parental death and want to spend more time with their ill parent.7 Perhaps because of this pull, some adolescents and parents in families with parental cancer reported that their families were more cohesive, more expressive, and less argumentative with one another than the norm.20 In addition, this and other studies demonstrate that sometimes adolescents in these families had lower levels of anxiety and fewer behavioral problems than their normative samples.20,21

Unfortunately, this analysis is inconsistent with most other results. One recent study looking at posttraumatic stress in adolescents with parental cancer discovered that 1–5 years after diagnosis, 21% of sons and 35% of daughters had clinically significant stress response symptoms.22 These results indicate that a cancer diagnosis can have a significant impact on a child, as increased stress was associated with behavioral and psychological problems. In fact, the study demonstrated that stress was higher amongst children of parents with cancer than amongst children treated for cancer themselves.22 One cancer survivor described her 15-year-old daughter’s experience post-diagnosis:

On the surface, she seemed perfectly functional. In reality, she was struggling. There were little signs. She moved all her things into our bathroom and began using it all the time, she became consumed with cooking and put together elaborate meals several times a week, she would leave her friends early on Friday nights to come home and watch a silly movie with me. She developed an eating disorder that almost got out of control.

For this patient’s daughter, normal adolescent emotions were exacerbated, and for lack of a better outlet she expressed her suffering through self-destructive behavior.

Coping

The coping ability of adolescents in response to parental cancer is highly variable. Like latency-aged children, adolescents feel incapable of controlling their parents’ illness. These older children respond to this feeling of helplessness by using emotion-focused coping, which is ineffective as it implies avoidance of and disengagement from the issues at hand. This coping strategy is linked to lower adaptation and higher anxiety and depression in adolescents who utilize it as compared to controls.5

Certain variables can moderate adolescent anxiety and aid adolescents in coping. One important variable is the maintenance of communication between parents and adolescents throughout the illness.10 While cancer only marginally affects the ability of parents and children to communicate with one another, recurrent disease and lengthy treatments can negatively impact on communication.23 It is therefore imperative that parents work to maintain open communication throughout their illness, even if they can only do so through text messaging or email. It is also important for parents to realize that their child might still be empathizing even if he or she is not verbally expressing this sympathy or distress. One patient’s 15-year-old son said nothing to his ill mother through her surgery, radiation, and chemotherapy despite the fact that his mother was open with him and told him everything. For years, she assumed that her illness had no effect on him. She only discovered its impact when he graduated high school and received an award for a poem he had written about her and dedicated to her that described how much he loved, respected, and admired her. Parents must remember that just because adolescents have trouble expressing their pain does not mean that they are not experiencing any.

Another important variable that affects adolescents’ coping abilities is complications associated with the illness. Studies demonstrate that adolescents have more trouble coping when their parents experience more complications during treatment, possibly because adolescents have a greater ability to empathize with others and therefore are troubled by pain and physical discomfort in their parents.11 While this is an uncontrollable aspect of the disease, parents should be aware of the implications that treatment complications, failures, or cancer recurrences can have on their adolescent.

Treatment and Recovery

As previously mentioned, the treatment of parental cancer will alter family routines, impacting children and those who love them. These modifications affect adolescents differently than latency-aged children as adolescents experience a change in their role in the family. These older children oftentimes have additional responsibilities including both household chores and caretaking tasks when their parents are ill, and these responsibilities can lead to emotional and behavioral problems.8,19,24 These problems partly develop because they have less time to engage in social or leisure activities to unwind and partly because these responsibilities change normal family patterns and routines.19,25 As Cancer Care For the Whole Patient,26 a new book by the Institute of Medicine of the National Academies, describes:

…cancer and its treatment and sequelae can limit the ability of patients and families to perform their usual personal roles and their roles in the family and the larger society. Unaddressed, these limitations can lead to emotional and mental health problems for both patient and family, and the inability to accomplish developmental tasks, such as attaining educational goals and establishing and maintaining social relationships, and to perform meaningful work inside and/or outside of the family.26

This situation can be minimized by building a network of family and friends who can help take on some of the responsibilities associated with parental illness.

Because treatment can last for years (and new treatment options have made cancer increasingly chronic), it is important for healthcare professionals and parents to attempt to normalize these adolescents’ lives in order to minimize anxiety levels. Studies report that adolescents in this situation demonstrate a desire to be a “normal teenager” and spend time with friends, get away from home over summers, and separate from the day-to-day management of parental illness.19 Parents and healthcare advisors should encourage adolescents to continue their normal activities and peer relations. It is important to make sure that children in high school do not feel compelled to stay at home after they graduate and go to a commuter college or no college at all. Parents should let adolescents know that it is okay to separate and move on. If adolescents are having trouble coping, many of the support groups available to younger children are also available to them, and these groups can help minimize behavioral problems and anxiety levels.10,19 Unfortunately, there are too few support groups available for adolescents and teenagers. Therefore, it is imperative that adolescents seek help when necessary from social workers and psychiatrists. Furthermore, professionally facilitated family meetings can be helpful in minimizing the disruption and negative consequences of parental cancer.

It may be pertinent at this juncture when treatment ends to include the child in physician visits. Meeting with the physician or other available members of the healthcare team in an informal manner for a soda or snack may help make adolescents more comfortable with the situation and less concerned for their parent. By establishing trust in the healthcare team, adolescents might also have fewer long-term concerns and be more willing to aid in their parent’s recovery process.

Terminal Illness/Death of a Parent

Despite being prepared for death, it will still be very difficult for a child to cope with parental demise. During these times, intra-familial and other social support can aid the child’s adjustment. Visitation to hospice should be determined by the family and social workers. Mechanisms to preserve the memory of a parent may take the form of videos, book projects, or photo albums. These keepsakes can serve as something tangible to hold onto.
Joelle was 34 years of age when she learned her cancer had metastasized, and despite many attempts to halt the progression of disease her response to treatments were disappointing. Her daughter Halle was 4 years of age at the time and enjoyed reading with her mother. Joelle started “Light One Little Candle” as a book project to encourage young mothers (or fathers) with cancer to read to their young children as a way to connect and to create memories. In the books, both on the nameplate and in the text, the mother can write notes to the child as she reads, thereby not only instilling a love of reading but also creating very specific memories for the child to hold on to. The Light One Little Candle program has given out over 10,000 books thus far from Boston, Massachussetts; Hartford, Connecticut; New York City; and San Diego, California. It is certainly a beautiful legacy and a gift that keeps on giving and has undoubtedly helped children through the grieving process. Joelle herself had many books for Halle with handwritten notes in them, some that she read to her and some that she put away for years to come. In addition, Joelle created memories for Halle through videos and gifts for future birthdays and special occasions.

The death of a parent from cancer brings up numerous separate issues for the child. Studies indicate that children, no matter the age, do indeed mourn, and therefore will severely mourn the death of a parent. However, the nature of children’s mourning differs significantly from that of an adult.27 Death from cancer is generally drawn out and painful, making it a difficult death for children to witness.27 Because a cancer death is generally anticipated, there is time for children to prepare themselves for the loss and for a parent and child to address the issue together. Studies show that people are more able to deal with their grief when the death is anticipated as opposed to acute.27

In general, children tend to have three questions immediately on the death of a loved one, namely, did it happen because of something they did, will it happen to them, and who will take care of them if it does happen? These questions should be addressed (whether they are articulated or not) as soon as possible.27 Children can obtain information through books geared toward their age group such as I Know I Made it Happen for younger children or How it Feels When a Parent Dies for older children.28 Moreover, all lines of communication must be kept open to ensure that these concerns are discussed openly and honestly.

Conclusion

Cancer is a disease that is affecting more Americans each year and will not go away any time soon. It is important for physicians and their medical team to start addressing the psycho-social consequences of the disease on not only the patient, but also on members of the patient’s family. Referrals to appropriate professionals such as social workers, school counselors, or psychiatrists are imperative. Cancer centers now have psycho-oncologists on staff who have obtained post-doctoral training in the field and are qualified to look at the psychological, social, behavioral, and ethical aspects of cancer. Psychosocial support has taken a back burner to virtually every facet of cancer medical care, which is focused on eradicating illness. As people are living longer with cancer, it is about time that we supplement the medical component with the human element of cancer and nurture the families who are impacted day to day by the disease. PP

References

1.    Ries LA, Melbert D, Krapcho M, et al, eds. National Cancer Institute. SEER Cancer Statistics Review, 1975-2005. Available at: http://seer.cancer.gov/csr/1975_2005. Accessed August 27,2008.
2.     Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96.
3.     Compas BE, Worsham N, Epping-Jordan JE, et al. When mom or dad has cancer: markers of psychological distress in cancer patients, spouses, and children. Health Psychol. 1994;13(6):507-515.
4.     Ventura SJ, Abma JC, Mosher WD, Henshaw SK. Estimated pregnancy rates by outcome for the United States, 1990–2004. National vital statistics reports; vol 56 no 15. Hyattsville, MD: National Center for Health Statistics; 2008.
5.     Compas BE, Worsham N, Ey S, Howell DC. When mom or dad has cancer: II. Coping, cognitive appraisals, and psychological distress in children of cancer patients. Health Psychol. 1996;15(3):167-175.
6.     Welch AS, Wadsworth ME, Compas BE. Adjustment of children and adolescents to parental cancer. Parents’ and children’s perspectives. Cancer 1996;77(7):1409-1418.
7.    Huizinga GA, van der Graaf WT, Visser A, Dijkstra JS, Hoekstra-Weebers JE. Psychosocial consequences for children of a parent with cancer: a pilot study. Cancer Nurs. 2003;26(3):195-202.
8.     Rosenthal E. Oncology Times, 10/25/07, Psycho oncology pioneer jimmie holland on her fight to have cancer patients’ distress recognized. Oncology Times. October 25, 2007;29:8-10.
9.    Visser A, Huizinga GA, van der Graaf WT, Hoekstra HJ, Hoekstra-Weebers JE. The impact of parental cancer on children and the family: a review of the literature. Cancer Treat Rev. 2004;30(8):683-694.
10. Su Y, Ryan-Wenger NA. Children’s adjustment to parental cancer: a theoretical model development. Cancer Nurs. 2007;30(5):362-381.
11. Visser A, Huizinga GA, Hoekstra HJ, van der Graaf WT, Hoekstra-Weebers JE. Parental cancer: characteristics of parents as predictors for child functioning. Cancer. 2006; 106(5):1178-1187.
12. American Cancer Society. Helping children when a family member has cancer: dealing with diagnosis. Available at: www.cancer.org/docroot/CRI/content/CRI_2_6X_Dealing_With_Diagnosis.asp. Accessed September 5, 2008.
13. Visser A, Huizinga GA, Hoekstra HJ, van der Graaf WT, Gazendam-Donofrio SM, Hoekstra-Weebers JE. Emotional and behavioral problems in children of parents recently diagnosed with cancer: a longitudinal study. Acta Oncologica. 2007;46(1):67-76.
14. Lacetti M, Vessey J. When a school-age child’s parent has cancer. J Spec Pediatr Nurs. 2007;12(4):297-299.
15. Rosenheim E, Reicher R. Informing children about a parent’s terminal illness. J Child Psychol Psychiatry. 1985;26(6):995-998.
16. Halseth S, Ulfsaet N. Having a parent with cancer: coping and quality of life of children during serious illness in the family. Cancer Nurs. 2003;26(5)355-362.
17. Christ GH, Siegel K, Freund B, et al. Impact of parental terminal cancer on latency-age children. Am J Orthopsychiatry. 1993;63(3):417-425.
18. Christ GH, Siegel K, Sperber D. Impact of parental terminal cancer on adolescents. Am J Orthopsychiatry. 1994;64(4):604-613.
19. Grabiak BR, Bender CM, Puskar KR. The impact of parental cancer on the adolescent: An analysis of the literature. Psychooncology. 2007;16(2):127-137.
20. Gazendam-Donofrio SM, Hoekstra JH, van der Graaf WT, et al. Family functioning and adolescents’ emotional and behavioral problems: when a parent has cancer. Ann Oncol. 2007;18(12);1951-1956.
21. Hoke LA. Psychosocial adjustment in children of mothers with breast cancer. Psychooncology. 2001;10(5):361-369.
22. Huizinga A, Visser A, van der Graaf WT, et al. Stress response symptoms in adolescent and young adult children of parents diagnosed with cancer. Eur J Cancer. 2005;41(2):288-295.
23. Huizinga GA, Visser A, van der Graaf WT, Hoekstra HJ, Hoekstra-Weebers JE. The quality of communication between parents and adolescent children in the case of parental cancer. Ann Oncol. 2005;16(12):1956-1961.
24. Gates MF, Lackery NR. Youngsters caring for adults with cancer. Image J Nurs Sch. 1998;30(1):11-15.
25. Nelson E, Sloper P, Charlton A, While D. Children who have a parent with cancer: a pilot study. J Cancer Educ. 1994;9(1):30-36.
26. Adler NE, Page AE, eds. Institute of Medicine (IOM), 2008. Cancer Care for the Whole Patient Meeting Psychosocial Health Needs. Washington, DC: The National Academies Press; 2008.
27. Koocher GP. Coping with a death from cancer. J Consult Clin Psychol. 1986;54(5):623-631.
28. Stuber ML. “What do we tell the children?”: understanding childhood grief. West J Med. 2001;174(3):187-191.

 

“I’m not asleep… but that doesn’t mean I’m awake.” –Author Unknown

 

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and chief medical officer of Avastra USA.

Disclosures: Dr. Erman is a consultant to Actelion, Cephalon, Mallinckrodt, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Cephalon, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, sanofi-aventis, and Takeda; has received grant/research support from Actelion, Cephalon, Eli Lilly, GlaxoSmithKline, Medicinova, Merck, Organon, Pfizer, sanofi-aventis, Schwarz Pharma, Takeda, Transcept, Vanda, and Wyeth; and owns stock in Cephalon, Forest, Neurocrine, Pfizer, sanofi-aventis, and Somaxon.


 

he disorder we now call narcolepsy was first named and described as a specific disorder by Gelineau1 in France in 1880. It can be argued that this recognition signaled the start of the field of sleep medicine. Gelineau coined the term “narcolepsy” to describe a syndrome of excessive sleepiness, characterized by an irresistable urge to sleep, at times accompanied by falls. These falls, secondary to a sudden loss of muscle tone, are now recognized as cataplexy.

Narcolepsy was well recognized as a disorder throughout the 20th century and, prior to the recognition of the widespread prevalence of sleep apnea in the 1980s, was presumed to be the basis for most complaints of “excessive sleepiness” reported to physicians by their patients. Unfortunately, this led to many patients without classic narcolepsy symptoms being diagnosed with narcolepsy and receiving treatment with classic stimulant medications such as methylphenidate and amphetamines. Since no objective basis for the diagnosis of narcolepsy existed, the complaint of sleepiness associated with various conditions and disorders, such as sleep apnea, inadequate sleep, depression, and chronic fatigue, was often the basis for a diagnosis of narcolepsy and treatment with stimulants. Many patients with complaints of sleepiness and fatigue received a diagnosis of narcolepsy, received amphetamines or other stimulants in treatment of this condition, and established long-term (often lifetime) dependency on the use of these medications to maintain “normal” function.

The discovery of the existence of rapid eye movement (REM) sleep by Aserinsky and Kleitman2 in 1953 using polysomnographic methodology established that formal criteria could be used to define parameters of sleep and wake. In 1960, Vogel3 demonstrated that specific abnormalities in the regulation and timing of REM sleep were associated with narcolepsy. These observations allowed the recognition that appearance of REM sleep during a nap, a frequent event in patients with the narcolepsy, is rarely–if ever–seen in healthy normal individuals without another sleep condition or who are not sleep deprived. When narcoleptics and normal controls are given the opportunity to take a series of naps over the course of the day in a structured testing situation, the presence of pathologic sleepiness overall and the occurrence of REM sleep early after sleep onset in these nap opportunities clearly differentiated healthy normal subjects and sleepy people without narcolepsy from those with narcolepsy.

Much work on the origins of narcolepsy, its diagnosis, and treatment have been performed at the Stanford Center for Narcolepsy Research, directed by William Dement, MD, with active collaboration by a large group of researchers, including Christian Guilleminault, MD, Mary Carskadon, PhD, and Merrill Mittler, PhD.

One of the early practical applications of scientific observations about the phenomenology of narcolepsy occurred in 1982. The realization that patients with narcolepsy would be sleepy when given the opportunity to nap, and that REM sleep would be seen in naps when they occurred, led to the development of a new and objective test for the diagnosis of narcolepsy, the Multiple Sleep Latency Test.4 This test allowed for formal testing of patients with complaints of sleepiness to determine whether objective sleepiness was present. When a diagnosis of narcolepsy could firmly be established, treating physicians could feel more confident about providing stimulant medications in treatment for indeterminate periods of time.

In the early part of the 20th century, it was widely believed that human narcolepsy was a familial disorder. Recent studies have shown that human narcolepsy is not a simple genetic disorder. For example, monozygotic twins are most frequently discordant for narcolepsy, indicating environmental factors in narcolepsy susceptibility.5 Efforts to characterize an immunologic or genetic basis for the development of human narcolepsy lead to the recognition that certain patterns of abnormalities in the immune system of patients with narcolepsy were seen at a disproportionately high level. The observation that narcolepsy is associated with a specific histocompatibility (HLA DR2) complex pattern was first reported in Japan in 1983.6 This finding was quickly confirmed to be present in non-Asian narcolepsy populations in Europe and North America.

The immune system and its relationship to the development of narcolepsy was of great interest to narcolepsy researchers. Patients who developed narcolepsy, usually in their teens or twenties, were typically observed to have been perfectly normal with regard to sleep, alertness, and muscle control (absence of any signs of cataplexy) at earlier ages. However, it was often possible to identify a specific point in time (eg, a specific school grade or work setting) as the onset of their problems with excessive sleepiness.

For many patients, there was a history of a period of stress or a physical illness that seemed to be associated with the onset of sleepiness complaints. This observation, combined with the HLA patterns seen in many patients, led to a hypothesis that narcolepsy could result from an autoimmune insult to the central nervous system. Many years of research at numerous instituions attempted to find such a specific autoimmune basis for the etiology of narcolepsy, without substantive results.

Progress in understanding the etiology of narcolepsy occurred in large part on the recognition that an animal model for the disorder existed. Canine narcolepsy was first described in 1973 at Stanford by Mitler and Dement.7 It was appreciated that an animal model for narcolepsy could help to establish a specific genetic basis for narcolepsy, and a breeding colony of narcoleptic dogs was established at Stanford. However, initial efforts to crossbreed affected animals from several species were not successful; the offspring of affected parents did not show signs of narcolepsy.

In 1975, three Dobermans with narcolepsy (two of which were littermates) were donated to the Stanford colony. The breeding of these animals led to the first successful genetic transmission of narcolepsy, with a litter of affected animals born at Stanford on July 29, 1976. Multiple cases of Labradors with narcolepsy were subsequently reported, and the trait was found to predictably be transmitted as a single autosomal recessive gene.8

In 1999, following years of effort to identify the specific genetic bias for the hereditary transmissibility of canine narcolepsy, According to one report,9 narcoleptic dogs demonstrated abnormalities in receptors for a previously identified neurotransmitter, hypocretin (aka, orexin). Coincidentally, a research group at the University of Texas Southwestern in Dallas, working with orexin knockout mice, made an independent and essentially simultaneous observation that these orexin knockout mice demonstrated sleepiness and cataplexy-like behavior suggestive of another animal model for narcolepsy.10

These neuroactive hormones had been previously identified, thought to possibly play a role in regulation of appetite (thus orexin), and recognized to be synthesized in the hypothalamus (thus hypocretin). Although this substance was shown to have some activating properties, there was no recognition that it could play a critical role in regulating levels of alertness.

The observation of abnormalities in hypocretin as a basis for canine and murine narcolepsy quickly lead to measurement of levels of hypocretin in humans. It was established in 2000, only a year after the publication of data on animal narcolepsy, that humans with narcolepsy do indeed have abnormalities in levels of hypocretin.11 In contrast to the abnormalities in hypocretin receptors seen in animal narcolepsy, humans with this disorder have very low (at times essentially undetectable) levels of hypocretin. Histopathologic studies have demonstrated apparent destruction of hypocretin secreting cells in the brains of patients with narcolepsy.12 This data suggest that autoimmune processes could target the small population of hypothalamic neurons secreting this compound, leading to narcolepsy on an autoimmune basis, as has long been suspected.

What is the import of these discoveries for the future of sleep medicine and sleep disorders? Identification of a specific etiology for a disease has always been critical in helping to identify possible treatments for the disorder. Without understanding what organism may have caused a specific infection, effective therapy cannot be administered.

Does the recognition of abnormalities in the orexin-hypocretin system afford practitioners the opportunity to treat narcolepsy more effectively? At the moment, the answer is no. Although it has been demonstrated that human narcolepsy seems to be caused by the loss of hypocretin secreting cells in the hypothalamus, there is currently no mechanism for administration of hypocretin to affected patients to ameliorate narcolepsy symptoms.

However, understanding of the role that abnormalities in the production or recognition of hypocretin may play in regulation of levels of alertness and sleepiness is already showing a promise as a therapeutic approach to be utilized for patients with several types of sleep disorders. The logic is simple and elegant. If absence of or insensitivity to hypocretin leads a disorder characterized by excessive sleepiness, what would result from production of a chemical compound capable of occupying the hypocretin receptor site in the hypothalamus, interfering with the normal action of hypocretin of promoting alertness? Presumably, the answer would be promotion of sleep initiation (ie, reducing sleep latency), the therapeutic effect  we expect from a hypnotic (“sleeping pill”) medication.

Conversely, could use of a hypocretin receptor agonist generate increased levels of alertness? Several pharmacologic companies are currently pursuing these lines of research, and it is possible that hypocretin receptor antagonists for treatment of insomnia may be available for human use within the next several years.

Animal research has taken the issue of treatment one step further. A recent publication13 showed that intranasal application of hypocretin in sleep-deprived rhesus monkeys could significantly improve performance in a short-term memory task. Deadwyler and colleagues13 noted that this method of administration appeared to produce a pronounced reversal of sleep deprivation-induced changes in brain metabolic activity, raising the question of whether, within a few years time, “natural” stimulants to counteract the symptoms of hypersomnia conditions such as narcolepsy, as well as the impact of inadequate sleep and sleep deprivation, may be available for human administration. PP

References

1. Gélineau J. De la narcolepsie. Gaz Hop (Paris). 1880;53:626-628; 1880;54:635-737.
2. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science. 1953;118(3062):273-274.
3. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry,. 1960;3:421-428.
4. Carskadon MA, Dement WC. The multiple sleep latency test: what does it measure? Sleep. 1982;5(suppl 2):S67-S72.
5. Honda M, Honda Y, Uchida S, Miyazaki S, Tokunaga K. Monozygotic twins incompletely concordant for narcolepsy. Biol Psychiatry. 2001;49(11):943-947.
6. Honda Y, Asake A, Tanaka Y, Juji T. Discrimination of narcolepsy by using genetic markers and HLA. Sleep Res. 1983;1(2):254.
7. Mitler MM, Dement WC. Sleep studies on canine narcolepsy: pattern and cycle comparisons between affected and normal dogs. Electroencephalogr Clin Neurophysiol. 1977;43(5):691-699.
8. Foutz A, Mitler M, Cavalli-Sforza L, Dement WC. Genetic factors in canine narcolepsy. Sleep. 1979;1(4):413-421.
9. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365-376.
10. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437-451.
11. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39-40.
12. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469-474.
13. Deadwyler S, Porrino L, Siegel J, Hampson R. Systemic and nasal delivery of orexin-a (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239-14247.

Psychiatric Dispatches

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New Mechanisms of Action Explored in Promising Alzheimer’s Disease Therapies

Two new therapies show promise targeting Alzheimer’s disease at little-explored mechanisms of action, researchers announced at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD). Such treatments may pave the way to safe and effective disease-modifying therapies for Alzheimer’s disease, a goal that has eluded researchers in recent years.

At ICAD, Philip Scheltens, MD, PhD, of the Alzheimer Center of the VU University Medical Centre, Amsterdam, the Netherlands, presented data from a 12-week, randomized, double-blind, placebo-controlled study of Souvenaid, a drink containing the nutrients uridine monophosphate, choline, omega-3 fatty acids, phospholipids, B vitamins, and antioxidants. Souvenaid had been shown to increase synapse formation in preliminary studies by the Massachusetts Institute of Technology. It is believed that the nutrients in Souvenaid impact the synthesis of the membrane phosphatides that compose neural synapses. The provision of these nutrients, it is hypothesized, could promote brain cell outgrowth, synapse formation, and neurotransmitter release, and could also improve cognitive function.

Two hundred twelve subjects with mild Alzheimer’s disease were recruited from the Netherlands, Germany, Belgium, and the United States. Of these, half were assigned to receive 125 ml of Souvenaid per day, and half received a control drink. None of the subjects had received prior treatment for their condition. The primary outcome measures were cognition on the Wechsler Memory Scale-revised and the modified Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). Secondary outcomes included the Mini Mental State Examination (MMSE), the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, Clinician’s Interview Based Impression of Change plus Caregiver Input (CIBIC-plus), the Quality of Life in Alzheimer’s Disease, and the Neuropsychiatric Inventory (NPI). This study also included an optional 12-week extension phase, which 85% of subjects who completed the first phase elected to participate in.

Investigators found a statistically significant benefit on the delayed verbal memory test in the Souvenaid group. There appeared to be no significant effect on the modified ADAS-cog. There was no decline in modified ADAS-cog and verbal memory in the control group during the 12 weeks of the study, however subjects with a higher baseline ADAS-cog score seemed to experience greater cognitive effect with Souvenaid.  Souvenaid was well tolerated and showed a good safety profile.

“We believe that medical foods such as Souvenaid can be a valuable part of Alzheimer’s disease management,” said Dr. Scheltens, and this trial showed proof of concept.

Mitochondrial function is another mechanism of action being explored in potential Alzheimer’s disease treatments. Dimebon, a product of Medivation that improves impaired mitochondrial function, showed efficacy in preserving function among subjects with Alzheimer’s disease in an 18-month extension trial. Initially, 183 subjects were randomized to dimebon or placebo for six months, after which subjects could elect to remain in the study for an additional six months. After the completion of both of these periods, an open-label extension was conducted in which 104 participants received dimebon 20 mg TID. Of these participants, 92 had completed 6 months of prior treatment with dimebon.

Jeffrey L. Cummings, MD, director of the Mary S. Easton Centre for Alzheimer’s Disease at the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues found that subjects who received dimebon through all 18 months of the study showed preservation of function close to their baseline measures. They showed benefit compared to projected placebo decline on the ADAS-cog, CIBIC-plus, ADCS-ADL, NPI, and MMSE. Those who had been randomized to placebo during the first 12 months, then to dimebon for open-label trial showed stabilization of their previous decline on all endpoints. Those who received dimebon for 18 months continued to show benefit over those receiving the agent for only six, suggesting this treatment may have disease-modifying properties. However, Dr. Cummings advised that “open-label extensions are not the same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution.” Phase III clinical trials are currently being planned.

Funding for the clinical trial of Souvenaid was provided by the Danone Research Centre for Specialised Nutrition. Funding for the 18-month extension trial of dimebon was provided by Medivation, Inc. (July 29, 2008. Alzheimer’s Association’s International Conference on Alzheimer’s Disease.) –RZ

High Incidence of Psychiatric Disorders in Youths Transferred to Adult Courts

Legal mandates in all states and the District of Columbia allow them to try juveniles in adult courts based on the type of offense, criminal history, and age of the offender. While the transferred youth population steadily climbs, primary care physicians are likely to encounter them, as these young individuals are at high risk for disorder. Jason J. Washburn, PhD, at Northwestern University Feinberg School of Medicine, and colleagues, compared the occurrence of psychiatric disorders among youths tried in adult court to that of youths processed in juvenile court.

They garnered a stratified random sample of 1,829 youths 10–18 years of age arrested in Chicago. One thousand seven-hundred fifteen of them (1,440 processed in juvenile court; 275 processed in adult criminal court) 13–18 years of age underwent version 2.3 of the Diagnostic Interview Schedule for Children.
Results, even after analyses controlled for felony-level violent crime, found males, African Americans, Hispanics, and older youths more likely to be processed in adult criminal court than females, non-Hispanic whites, and younger youths. Sixty-eight percent of youths processed in adult criminal court presented with ≥1 psychiatric disorder, and 43% had ≥2 types of disorders; such figures and findings were essential the same for those processed in juvenile court. However, the most interesting finding concerned juvenile offenders sentenced to prison in adult criminal court.

“These youths [sentenced to prison in adult court] were not only more likely to have disruptive behavior and substance use disorders, as might be expected from more ‘antisocial’ youths, but they were also more likely to have comorbid affective and anxiety disorders,” Washburn said. “These youths who were tried as adults, found guilty, and sentenced to prison had nearly three times the odds of having comorbid affective and anxiety disorders than youths given a lesser sentence.”

It is important to note the study’s dependence on self-report since parents of the offenders could not be interviewed and a majority of them could not be located. Such dependence possibly underestimates actual rates of certain disorders (ie, disruptive behavioral disorders).

Washburn and colleagues’ study outlines the lack of mental health care available for males coming from racial-ethnic minority groups. Psychiatric services within community and correctional systems for youths processed in adult criminal court, particularly those sentenced to prison, are needed.

“Because many of these youths are unlikely to receive appropriate treatment, primary care physicians can be a critical resource for identifying and connecting this vulnerable population with services,” Washburn added.

Funding for this study was provided by grants from the Division of Services and Intervention Research; Center for Mental Health Research on AIDS of the National Institute of Mental Health; Office of Juvenile Justice and Delinquency Prevention, US Department of Justice; National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH); Center for Mental Health Services, Center for Substance Abuse Prevention, and Center for Substance Abuse Treatment of the Substance Abuse and Mental Health Services Administration; National Center on Injury Prevention and Control and National Center for HIV, Sexually Transmitted Disease, and Tuberculosis Prevention of the Centers for Disease Control and Prevention; NIH Office of Research on Women’s Health; NIH Center on Minority Health and Health Disparities; US Department of Housing and Urban Development; NIH Office on Rare Diseases; US Department of Labor; William T. Grant Foundation; Robert Wood Johnson Foundation; John D. and Catherine T. MacArthur Foundation; Open Society Institute; and Chicago Community Trust. (Psychiatr Serv. 2008;59(9):965-973.) –ML

Acute Stress Disorder Not Effective Predictor of Posttraumatic Stress Disorder

Although prior studies have shown evidence that the presence of acute stress disorder can predict the later onset of posttraumatic stress disorder (PTSD), other studies have shown mixed or conflicting results. Additional studies examining the relationship between PTSD and acute stress disorder have also been limited due to single site study locations and small sample sizes. Recently, researchers at the School of Psychology at the University of New South Wales in Sydney, Australia evaluated any possible relationship between the two disorders with a large-scale, multi-site study in order to reduce limitations found with prior studies.

Richard A. Bryant, PhD, and colleagues examined 597 patients admitted to four major trauma hospitals during a 1-year period for presence of acute stress disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Among patients assessed, 62% suffered injury due to automobile accident, 16% due to fall, 8% due to industrial accident, and 5% due to assault; 9% were admitted to trauma hospitals for other reasons. All patients were randomly selected for screening during hospital admission, which occurred within 1 month of trauma exposure, and reassessed for PTSD at 3 months following the initial assessment (N=507). Among patients who met criteria for PTSD at follow-up, the authors studied how many also presented with acute stress disorder at first assessment to determine predictive rates between the disorders.

Bryant and colleagues found that 33 patients met DSM-IV criteria for acute stress disorder and 49 patients met diagnostic criteria for PTSD at 3-month follow-up. Fifteen patients diagnosed with acute stress disorder and 34 patients who were not diagnosed with acute stress disorder were later diagnosed with PTSD at follow-up. For patients who experienced brain injury in addition to other trauma, presence of acute stress disorder predicted later development of PTSD in 58% of all patients with brain injury as compared to 31% among all patients presenting with trauma.  

Due to the main findings, the authors concluded that the majority of patients who develop chronic PTSD do not initially present with acute stress disorder. The study’s results are similar to results found in other studies and illustrate that presence of acute stress disorder is not an effective tool to predict chronic PTSD. The authors recommend researchers seek to create improved tools for physicians to determine the development of chronic PTSD among trauma patients as acute stress disorder may be more predictive of PTSD in patients whose trauma occurred due to non-accidental incidence, such as physical assault or military combat. Bryant and colleagues added that patient heart rates or mood states following trauma may be better predictors of subsequent chronic PTSD development.

 
Funding for this research was provided by the Australian National Health and Medical Research Council. (J Clin Psychiatry. 2008;69(6):923-929.) –CP

Childhood Abuse May Lead to Adult Obesity

Obesity is a continuously spreading global epidemic. While the disease has been linked to mental disorders such as anxiety and depression, whether these conditions truly lead to mid-life obesity is unknown. In addition, historic and contextual factors have been seldom researched. However, a recent study of 9,310 members of the 1958 British birth cohort by Claudia Thomas, PhD, of the University College of London and colleagues found that physical abuse during childhood served as a precursor to mid-life obesity.

Each member was evaluated for negative experiences (ie, verbal, physical, or sexual abuse, parental depression, authoritarian upbringing, parental separation/divorce) at 7, 11, and 16 years of age. At 45 years of age, subjects underwent a biomedical interview, ascertaining their body mass index (BMI), waist circumference, and glycosylated hemoglobin level. Total obesity was defined by a BMI of ≥30, and a waist circumference of ≥102 cm and ≥88 cm indicated central obesity for men and women, respectively. Any individual with a glycosylated hemoglobin level of ≥6 was considered obese. The researchers used the negative-experience findings and the data gathered from the biomedical interviews to determine whether negative childhood experiences were associated with obesity, specifically at 45 years of age.

Results revealed that mid-life obesity risk increased by 20% to 50% for those who experienced negative childhood events. Adverse childhood events most strongly associated with obesity were indicated in members with glycosylated hemoglobin levels of ≥6. However, most associations were explained by adjustment for adulthood mediators (eg, obesity). Effects of other adversities exhibiting milder emotional neglect and less harsh family environments were mostly due to socioeconomic factors during upbringing.

Though findings indicate childhood adversities increase risk of obesity in adulthood, further research is needed to better understand interrelations among the adversities, social contexts in which they occur, and trajectories from harsh childhood circumstances to adult disease. (Pediatrics. 2008;121(5):e1240-e1249.) –ML

Paternal Age and Risk of Bipolar Disorder

Advanced age of fathers or mothers can increase the risk of bipolar disorder in their offspring, although the effect of paternal age is much more significant, especially in the risk of early-onset bipolar disorder. A large, national, case-control study from Sweden suggests that the risk of developing bipolar disorder is higher in the offspring of older fathers.

Emma M. Frans, M.Med.Sc., at the Karolinska Institutet, in Stockholm, Sweden, and colleagues selected 13,428 people with a bipolar disorder diagnosis from the Swedish national databases Multigeneration Register and the Hospital Discharge Register, each of whom were required to have had a bipolar disorder diagnosis on ≥2 separate hospital admissions. For each person in the bipolar disorder group, the researchers chose five random, age- and sex-matched controls without bipolar disorder.

The researchers controlled for parity, maternal age, socioeconomic status, and family history of psychotic disorders, finding that the offspring of men ≥55 years of age were 1.37 times more likely to be diagnosed with bipolar disorder (CI, 1.02–1.84), compared to the offspring of men 20–24 years of age. Advanced maternal age was less significant. The effect of advanced paternal age was much stronger for early-onset cases of bipolar disorder (odds ratio, 2.63; CI, 1.19–5.81), although there was no link with maternal age. (Arch Gen Psychiatry. 2008;65(9):1034–1040.) –LS

Psychiatric Disturbance in Low Birth Weight Children from Urban and Suburban Communities

According to previous research, children born with low weight (≤5.5 pounds), very low weight (≤3.3 pounds), and extremely low weight infants (≤2.2 pounds) may have higher risk of externalizing (ie, delinquent and aggressive behavior), internalizing (ie, withdrawn behavior, anxiety/depression), and attention (ie, symptoms of attention-deficit/hyperactive disorder) problems. Despite advances in neonatal medicine increasing survivorship of low birth weight infants, Naomi Breslau, PhD, and Kipling M. Bohnert, BA, of Michigan State University in East Lansing investigated the long-term effects of low birth weight on psychiatric problems in both socially disadvantaged children and middle-class children.

The study involved a stratified random sample of 823 urban (n=413) and suburban (n=410) low and normal birth weight children from newborn discharge lists (from 1983 through 1985) in two Detroit, Michigan hospitals.  Mothers and teachers used the Child Behavior Checklist and Teacher’s Report Form to rate children’s attention, externalizing, and internalizing problems at 6, 11, and 17 years of age. Standard cutoffs were used to identify infants with psychiatric disturbances above normal range.

Results found that psychiatric outcomes of low birth weight did not vary across age. However, low birth weight children had moderate excesses of externalizing (adjust odds ratio [AOR]=1.53; P=.001) and internalizing (AOR=1.28; P=.02) disturbances. Children from the urban cohort demonstrated greater risk of attention problems associated with low birth weight, with very low birth weight infants having higher risk than heavier low birth weight infants. Interestingly, the suburban counterparts showed no increased risk for attention problems associated with low birth weight.

The data indicate that low birth weight effects on psychiatric disturbance are relatively stable during the period of school attendance. However, the differential effect of low birth weight on attention problems between the urban and suburban communities suggests a relationship between prenatal adversity and social environment.

Funding for this research was provided by grants from the National Institute of Mental Health and the National Institute on Drug Abuse. (Arch Gen Psychiatry. 2008;65(9):1080-1086.) –ML


Psychiatric dispatches is written by Michelisa Lanche, Carlos Perkins, Jr, Lonnie Stoltzfoos, and Rebecca Zerzan.

 

Needs Assessment: Breast cancer reconstruction is powerful in helping patients recover from breast cancer therapy, but it remains underutilized in the United States healthcare system. It is essential for clinicians involved in the early phases of breast cancer diagnosis to understand factors involved in breast cancer reconstruction and to be able to provide access to information or specialists who can adequately educate patients during their decision-making process.

Learning Objectives:
• Identify the practical, psychological, and clinical factors involved in a woman’s decision to undergo breast cancer reconstruction
• Summarize the types of breast reconstruction and their advantages/disadvantages
• Evaluate the available data regarding the psychological impact of breast cancer reconstruction and determine how this can be helpful in counseling patients


Target Audience:
Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: August 21, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by October 1, 2010 to be eligible for credit. Release date: October 1, 2008. Termination date: October 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Primary Psychiatry. 2008;15(10):72-80

 

Dr. Ceradini is chief resident at the Institute of Reconstructive Plastic Surgery at New York University (NYU) Langone Medical Center. Dr. Levine is assistant professor of surgery, director of microsurgery, and director of Bellevue Hospital Plastic Surgery at the Institute of Reconstructive Plastic Surgery at NYU Langone Medical Center.

Disclosures: Drs. Ceradini and Levine report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Jamie P. Levine, MD, New York University Langone Medical Center, TH-169, 550 1st Avenue, New York, NY 10016; Tel: 212-263-8452; Fax: 212-263-7002; E-mail: Jamie.Levine@nyumc.org.


Abstract

Breast cancer often leads to significant alteration of body image and disfigurement of the breast. Reconstruction for breast cancer defects can provide the patient with a restored breast contour. The potential benefit of breast cancer reconstructive surgery is to increase the patient’s post-surgical quality of life and alleviate the posttraumatic psychological sequelae of breast cancer surgery. Time of breast cancer diagnosis is an important point of access for patients to receive information on breast reconstruction. Access to this information and plastic surgeons in the early phases of diagnosis is critical to a patient’s decision to undergo reconstructive surgery, but is currently underutilized in the United States. Breast cancer reconstruction is a complex process that should be treated in a multidisciplinary fashion. This process must begin with the identification and treatment of psychological issues preceding or accompanying breast cancer diagnosis. These psychological problems should be addressed immediately and can significantly influence a patient’s decision toward and level of satisfaction with breast cancer reconstruction. Breast reconstruction continues to be an essential element in helping patients recover from the diagnosis and treatment for breast cancer.

Introduction

The evolution of surgical decision making in breast cancer treatment has created a challenging environment for breast cancer reconstruction. Breast cancer is the most common form of cancer diagnosed in women. In 2007, it was the second leading cause of cancer mortality. Current data suggests that one in eight women will be diagnosed with breast cancer in their lifetime. While the incidence of breast cancer has progressively increased in the United States over the past 2 decades, the mortality from breast cancer has declined largely due to better detection and improved therapeutic interventions.1 Unlike the vast majority of cancers, breast cancer is unique in that the treatment often leads to significant alteration of body image2,3 and disfigurement of the breast, which is considered to be a major symbol of femininity and sexuality.4,5 There has been a trend over the past decade toward therapeutic interventions attempting to preserve as much of the native breast as possible to avoid these issues, particularly breast conservation therapy (BCT).

Along with these changes in the approach to breast cancer therapy, the indications, options, and ultimate aesthetic outcomes of breast cancer reconstruction have changed. It is estimated that 57,102 breast reconstructions were performed in 2007 compared to 80,908 performed in 2000.6 This reduction in the rate of breast reconstruction likely reflects the trend toward earlier detection and BCT for smaller tumors. The theoretical advantage of breast cancer reconstruction is to recreate the patient’s breast contour following mastectomy, thereby restoring the feminine form, increasing quality of life (QOL), and alleviating the posttraumatic psychological sequelae of breast cancer surgery. Indeed, while there is tremendous interest in and investigation into the psychological issues of breast cancer, the study of the psychology of breast cancer reconstruction is in its infancy. This article reviews clinical data and specific psychological issues in breast cancer reconstruction to facilitate counseling of these patients during their treatment.

Preoperative Decision Making in Breast Cancer Reconstruction: Psychological Impact of the Breast Cancer Diagnosis

The diagnosis of breast cancer frequently leads to significant psychological problems that can interfere with patients’ course of treatment.7 Patients often learn of their diagnosis from their primary care physician or gynecologist who refers them to a surgical oncologist. Prior to their surgical consultation, >40% of newly diagnosed breast cancer patients rate their psychological distress as clinically significant resulting in practical, family-related, emotional, and physical problems. In addition, rates of major depressive disorder (11%) and posttraumatic stress disorder (10%) in these patients significantly interfere with their activities of daily function.7 Despite these statistics, many women are reluctant to discuss psychological distress8 and few are screened for distress during their surgical work up and treatment.9 These problems can persist over 10 years following treatment,10 indicating that early identification and treatment is critical to long-term psychological well being. Furthermore, early intervention may facilitate a patient’s decision making for breast reconstruction and ultimately influence her satisfaction with the final appearance. Examination of women with higher levels of preoperative affective distress, depression, anxiety, and somatic preoccupation revealed they were significantly less satisfied with both the general and aesthetic outcome of their breast reconstruction.11 This suggests that mental healthcare providers have an integral role in the pre- and postoperative treatment of breast cancer. In most multidisciplinary cancer centers, psychological evaluation and support play an important role in both the initial evaluation and the patient’s long-term care.

Patient Decision Making and Access to Breast Reconstruction

Within 2 weeks following diagnosis, patients may have up to four medical or surgical consultations, including those by radiation oncologists and a reconstructive plastic surgeon, who will outline a treatment plan collectively. The oncologic treatment algorithm is largely driven by data and requires very few choices by the patient; that is, given the imaging findings and clinical stage of breast cancer, the survival of various operative approaches, surgical margins, and adjuvant therapy have been well studied and guide patients’ decision making. However, one of the few critical decisions a patient needs to make regarding oncologic therapy in early breast cancer is whether to have a mastectomy or undergo BCT. This decision is usually reserved for patients with stage I or II disease, and data from multiple studies has established that the long-term survival between these two treatment modalities is equivalent up to 20 years post-therapy.12,13 Furthermore, emerging neoadjuvant treatment protocols may facilitate BCT in select patients who would otherwise require a formal mastectomy. This is usually a discussion between the patient and an oncologic surgeon, and it does not necessarily involve a reconstructive surgery consultation. This is unfortunate, as plastic surgeons utilize numerous approaches to local tumor resection to minimize the aesthetic impact of breast excision frequently overlooked by oncologic surgeons. In fact, early discussion of reconstruction may also allow patients to more comfortably choose mastectomy over BCT. The aesthetic consequences of a lumpectomy excision in a relatively small breast with postoperative radiation (ie, BCT) must be weighed against a total mastectomy with reconstruction (Figure 1). In certain circumstances, the mastectomy with reconstruction will actually provide a better aesthetic outcome. Therefore, involvement of the reconstructive surgeon during the treatment planning process may facilitate decision making by providing patients with a reasonable expectation of aesthetic outcome, regardless of the mode of therapy selected.

 

 

 
Despite the potential advantages offered by BCT, mastectomy remains the treatment of choice for a select number of early cancers and the vast majority of more advanced cancers. The rate of breast reconstruction following mastectomy in the US has increased over the past 3 decades from 3.4% in the mid 1980s, to 8.3% in the early 1990s, to nearly 40% in the 2000s.14,15 Younger age seems to be the most powerful predictive factor for breast cancer reconstruction. Higher income, higher levels of education, race, and tumor stage also play a significant role. The seemingly low global rate of reconstruction following mastectomy may be explained by a failure to adequately inform patients of their reconstructive options at the time of clinical decision making. A population-based study by Morrow and colleagues15 demonstrated that while 78% of breast cancer patients report some discussion of breast reconstruction, <12% could answer three basic questions on breast reconstruction that would be required for informed consent. In addition, more recent data suggest that only 33% of general surgeons discuss breast reconstruction with patients during consultation.18 Patients who understand their reconstructive options were four times more likely to opt for mastectomy with reconstruction than those who were not counseled on reconstruction. The desire to avoid more surgery and the belief that breast reconstruction was not important were the most common reasons to avoid reconstruction.18 This loss of first-line counseling is clearly a major barrier to informed decision making in breast cancer reconstruction. These data become even more interesting when compared to a healthcare system where breast reconstruction is universally proposed during the surgical oncology consultation. Under these conditions, investigators in France report that 81% of breast cancer patients evaluated for mastectomy selected breast reconstruction, more than double the number of US women in the busiest centers.19 These data strongly suggest that one’s being adequately informed about breast cancer reconstruction and having access to reconstructive options significantly impacts a patient’s decision on breast cancer reconstruction.

Immediate versus Delayed Reconstruction

In the majority of cases, immediate breast reconstruction following mastectomy is considered the standard of care and affords a number of psychological benefits compared to delayed reconstruction, including a decrease in post-mastectomy anxiety and depression as well as improved self-esteem and sexual satisfaction.20 In addition, prospective studies suggest that the QOL 1 year following immediate reconstruction approaches that of age-matched control subjects without breast cancer.21 However, after 1 year, there appears to be no difference in the general and aesthetic satisfaction with reconstruction between immediate and delayed reconstruction.22

There is still a significant role for delayed reconstruction, particularly in patients with advanced cancers who will require postoperative radiation therapy. Radiation causes progressive fibrosis and microvascular obliteration that manifests as poor wound healing and scar contracture, compromising the tissue health and the ultimate aesthetic outcome of the breast reconstruction. Due to these potential complications, most surgeons would defer reconstruction in this patient population until after radiotherapy when the rate of complications approaches that of non-irradiated patients (Figure 2).23

 

Autologous Tissue versus Implant-based Reconstruction

There are two broad classifications of breast reconstruction following mastectomy. One is the use of prosthetic implants inserted under the skin and muscle of the mastectomy flaps, and the other is transfer of the patient’s own autologous tissue into the mastectomy defect to recreate the contour of the breast mound (Figures 3 and 4). The choice of reconstructive methodology depends on numerous factors, including patient preferences, surgical expertise, stage of disease, potential for postoperative radiation, availability of donor tissue, and general medical health of the patient preoperatively. The potential advantages and disadvantages of these reconstructive options are summarized in the Table.

 

 

 

 
Implant-based reconstruction has evolved significantly over the past decade and, according to 2007 Americian Society of Plastic Surgeons statistics, accounts for approximately 75% of breast reconstruction performed in 2007.6 Typically, this reconstruction can be performed either as a single immediate procedure with insertion of a long-term prosthesis at the time of mastectomy or more commonly as a two-stage procedure, wherein a temporary tissue expander is inserted at time of mastectomy, expanded in an office setting over 1–2 months, and then replaced with a long-term prosthesis (Figures 5 and 6). Very high levels of patient satisfaction have been reported using these techniques.24 The down side of this approach is that it requires a two-stage approach, as noted above, and the implants need to be exchanged at regular intervals based on the approximate 10-year lifespan of the implant device.

 

 

Autologous breast reconstruction utilizes a patient’s own tissue to recreate the breast shape, most often involving the transfer of excess skin, fat, and sometimes muscle from a patient’s abdomen to the mastectomy defect. Compared to implant-based reconstruction, the operative time and hospital stay following these procedures is significantly longer. While this reconstruction creates a more natural breast, removal of this “donor tissue” from its native location can weaken the abdominal wall. This has not been found to affect health-related and physical QOL using standardized measures, but it may limit more strenuous physical exercise.25 Based on prospective studies, women selecting autologous reconstruction are aesthetically more satisfied with their reconstruction than women who opt for implant-based reconstruction while the levels of general satisfaction were comparable 2 years postoperatively.22,26,27

In either method, the final stage of reconstruction is the re-creation of the nipple-areolar complex (Figure 7). This typically occurs in a staged fashion under minimal anesthetic. Local skin flaps are re-arranged in such a way to create a projecting nipple. Finally, the surrounding skin and reconstructed nipple can be tattooed to match the areolar color of the contralateral side to complete the breast reconstruction.

 

Impact of Post-mastectomy Radiation

Another important preoperative consideration in breast reconstruction relates to the increasing role of post-mastectomy radiation in breast cancer therapy.28 Frequently, the ultimate oncologic stage is uncertain at the time of mastectomy as definitive pathologic analysis is required to determine the involvement of the axillary lymph nodes. This presents several issues with clinical decision making for breast reconstruction. First, and most importantly, the patient will not know the extent of postoperative adjuvant therapy required (ie, radiation and/or chemotherapy). While breast reconstruction has not been shown to impact the administration of postoperative chemotherapy, radiation, or the ability to detect locoregional recurrence,29-33 complications of the reconstruction, including problems with wound healing can delay adjuvant therapy, which is a source of anxiety for both patient and physician.

Second, whether or not the patient will require radiation potentially changes the optimal reconstructive plan. If this is ultimately determined 1 week following mastectomy after the pathology has been finalized, it presents an obvious clinical dilemma. When it is certain that a patient will not require postoperative radiation, all reconstructive options are available to him or her. Alternatively, if it is known that the patient will definitely require postoperative radiation, then most surgeons would alter their reconstructive plan to either delay reconstruction all together or offer a very limited number of options due to the known increase in complications related to reconstruction after radiation therapy. One such option may be the temporary placement of a tissue expander to maximize skin stretch prior to radiation, which is converted to another form of reconstruction after radiation treatment is completed. However, there is no consensus among plastic surgeons on the use of this particular technique.

In patients presenting with intermediate-sized tumors and clinically negative axillary lymph nodes, it is unknown at the time of mastectomy whether the patient will receive postoperative radiation therapy. Sentinel lymph node biopsy has become the standard tool used to detect involvement in the clinically negative axilla. A negative sentinel node in experienced hands has a 5% to 10% false-negative rate on intraoperative evaluation, making the likelihood of postmastectomy radiation very low when the sentinel node is negative.34 Conversely, a positive sentinel node mandates a formal axillary dissection to quantify the number of nodes involved determined by pathologic diagnosis several days later. Currently, ≥4 positive nodes are an indication for radiotherapy. Again, the uncertainty of postoperative radiotherapy in this situation and how reconstruction should be managed has been the topic of much debate.35,36

Psychological Outcomes of Breast Cancer Reconstruction

Breast reconstruction is powerful in helping patients cope with and recover from the sequelae of breast cancer. The most important measures of success in reconstruction are the level of improvement in QOL and patient satisfaction. In studying these outcomes, it is difficult to utilize prospectively randomized trials to evaluate breast cancer reconstruction, as patient decision making is essential and serves as the basis for this elective procedure. As a result, there are a variety of studies with varied designs and endpoints that must be interpreted wholly rather than individually.

Rubino and colleagues37 retrospectively examined QOL, sexual function, anxiety, and depression of healthy women, mastectomy-only patients, and mastectomy with reconstruction patients at 1 year postoperatively in Italy. They found that after one year there was no statistical difference between healthy patients and reconstructed patients using measures of social and sexual relationships as well as overall QOL. Further, they found that indicators of depression were less severe in reconstructed patients compared to mastectomy-only patients, while levels of anxiety remained similar between these groups. Although reporting relatively few numbers, they identified that a pre-existing psychological disorder was an indicator for postoperative dissatisfaction with reconstruction. They did not demonstrate any significant difference between the type and timing of breast reconstruction. While these data suggest a significant benefit to breast reconstruction, it is unclear whether there were baseline psychological differences between the two groups preoperatively (ie, patients with higher QOL standards may opt to undergo breast reconstruction more frequently). Nonetheless, these data provide strong evidence that patients benefit from breast reconstruction.

Elder and colleagues21 prospectively compared QOL in a broad range of categories under the Medical Outcome Study 36-Item short form in Swedish women who underwent immediate implant-based reconstruction compared to a healthy reference population at 1 year. These investigators found that, like others before them, the QOL measures were lower pre-operatively in the breast cancer group than the reference population. However, 1 year following surgery, they found that QOL measures of patients who underwent immediate breast reconstruction returned to levels comparable to that of the reference population with a high rate of reconstruction satisfaction. While this study did not analyze a group that underwent mastectomy-only or breast-conserving surgery, these data seem to support the psychological benefits of immediate breast reconstruction.

Ananian and colleagues19 prospectively examined factors involved in patient decision making for breast cancer reconstruction in a French healthcare system that universally offers reconstruction (without added cost) to mastectomy patients. This is important because reconstruction is not a universally discussed topic during oncologic consultation in the US. They found a strikingly high rate of breast reconstruction following mastectomy (81%). Greater awareness of body image was an important factor in the decision to reconstruct while fears of additional surgery prevented most women who did not choose to have reconstruction from choosing this pathway. Patients selecting reconstruction were more often younger, active, and more educated patients who were with a partner. Furthermore, 83% of patients who chose to have reconstruction selected immediate reconstruction, most often predicted by breast symptoms, greater preoperative appetite loss, lower body mass index, and a more patient-centered doctor-patient relationship. Due to the nature of the healthcare system, this study essentially excluded issues of patient access to reconstruction information and economic restraints, focusing primarily on patient decision making. The higher rate of reconstruction (over twice that observed in the US) indicates the great influence that patient access to reconstruction information has on decision making in breast cancer reconstruction. These data suggest that when patients have access and are offered the option of reconstruction in a multidisciplinary and non-biased fashion, reconstructive rates will be high.

Harcourt and colleagues38 prospectively compared QOL indicators in women in the United Kingdom undergoing mastectomy alone, mastectomy with immediate reconstruction, and mastectomy with delayed reconstruction. Based on their data, they failed to identify a consistent benefit of immediate breast reconstruction in QOL and psychological variables but noted a significant improvement in a small sample of delayed reconstruction patients. However, there was a notable difference in the mean age of the mastectomy-only group compared to the two reconstructed groups (approximately 10 years), and as noted previously, age is the most powerful predictor of the decision to reconstruct. It has been suggested that possible reasons why older women are less likely to undergo reconstruction include the reluctance to undergo multiple additional procedures to complete the reconstruction, decreased importance of body image compared to younger patients, and the bias of surgeon selection of younger healthier patients who would tolerate a prolonged procedure.15

Based on the above studies, although somewhat disparate in terms of study designs and goals, it would seem that women’s attitudes toward breast reconstruction vary according to geographic and cultural differences. Mullan and colleagues39 specifically addressed this question, prospectively comparing the QOL of women from different countries undergoing mastectomy with reconstruction to healthy controls. They also observed an improvement in the psychological profile of women undergoing reconstruction but noted that country of origin and cross-cultural factors do not seem to contribute to the QOL benefit to breast reconstruction in these populations. As with earlier studies, however, there was no comparison to a mastectomy without reconstruction group. It has been reported that breast cancer patients experience some degree of improvement of QOL and psychological measures during the first year following mastectomy.

The Michigan Breast Reconstruction Outcome Study26,40 is a large prospective study underway examining patient satisfaction and QOL outcomes in patients undergoing different types of breast reconstruction. These investigators did not include a mastectomy-only group or a healthy reference population, as their goal was to compare procedure choice. Although still in data collection, patients who underwent autologous tissue reconstruction were more aesthetically satisfied 2 years postoperatively than patients who underwent implant-based reconstruction. The levels of general satisfaction with the reconstructive procedure were comparable at 2 years. It will be interesting to follow the outcome of this study to see if patient preference for autologous reconstruction persists beyond 5 years.

Parker and colleagues41 prospectively compared outcomes in patients with early breast cancer (stage I or II) who underwent mastectomy alone, mastectomy with reconstruction, and breast-conserving therapy. They found no differences in the majority of QOL and psychological outcomes 2 years following treatment. Specifically, they provided evidence that all three groups experience significant improvement in psychological functioning at two years, often returning to preoperative levels (ie, post-cancer diagnosis) but did not find that reconstruction differed from BCT significantly in level and rate of improvement. They found that patients reconstructed with autologous tissue were somewhat more satisfied with the appearance of their abdominal area (Figure 8) and that there was less of a decline in sexual function. While this study seems to conclude that BCT and reconstruction are equivalent in terms of outcomes, it is unclear how each patient was presented with their surgical options and how decision making was influenced by the surgeons. For example, in patients with large breasts, a small peripherally located tumor would likely have good to excellent cosmesis following BCT, and most plastic surgeons would agree that a formal “reconstruction” would not be required. Alternatively, in patients with small breasts for whom a significant percentage of the breast will be taken with the specimen, reconstruction would likely provide a better cosmetic outcome than BCT. The relationship between tumor size and the percent of breast parenchyma required for resection is an important factor that is often overlooked in outcome studies. It is unclear how these factors influenced the results reported in this study.

 

 

 

Conclusion

Breast cancer reconstruction is a complex process that should begin with the identification and treatment of psychological issues preceding or accompanying the diagnosis of breast cancer. Access and delivery of breast cancer reconstruction information to eligible patients remains widely underutilized. The time of breast cancer diagnosis is an important point of access for patients to either receive actual information or to be instructed on where to find information on breast reconstruction. Early consultation with a reconstructive plastic surgeon may facilitate patient decision making, optimizing the aesthetic outcome of breast reconstruction. Thus, a close collaboration between primary providers, oncologic surgeons, and plastic surgeons is essential. Several studies demonstrate positive psychological and QOL outcomes following breast cancer reconstruction and, in some cases, near normalization of these parameters when compared to healthy individuals. Breast cancer reconstruction continues to be an essential element in helping patients recover from breast cancer diagnosis and therapy. PP

References

 

1.    American Cancer Society. Cancer Facts & Figures: 2007. Atlanta, GA: American Cancer Society; 2007.
2.    Bard M, Sutherland AM. Psychological impact of cancer and its treatment. IV. Adaptation to radical mastectomy. Cancer. 1955;8(4):656-672.
3.    Bard M. The sequence of emotional reactions in radical mastectomy patients. Public Health Rep. 1952;67(11):1144-1148.
4.    Goin MK, Goin JM. Psychological reactions to prophylactic mastectomy synchronous with contralateral breast reconstruction. Plast Reconstr Surg. 1982;70(3):355-359.
5.    Steinberg MD, Juliano MA, Wise L. Psychological outcome of lumpectomy versus mastectomy in the treatment of breast cancer. Am J Psychiatry. 1985;142(1):34-39.
6.    American Society of Plastic Surgeons. 2007 Reconstructive Surgery Procedures. Arlington Heights, IL: American Society of Plastic Surgeons; 2007.
7.    Hegel MT, Moore CP, Collins ED, et al. Distress, psychiatric syndromes, and impairment of function in women with newly diagnosed breast cancer. Cancer. 2006;107(12):2924-2931.
8.    Koopman C, Angell K, Turner-Cobb JM, et al. Distress, coping, and social support among rural women recently diagnosed with primary breast cancer. Breast J. 2001;7(1):25-33.
9.    Fallowfield L, Ratcliffe D, Jenkins V, Saul J. Psychiatric morbidity and its recognition by doctors in patients with cancer. Br J Cancer. 2001;84(8):1011-1015.
10.    Kornblith AB, Herndon JE 2nd, Weiss RB, et al. Long-term adjustment of survivors of early-stage breast carcinoma, 20 years after adjuvant chemotherapy. Cancer. 2003;98(4):679-689.
11.    Roth RS, Lowery JC, Davis J, Wilkins EG. Psychological factors predict patient satisfaction with postmastectomy breast reconstruction. Plast Reconstr Surg. 2007;119(7):2008-2015.
12.    Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1995;333(22):1456-1461.
13.    Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227-1232.
14.    Rowland JH, Desmond KA, Meyerowitz BE, Belin TR, Wyatt GE, Ganz PA. Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst. 2000;92(17):1422-1429.
15.    Morrow M, Mujahid M, Lantz PM, et al. Correlates of breast reconstruction: results from a population-based study. Cancer. 2005;104(11):2340-2346.
16.    Morrow M, Scott SK, Menck HR, Mustoe TA, Winchester DP. Factors influencing the use of breast reconstruction postmastectomy: a National Cancer Database study. J Am Coll Surg. 2001;192(1):1-8.
17.    Christian CK, Niland J, Edge SB, et al. A multi-institutional analysis of the socioeconomic determinants of breast reconstruction: a study of the National Comprehensive Cancer Network. Ann Surg. 2006;243(2):241-249.
18.    Alderman AK, Hawley ST, Waljee J, Mujahid M, Morrow M, Katz SJ. Understanding the impact of breast reconstruction on the surgical decision-making process for breast cancer. Cancer. 2008;112(3):489-494.
19.    Ananian P, Houvenaeghel G, Protière C, et al. Determinants of patients’ choice of reconstruction with mastectomy for primary breast cancer. Ann Surg Oncol. 2004;11(8):762-771.
20.    Al-Ghazal SK, Sully L, Fallowfield L, Blamey RW. The psychological impact of immediate rather than delayed breast reconstruction. Eur J Surg Oncol. 2000;26(1):17-19.
21.    Elder EE, Brandberg Y, Bjorklund T, et al. Quality of life and patient satisfaction in breast cancer patients after immediate breast reconstruction: a prospective study. Breast. 2005;14(3):201-208.
22.    Alderman AK, Wilkins EG, Lowery JC, Kim M, Davis JA. Determinants of patient satisfaction in postmastectomy breast reconstruction. Plast Reconstr Surg. 2000;106(4):769-776.
23.    Williams JK, Bostwick J 3rd, Bried JT, Mackay G, Landry J, Benton J. TRAM flap breast reconstruction after radiation treatment. Ann Surg. 1995;221(6):756-764.
24.    Cordeiro PG, McCarthy CM. A single surgeon’s 12-year experience with tissue expander/implant breast reconstruction: part II. An analysis of long-term complications, aesthetic outcomes, and patient satisfaction. Plast Reconstr Surg. 2006;118(4):832-839.
25.    Dian D, Schwenn K, Mylonas I, Janni W, Friese K, Jaenicke F. Quality of life among breast cancer patients undergoing autologous breast reconstruction versus breast conserving therapy. J Cancer Res Clin Oncol. 2007;133(4):247-252.
26.    Alderman AK, Kuhn LE, Lowery JC, Wilkins EG. Does patient satisfaction with breast reconstruction change over time? Two-year results of the Michigan Breast Reconstruction Outcomes Study. J Am Coll Surg. 2007;204(1):7-12.
27.    Cederna PS, Yates WR, Chang P, Cram AE, Ricciardelli EJ. Postmastectomy reconstruction: comparative analysis of the psychosocial, functional, and cosmetic effects of transverse rectus abdominis musculocutaneous flap versus breast implant reconstruction. Ann Plast Surg. 1995;35(5):458-468.
28.    Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19(5):1539-1569.
29.    Kroll SS, Khoo A, Singletary SE, et al. Local recurrence risk after skin-sparing and conventional mastectomy: a 6-year follow-up. Plast Reconstr Surg. 1999;104(2):421-425.
30.    Huang CJ, Hou MF, Lin SD, et al. Comparison of local recurrence and distant metastases between breast cancer patients after postmastectomy radiotherapy with and without immediate TRAM flap reconstruction. Plast Reconstr Surg. 2006;118(5):1079-1086.
31.    Singletary SE. Skin-sparing mastectomy with immediate breast reconstruction: the M. D. Anderson Cancer Center experience. Ann Surg Oncol. 1996;3(4):411-416.
32.    Noone RB, Frazier TG, Noone GC, Blanchet NP, Murphy JB, Rose D. Recurrence of breast carcinoma following immediate reconstruction: a 13-year review. Plast Reconstr Surg. 1994;93(1):96-106.
33.    Eberlein TJ, Crespo LD, Smith BL, Hergrueter CA, Douville L, Eriksson E. Prospective evaluation of immediate reconstruction after mastectomy. Ann Surg. 1993;218(1):29-36.
34.    Cody HS 3rd, Hill AD, Tran KN, Brennan MF, Borgen PI. Credentialing for breast lymphatic mapping: how many cases are enough? Ann Surg. 1999;229(5):723-726.
35.    Pomahac B, Recht A, May JW, Hergrueter CA, Slavin SA. New trends in breast cancer management: is the era of immediate breast reconstruction changing? Ann Surg. 2006;244(2):282-288.
36.    McCarthy CM, Pusic AL, Disa JJ, McCormick BL, Montgomery LL, Cordeiro PG. Unilateral postoperative chest wall radiotherapy in bilateral tissue expander/implant reconstruction patients: a prospective outcomes analysis. Plast Reconstr Surg. 2005;116(6):1642-1647.
37.    Rubino C, Figus A, Lorettu L, Sechi G. Post-mastectomy reconstruction: a comparative analysis on psychosocial and psychopathological outcomes. J Plast Reconstr Aesthet Surg. 2007;60(5):509-518.
38.    Harcourt DM, Rumsey NJ, Ambler NR, et al. The psychological effect of mastectomy with or without breast reconstruction: a prospective, multicenter study. Plast Reconstr Surg. 2003;111(3):1060-1068.
39.    Mullan MH, Wilkins EG, Goldfarb S, et al. Prospective analysis of psychosocial outcomes after breast reconstruction: cross-cultural comparisons of 1-year postoperative results. J Plast Reconstr Aesthet Surg. 2007;60(5):503-508.
40.    Wilkins EG, Cederna PS, Lowery JC, et al. Prospective analysis of psychosocial outcomes in breast reconstruction: one-year postoperative results from the Michigan Breast Reconstruction Outcome Study. Plast Reconstr Surg. 2000;106(5):1014-1025.
41.    Parker PA, Youssef A, Walker S, et al. Short-term and long-term psychosocial adjustment and quality of life in women undergoing different surgical procedures for breast cancer. Ann Surg Oncol. 2007;14(11):3078-3089.

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Donald S. Robinson, MD

Primary Psychiatry. 2008;15(10):32-34
 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, Epix, Johnson and Johnson, PGxHealth, Pfizer, QRx Pharma, and Schering.


Osteoporosis is a common medical condition among older aged adults in the United States. It is estimated that 50% of women and 20% of men >50 years of age of Caucasian descent are afflicted, and as a result, they carry higher risk for osteoporotic fractures during their lifetime.1 Osteoporosis represents a major public health concern, with an estimated annual cost of $17 billion in the US alone.2,3 Numerous widely prescribed medications may have heightened risk for osteoporotic fractures. A recent example is linkage between popular drugs prescribed for heartburn and acid reflux, the proton pump inhibitors (eg, omeprazole), and hip fracture.4 While the mechanism of this increased risk is unclear, it is speculated that inhibiting stomach acid by proton pump-inhibiting drugs speeds up bone demineralization.

Several psychotropic medications are implicated in increased risk of osteoporotic fracture.5-7 Selective serotonin reuptake inhibitors (SSRIs), in particular, are linked to greater susceptibility to bone fractures. This raises concerns because of the likelihood of long-term exposure to SSRIs at both ends of the age spectrum, ie, children and adolescents as well as older adults. These age groups appear to be more susceptible to potential adverse effects of certain psychotropic agents on skeletal health. A recent large epidemiologic study of residents enrolled in the provincial healthcare system of the Province of Manitoba, Canada implicates psychotropic medications as a cause of bone fragility fractures in older adults.8

Role of Neurotransmitter Systems in Bone Metabolism

There are convincing data that the nervous system exerts a significant physiologic influence on bone and periosteum tissue. These structures have sympathetic nerve fiber and sensory innervation. Studies show that nerve terminals innervating bone contain several neuropeptides, including calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y.9 Current investigations suggest that neurotransmitters play a role in regulating bone metabolism. Studies in rodents with genetically deleted transporter for the neurotransmitter dopamine find reduced cancellous bone mass of vertebrae and tibia and decreased femur length and thickness.10 Impairment of the dopamine transporter appears to affect skeletal structure and integrity during growth periods.

Serotonin (5-HT) receptors have been isolated from osteoblastic cells, the major cell type involved in bone production. The 5-HT transporter (5-HTT) appears to be an important modulator of bone cell activity.10,11 Rodents with genetically deleted 5-HTT transporter have significantly less bone mineral content. Bone mineral content is diminished in normal animals treated chronically with fluoxetine.11 This fluoxetine effect was most prominent at weight-bearing sites of skeletal bone.

Several 5-HT receptor subtypes have been identified in osteoblasts, osteoclasts, and periosteal fibroblasts, including 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors.11,12 Osteoblasts appear to contain a functional 5-HT receptor system intracellularly as well as an intrinsic 5-HT uptake mechanism to modulate the effects of this neurotransmitter on bone metabolism. Abnormalities ascribed to chronic fluoxetine administration are of concern because SSRIs are often prescribed to children and adolescents as well as older adults who are at greater risk for age-related osteoporosis.

Population Studies of SSRI Use and Fragility Fractures

Several prior studies show that SSRI treatment is associated with lower bone mineral density13,14 and increased fracture risk.8,15-18 Utilizing healthcare administrative data, studies15-18 find that SSRI use correlates with incidence of fragility fractures. However, these investigations all suffer the drawback that they failed to adequately control for potential confounding factors, including concomitant medications, lifestyle differences, and health conditions that might affect bone density.

In a recent large population study,7 investigators involved in the Canadian Multicentre Osteoporosis Study examined SSRI use and fracture risk due to bone fragility. They conducted a population-based, randomly selected, prospective cohort study of >5,000 community-dwelling adults ≥50 years of age. Clinical fragility fractures were defined as those due to minimal trauma and documented by radiography. The subjects were participants in a long-term osteoporosis study living near seven regional urban centers in Canada. As part of the osteoporosis study, subjects underwent an in-depth health status interview at entry, and again 5 years later. Data on medication use, dosage, type of drug, and frequency of use were collected. Only data on SSRIs available for prescription at the time of the initial interview were analyzed. Bone-mineral density of the lumbar spine and hip was measured by radiography. Fragility fractures were categorized as those due to minimal trauma, eg, falling from bed, chair, or upright standing position.

The study enrolled 6,005 subjects ≥50 years of age; 997 subjects were excluded for incomplete or missing data. Of the remaining 5,008 subjects, 609 (12.2%) reported depressive symptoms, and 137 (2.7%) were found to be chronic SSRI users. This prevalence of SSRI use was similar to that reported by Canadian and US general populations.7 After adjusting for potential confounding factors documented by the in-depth interview, the findings clearly showed that daily SSRI use is correlated with heightened risk of fragility fracture (hazard ratio, 2.0; 95% confidence interval 1.3–3.1). Anatomic location of fractures sustained by SSRI users were: forearm (40%), foot and ankle (21%), hip (13%), rib (13%), femur (9%), and back (4%). Chronic SSRI use was associated with reduced bone mineral density of the hip and lumbar spine.

Case-Controlled Study of Fracture Risk and Use of Psychotropic Medications

University of Manitoba investigators utilizing provincial healthcare data recently reported the largest, most definitive study to date of psychotropic drug use and osteoporotic fractures.8 This case-controlled study accessed patient population data from the Manitoba Department of Health to assess health status and concurrent medication use of patients with recorded bone fractures. Manitoba Health provides comprehensive coverage for essentially all residents of the province of Manitoba, and claims data and pharmacy records are relatively complete for the provincial population. Patients ≥50 years of age with diagnosis of vertebral, wrist, or hip fractures were selected for study. Each patient was randomly matched to three controls based on year of birth, sex, ethnicity, and comorbidity index calculated from diagnostic codes. Only subjects with continuous coverage for health services from the Manitoba government between the years 1988 and 2004 were included. Exclusions were for incomplete medication data, long-term care facility residency, and exposure to drugs that might affect osteoporosis, eg, parathyroid hormones, estrogens, or biphosphanates.

Of 15,797 fracture cases, 99.5% of cases were successfully matched to three control subjects. There were three categories of medication usage, namely, none, past use, and current use within 3 months preceding bone fracture. Potential confounders adjusted for in the statistical analysis were diagnostic codes recorded during the 3-year pre-fracture period for diabetes, heart disease, epilepsy, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), dementia, schizophrenia, and home health care (as a proxy for fragility). Multivariate statistical analyses were employed to control for demographic variables, including income and place of residence, and confounding medical diagnoses and medication usage.

Osteoporotic Fractures and Psychotropic Drug Use

Analysis of demographic variables showed that fractures were more common among urban dwellers and those with the lowest incomes.8 Fractures were more prevalent in subjects with diagnoses of diabetes; epilepsy; arthritis; COPD; and psychiatric diagnoses for depression, substance abuse, schizophrenia, and dementia. Antidepressant and benzodiazepine usage was significantly higher among the fracture cases (Table).

 

 

Depression, dementia, schizophrenia, and substance abuse disorders all correlated with higher fracture risk. Among psychotropic agents, SSRIs were the medication most strongly associated with fractures, even after adjusting for medical and psychiatric diagnoses and concurrent medications. The odds ratio of 1.45 with chronic SSRI usage observed in this study falls within the range reported previously and provides compelling evidence that SSRIs are a significant risk factor for fragility fractures in older adults. This multivariate statistical analysis found that the dosage of both SSRIs and benzodiazepines correlated with fracture risk, unlike other antidepressants, antipsychotics, and lithium.

Conclusion

Population studies show a relationship between psychotropic drug usage and risk of fractures resulting from bone fragility. The mechanism of this heightened susceptibility to bone fracture is unclear. Bone-mineral metabolism appears to be controlled, in part, by serotonin-modulated systems, which could account for the susceptibility of older individuals taking SSRIs to osteoporotic fractures. Unresolved is the issue of how SSRIs might impact bone-mineral accrual in the growing skeleton during phases of growth and development in younger subjects. PP

References

1.    US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
2.    Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761-1767.
3.    Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465-475.
4.    Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.
5.    Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf. 2007;30(2):171-184.
6.    Howard L, Kirkwood G, Leese M. Risk of hip fracture in patients with a history of schizophrenia. Br J Psychiatry. 2007;190:129-134.
7.    Richards JB, Papaoianna A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Int Med. 2007;167(2):188-194.
8.    Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 2008;28(4):384-391.
9.    Hill EL, Elde R. Distribution of CGRP-, VIP-, DβH-, SP-, and NPY-immunorecative nerves in the periosteum of the rat. Cell Tissue Res. 1991;264(3):469-480.
10.    Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 2001;29:477-486.
11.    Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology. 2005;146(2):685-693.
12.    Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ. Expression of serotonin receptors in bone. J Biol Chem. 2001;276(31):28961-28968.
13.    Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240-1245.
14.    Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use. Arch Intern Med. 2007;167(12):1246-1251.
15.    Liu B, Anderson G, Mittmann N, Axcell T, Shear N. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 1998;351(9112):1303-1307.
16.    Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A. Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol. 2003;158(1):77-84.
17.    Schneeweiss S, Wang PS. Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol. 2004;24(6):632-638.
18.    Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 2006;17(6):807-816.