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. 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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Dr. Peselow is research professor at New York University (NYU) School of Medicine in New York City. Dr. Malavade is clinical assistant professor of psychiatry at NYU School of Medicine and house staff of Out-Patient Services at Bellevue Private Hospital in New York City. Dr. Lowe is clinical assistant professor of psychiatry at NYU School of Medicine. Dr. Glick is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in California.

Disclosure: Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer. Dr. Malavade is a consultant to and on the speaker’s bureau of Eli Lilly. Dr. Lowe reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Glick is a consultant to Bristol-Myers Squibb, Janssen, Lunbeck, Organon, Pfizer, Shire, Solvay, and Vanda; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen, Pfizer, and Shire; receives research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, Shire, and Solvay; and owns stock in Forest as well as Johnson and Johnson.

Please direct all correspondence to: Eric D. Peselow, MD, Research Professor, School of Medicine, Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016-8304; Tel: 917-376-6755; Fax: 718-763-1677; E-mail: ericpes@mindspring.com.


 

Focus Points

• Numerous agents throughout history have been used to treat mental illness.
• Orthomolecular psychiatrists have thought that vitamins and amino acids have helped with respect to mental illness in part as a result of their effects on neurotransmitter systems.
• Herbal medications are agents derived from natural products that can be bought over the counter without Food and Drug Administration regulation.
• Herbal medications include Sam-e, inositol, and St. John’s wort, among others.
 

Abstract

Throughout history numerous medications and unique treatments have been tried to diminish the frequency and severity of psychiatric symptoms. Some discovered by serendipity, such as lithium, chlorpromazine, monoamine oxidase inhibitors, and tricyclic antidepressants, have been efficacious and continue to be mainstays of psychiatric treatment. Others, such as insulin coma therapy, chemical convulsive therapies, and continuous sleep therapy, have passed into history. However, due to the fact that Food and Drug Administration-approved drugs have side effects and are efficacious no more than 66% of the time, there has been a need for patients and physicians to attempt to find other agents. This article discusses current orthomolecular agents (amino acids) and herbal agents (Ginkgo biloba, St. John’s wort) and assesses their current utility in treating psychiatric illness.

Introduction: Treatments of Historic Significance

Biological therapies for the treatment of mental disorders have been available since the dawn of civilization. Herbs, potions, and other treatments for emotional disturbance date back thousands of years. In the 20th century, many new pharmacologic and other biological therapies have been developed to treat psychiatric disorders. Some treatments, such as insulin coma therapy, have not survived. It remains to be seen whether newer interventions, described below, will become important tools in modern psychiatric practice or will be quickly dispatched to the vaults of history.

Historic Drugs

Fenfluramine

Fenfluramine, which in 1997 was available for use in decreasing appetite, was presumed to exert its effects through a serotonergic mechanism; however, it was not a stimulant. In 1987, d-fenfluramine, one of its isomers, was introduced in the United States after having been available in Europe for some time and was widely used alone or in combination with phentermine as “fen-phen” in obesity programs. d-Fenfluramine turned out to be associated with changes in the heart valves and with occasionally fatal pulmonary hypertension and was withdrawn from the US market.1,2

Chemical Convulsive Therapies

Convulsive therapies for the treatment of serious psychiatric disorders date back hundreds of years, with the Swiss physician Paracelsus reportedly giving camphor by mouth to induce seizures and to treat lunacy in the 16th century. Several European manuscripts from the 1700s describe the benefits of camphor-induced seizures for the treatment of mania and other forms of insanity. These manuscripts were largely forgotten until the work of Ladislas von Meduna in the 1930s. Von Meduna had experimented with intramuscular (IM) camphor monobromide, caffeine, strychnine, brucine, and other compounds in the treatment of schizophrenia.

The two most common convulsant therapies used for the treatment of dementia praecox were pentylenetetrazol and hexafluorodiethyl ether. Pentylenetetrazol was reliable and was more soluble than many other compounds and also had a quicker onset of action. These latter two agents were inhaled as vaporizers, and both produced convulsions; they were essentially introduced as substitutes for electroconvulsive therapy (ECT). Von Meduna typically used an initial 5 mL dose of a 10% solution of pentylenetetrazol, followed by additional doses every minute if convulsions were not achieved.3-5

The major drawbacks of these chemical convulsions is that seizures sometimes did not occur and patients would experience significant preictal discomfort, including nausea and anxiety, and, thus, would tend to decline further treatment. In the late 1930s and early 1940s, chemical convulsive therapy was replaced by the considerably more reliable ECT, which has greater safety and ease of administration.4

Coma-Inducing Therapies

Insulin coma therapy emerged at approximately the same time in the 1930s as ECT. In 1933, Manfred Sakel observed that dementia praecox patients who went into a coma tended to come out of the coma less symptomatic, exhibiting less severe psychotic symptoms. The treatment involved using incrementally higher doses of IM insulin until the patient became comatose. Comas were initially terminated with glucagon after approximately 15 minutes, but an attempt was made to increase subsequent comas to a maximum of 60 minutes. Patients often required ≥60 treatments before results were observed. Complications, including arrhythmias and laryngeal spasms, were not uncommon, and insulin coma therapy had a fatality rate of at least 1% and, in some samples, considerably higher. The danger of the procedure and a controlled study6 in 1962 that suggested that it was no more effective than a similar period of unconsciousness induced by barbiturates hastened the demise of the procedure. The risk of death (caused by irreversibility of the coma) and intellectual impairment led to a general abandonment of this treatment in the US.

However, some patients clearly appeared to respond to insulin coma therapy who did not respond to other available treatments. Insulin coma treatment had its best results in the treatment of the excited paranoid and catatonic patient.7

Variations of insulin coma therapy included atropine coma therapy used briefly in the 1950s. Atropine in doses of as low as 15 mg/day IM and as high as 200 mg/day was given to induce comas lasting 6–8 hours. If the patient did not wake up spontaneously, the coma was aborted by IM physostigmine. The patient would take warm and cold showers on awakening. Scopolamine, which has actions similar to atropine, was used in a like manner between 5 mg/day and 100 mg/day and was administered as much as 6 times/week.

As with insulin coma therapy, atropine coma therapy was said to be effective for the treatment of schizophrenia and mania. The most serious complications were hyperthermia (which were treated aggressively with ice packs) and rhabdomyolysis. By the late 1950s, coma therapies had been all but abandoned for safer treatments, including ECT and effective antipsychotics.8

Continuous Sleep Therapy

Continuous sleep therapy was introduced by Klaesi in 1920. It continued in use through the 1930s and 1940s. It involved therapies that altered consciousness for extended periods by seizure or coma, as these were thought to be effective in the treatment of psychosis. Even earlier, psychosis was treated by inducing a state of continuous sleep by giving barbiturates, chloral hydrate, or paraldehyde to induce sleep for 20 hours/day. This was repeated for periods ranging from 10 days to 3 weeks. There were brief interruptions from the sleep to allow the patient to eat and to use the bathroom. Complications of barbiturate-induced continuous sleep included allergic reactions, seizures and delirium on withdrawal, and respiratory depression ending in death. Later, the combination of chlorpromazine with benzodiazepines and other hypnotics was used to keep patients asleep for therapeutic purposes. Electrosleep therapy was introduced by Giljarowski in Russia in 1942, whereby a low level of electric current passed through electrodes applied to the patient’s head produced sleep. This was done for 1–2 hours/day for as long as 3 days. Although there are some reports of improvement in anxiety states, obsessive-compulsive disorder (OCD), and schizophrenia, no controlled data are available to support these claims for these treatments. Given the significant morbidity and clear lack of efficacy of this method, it was largely abandoned in the US by the 1960s.9

Hallucinogen Therapy

Many cultures have used hallucinogens, including mescaline, psilocybin, and ergots, for thousands of years to gain spiritual and personal insight. These agents had been used experimentally through the early 1950s. Lysergic acid diethylamide (LSD) was synthesized in the 1930s and was marketed to psychiatrists and other practitioners in the late 1940s under the trade name Desylid as a tool for understanding psychosis and for facilitating psychotherapy. The model psychosis produced by LSD was used to see if it could illuminate the understanding of the schizophrenic process. Using LSD reportedly helped patients capture repressed memories and deal with anxiety, and it allowed patients to gain insight through an analysis of the primary process induced by the hallucinogen. Oral doses of 150–250 mg were administered occasionally by psychiatrists throughout the 1950s and early 1960s to facilitate psychotherapy with some patients.10,11 In the 1960s, Timothy Leary advocated the widespread use of hallucinogens, but the drugs were outlawed as class I controlled substances in 1965.

Although, overall, these agents are no longer used for therapeutic purposes in this country, LSD has fulfilled part of its early promise as a probe for psychosis. More recent understanding of the pharmacology of LSD and its affinity to serotonin (5-HT)2 receptors has supported the interest in developing 5-HT–dopamine antagonists (atypical antipsychotics) with the 5-HT2 receptor-blocking properties. Advocates in the 21st century suggest there may be a role for hallucinogens in psychiatry.12

Detoxification Therapies

The notion that some mental disorders may be related to a toxin of some sort is old. Various methods have been used to combat potential toxins suspected to be included in the etiology of psychosis. In 1949, Kielholz13 suggested that an endotoxin in the blood caused catatonic schizophrenia. More recent attempts to deal with suspected toxins include the use of blood transfusions in the 1940s and 1950s and hemodialysis in the 1970s. In 1977, Wegemaker and Cade14 began to hemodialyze patients with schizophrenia with the hope of removing toxic polypeptides from their blood to alleviate symptoms. A few case reports15,16 in the late 1970s suggested that hemodialysis was an effective short-term and maintenance treatment in some schizophrenic patients. Patients were dialyzed daily until improvement was seen and were then maintained with dialysis every 2–8 weeks. Several patients were said to recover with hemodialysis and to relapse when the treatments were stopped. The investigators presumed that a leucine-containing endorphin was the responsible toxin, but they (and other investigators) were unable to replicate their initial findings. To date, it is believed that the previously mentioned treatments are of no appreciable value. Thus, the hemodialysis joined blood transfusions and other detoxification therapies in the annals of psychiatric history.

Unconventional Treatments: Will They Become Standard in the Future or Will They Fade into History?

Orthomolecular Psychiatry

Some physicians practice holistic medicine with the idea that physical and emotional illness can be caused by deficiencies in naturally occurring substances. It is their belief that these patients can be treated with organic preparations, including vitamins, minerals, amino acids, and, perhaps, herbs and roots. For psychiatric symptoms, practitioners subscribe to the belief that biochemical derangements exist that can be treated with large quantities of agents that compensate for the disorder. Agents used include the B vitamins, lecithin, vitamin C, tryptophan, phenylalanine, and folic acid.

Megavitamin therapy was introduced into psychiatry in 1952 by Osmond and Smythies17 and Hoffer and colleagues.18 Their hypothesis was that faulty adrenalin metabolism in schizophrenia caused the production or inadequate removal of highly toxic methylated biogenic amines. These amines were thought to be the basis for symptoms such as hallucinations. Treatment with large doses of vitamins, such as nicotinic acid, which is converted in the body to nicotinamide, is thought to be instrumental in causing demethylation of such biogenic amines, making them nontoxic and thus reducing psychotic symptoms.

In 1968, Pauling coined the term orthomolecular to refer to the connection between the mind and nutrition.19 Research articles19 were compiled supporting the notion that taking many times the recommended minimum daily dose of vitamins is useful in the treatment of schizophrenia and other psychiatric disorders. Pauling20 suggested that large (mega) doses of vitamin C (ascorbic acid) combined with niacin, pyridoxine (vitamin B6), and folic acid (vitamin B12) were effective in the treatment of mental illness.

Although some severe vitamin deficiencies may result in syndromes with a psychiatric component (eg, niacin deficiency resulting in pellagra), empirical data and an American Psychiatric Association task force have failed to find evidence supporting the notion that schizophrenia and other disorders respond to vitamin therapies. However, that is not to say that vitamins and amino acids are of no importance in preserving mental health. Evidence indicates that severe vitamin deficiencies can result in psychiatric symptoms and that amino acid supplements may be pharmacologically useful in the treatment of some disorders. These are briefly reviewed in the following sections.

Thiamine, Vitamin B12, and Folate

In industrialized societies, severe vitamin deficiencies are rarely encountered, except in certain populations. Those who are elderly, alcohol dependent, or chronically ill or who have certain types of gastrointestinal surgery are at greatest risk. Among the forms of vitamin deficiency most commonly encountered in the emergency room is acute thiamine depletion from alcohol dependence. Thiamine deficiency is seen in patients who have beriberi. Although the chronic forms of thiamine deficiency that lead to beriberi are rarely seen in the Western world, the fulminant depletion of already low stores of thiamine results in Wernicke’s encephalopathy and Korsakoff’s syndrome. Wernicke’s encephalopathy21 classically presents with the triad of ataxia, ophthalmoplegia, and mental confusion, but confusion and a staggering gait are perhaps most common. Although Wernicke’s encephalopathy is an acute process, Korsakoff’s syndrome22 may be the permanent residue of this encephalopathy. Patients with Korsakoff’s syndrome exhibit a well-circumscribed retrograde and anterograde amnesia that results from destruction of the mammillary bodies, and psychotic symptoms are also reported. Wernicke’s encephalopathy is a medical emergency that responds to acute treatment with 50 mg of thiamine intravenously followed by 250-mg IM injections daily until a normal diet is attained. The treatment of uncomplicated acute thiamine deficiencies usually involves 100 mg given orally 1–3 times per day. Thiamine deficiency is also seen in peripheral neuritis associated with pellagra, and should be considered in alcoholic patients with altered sensorium. Dietary sources of thiamine include legumes, pork, beef, whole grains, fresh vegetables, and yeast. Complete dietary abstinence can lead to a disease state in 3 weeks.23

Vitamin B12 deficiency or pernicious anemia is often seen in elderly adults, patients with gastric surgery, and malnourished depressed patients.24 Vitamin B12 is used in the treatment of pernicious anemia; vitamin B12 deficiency; or increased vitamin B12 requirements due to pregnancy, hemorrhage, malignancy, thyrotoxicosis, or liver or kidney disease.25 In addition, anticonvulsants may decrease the absorption of vitamin B12. The most typical psychiatric presentations include apathy, malaise, depressed mood, confusion, and memory deficits. Vitamin B12 concentrations of 150 mg/mL of serum are sometimes associated with these symptoms. Vitamin B12 deficiency is a more common cause of reversible dementia and is typically assessed in dementia evaluations. The treatment of pernicious anemia usually involves daily IM injections of 1,000 mg of vitamin B12 for approximately 1 week, followed by maintenance doses of 1,000 mg every 1–2 months.26

Folic acid is used in the treatment of megaloblastic and macrocytic anemias due to folate deficiency.27 Folate deficiency has been associated with depression and dementia. Other psychiatric symptoms occasionally associated with folic acid deficiency include paranoia, psychosis, agitation, and confusion.28-30 The relationship of folate to depression has been debated over the years. Folate deficiency may be the consequence of anorexia in depressed patients and may also contribute to depression by interfering with the synthesis of norepinephrine and 5-HT. Folate deficiency has been associated with anticonvulsant use (particularly phenytoin, primidone, and phenobarbital) and the sex steroids, including oral contraceptives and estrogen replacement. Perhaps the most common cause of folate deficiency is the malnourishment associated with alcoholism. Many folate deficiencies respond to folate 1 mg/day orally; however, some more severe forms may require dosages of 5 mg as much as three times a day. Dietary supplements of folic acid are often necessary to prevent neural tube defects in pregnant women, particularly those taking anticonvulsants.31

Amino Acids

Amino acids provide the substrate for neurotransmitters and have been used as adjunctive agents in the treatment of depression and sleep. L-Tryptophan was used for many years in the US and elsewhere to treat insomnia and to augment standard antidepressants. L-Tryptophan, the precursor to 5-HT, must be obtained from the diet.

It was believed that, after oral administration of L-tryptophan, free and protein-bound L-tryptophan increase rapidly, and the free fraction is transported into the central nervous system (CNS). It is hypothesized that CNS levels of tryptophan may stimulate 5-HT synthesis and may reverse the depressive episode. Mendels and colleagues32 did not confirm these findings.

L-Tryptophan had been used for many years combined with antidepressants or lithium to decrease response time and had been reported as a reasonable adjunct in converting partial antidepressant responders to full responders.33

Combination treatments of monoamine oxidase inhibitors plus tryptophan have suggested antidepressant efficacy. L-Tryptophan was also noted to be effective when added to clomipramine but did not seem to be effective when added to tricyclic antidepressants (TCAs).

Patients who respond to serotoninergic antidepressants may rapidly relapse into depression on a diet that is deficient in L-tryptophan. Interestingly, patients who respond to more noradrenergic antidepressants appear less vulnerable to relapse with an L-tryptophan–free diet.

The immediate precursor of 5-HT, 5-hydroxytryptophan, has been shown efficacious in two studies34,35 as an augmenter to chlorimipramine. Numerous small studies36 have suggested that, although tryptophan or 5-hydroxytrptophan did have some effect on augmenting antidepressants, it had little antidepressant effect of its own.37

L-Tryptophan was also used as an over-the-counter (OTC) treatment of insomnia in the US. Numerous studies38 suggested that L-tryptophan in doses of 1–6 g before bedtime decreased sleep latency. L-Tryptophan has been unavailable in the US since 1989 because of its association with the eosinophilia-myalgia syndrome, which may have been secondary to an impurity resulting from the processing of the compound. Before this finding, it was believed that, with the exception of rare nausea or the exacerbation of psoriasis, L-tryptophan was well tolerated.

Another amino acid that has been examined as an augmentor to antidepressants is phenylalanine. Phenylalanine is converted to tyrosine as a catecholamine precursor. Phenylalanine has been added to selegiline successfully in the treatment of some patients with refractory major depressive disorder (MDD). However, Mann and colleagues39 noted minimal improvement in depressive symptoms with phenylalanine alone. Tyrosine has been investigated as an augmentor to TCAs and may also have some mild antidepressant activity itself.

Conclusions Regarding Orthomolecular Agents

The above agents are frequently used and promoted for overall mental and physical health. How useful they will prove remains to be seen.

Herbal Agents

Natural medications are medications that are derived from natural products, and are not approved by the US Food and Drug Administration for their proposed indication. In the US, the public spends approximately $4 billion on supplements with little or no data on what to expect.40 Consumers often believe that because a remedy is “natural” it is, therefore, safe. Moreover, since these remedies are most often purchased OTC, there is no clear mechanism for reports of toxicity to reach those who use them.40

Herbal agents used in mood disorders include omega-3 fatty acids, St. John’s Wort, S-Adenosylmethionine (SAMe) and inositol.

Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated lipids which are cardioprotective.41 The most promising data, however, are in the treatment of both bipolar disorder and unipolar depression; positive studies42-45 have been reported in each of these domains. Psychotropically active doses are generally thought to be in the range of 1–2 g/day, with dose-related gastrointestinal distress being the major side effect. There is also a theoretical risk of increased bleeding, so concomitant use with high-dose nonsteroidal anti-inflammatory drugs or anticoagulants is not recommended.

St. John’s Wort

St. John’s Wort (Hypericum perforatum L.) is one of the biggest-selling natural medications on the market. There have been 27 studies46 looking at St. John’s Wort versus placebo. In MDD there is thought to be minimal benefit; in non-MDD or milder depression there is thought to be possible benefit. St. John’s Wort versus standard antidepressants (TCAs and selective serotonin reuptake inhibitors yield similar efficacy.47 Suggested doses range from 900–1,800 mg/day depending on the preparation, and adverse effects include dry mouth, dizziness, constipation, and phototoxicity. Care should be taken in patients with bipolar disorder due to the possibility of a switch to mania. St. John’s Wort may reduce the therapeutic activity of numerous common medications, including warfarin, cyclosporine, oral contraceptives, theophylline, digoxin, and indinavir.

S-Adenosylmethionine

SAMe is an essential methyl group transfers. It is the principal methyl donor in the one-carbon cycle with SAMe levels depending on levels of the vitamins folate and B12. SAMe is involved in the methylation of neurotransmitters.

SAMe has been shown to elevate mood in depressed patients in doses of between 300–1,600 mg/day. Studies48,49 support antidepressant efficacy of SAMe when compared with placebo and TCAs. Potential adverse effects are relatively minor and include anxiety, agitation, insomnia, dry mouth, bowel changes, and anorexia. Sweating, dizziness, palpitations, and headaches have also been reported.

Inositol

Inositol is a natural isomer of glucose that is present in common foods. Inositol has been found in various small studies50-53 to be effective in the treatment of depression, panic disorder, OCD, and possibly bipolar depression. Effective doses are thought to be in the range of 12–18 g/day. Adverse effects are generally mild and include gastrointestinal upset, headache, dizziness, sedation, and insomnia.

Herbal Agents Used for Anxiety Disorders: Melatonin, Valerian, and Kava

Melatonin

Melatonin is a hormone derived from 5-HT and manufactured in the pineal gland. It is actually commercially available, as supplies are derived synthetically or from hog pineal glands. It is useful for individuals who travel across several time zones, as it can help rest one’s biological clock by reorganizing one’s circadian rhythm.

Melatonin is a popular OTC hormone used by many Americans on a regular basis for insomnia, and anecdotal reports54 suggest that melatonin can reduce the insomnia associated with jet lag. The hormone is released naturally by the pineal gland early in the sleep cycle and appears to contribute to natural sleep cycles. A number of small, brief studies55 melatonin can act as a hypnotic in doses of 0.2 mg and 5.0 mg at night, although other placebo-controlled studies55 have disagreed on the efficacy of melatonin versus placebo in doses ranging from 0.5 mg to 10.0 mg/day. Some uncontrolled reports55 suggest that melatonin has mild antidepressant effects. However, because of its reciprocal relationship to beta-adrenergic receptor activity, it may worsen depression in some patients.

High doses may cause daytime somnolence and confusion. The drug can interact with the hypothalamic-pituitary-adrenal axis and thymus and can cause immunosuppression; thus, it must be used cautiously with steroids. The long-term effects of melatonin use are unknown and the efficacy of melatonin has been inconclusive at this time given the widespread use of the drug. Indeed, a recent study by Spitzer and colleagues56 showed no significant differences between melatonin and placebo (dose range from 0.5–5.0 mg) in the treatment of jet lag.

Valerian

Valerian (Valeriana officinalis) is a flowering plant extract that has been used to promote sleep and to reduce anxiety for over 2,000 years. Valerian was thought to be better than placebo in six of seven double-blind studies57 of insomnia (though Valerian has an odor which may have compromised the blind). The onset of action is slow, taking 2–3 weeks to have an effect. Sedative effects are dose-related with usual dosages in the range of 450–600 mg approximately 2 hours before bedtime. In anxiety disorders, there have only been open studies.58 Adverse effects, including blurry vision, gastrointestinal symptoms, headache, and a mild hangover seem to be uncommon.

Kava

In treating anxiety, kava has been effective in seven double blind studies.1 A meta analysis of three of thes studies59 has shown that kava is superior to placebo on the Hamilton Rating Scale for Anxiety. The suggested dose is 60–120 mgday. Major side effects include gastrointestinal upset, headaches, and dizziness. Toxic reactions, including ataxia, hair loss, respiratory problems, yellowing of the skin, and vision problems, have been seen at high doses or with prolonged use. There have also been more than 70 published reports60 of severe hepatotoxicity worldwide. Overall, worldwide there have been 11 cases of liver transplants and four deaths associated with Kava.60 Kava has been banned in the European Union and Canada and has an FDA advisory in the US.

Herbal Agents Used for Cognitive Disorders and Dementia

Ginkgo biloba has been used in Chinese medicine for thousands of years. This natural medication comes from the seed of the Gingko tree and has generally been used for the treatment of impaired cognition and affective symptoms in dementing illnesses; however, there may be a role in the management of antidepressant-induced sexual dysfunction.

The suggested dose of ginkgo biloba is 120–240 mg/day with a minimum 8-week course of treatment. However, it may take up to 1 year to appreciate the full benefit. Since ginkgo has been shown to inhibit platelet-activating factor and has been associated with increased bleeding risk (though results are mixed), it should probably be avoided in those at high risk of bleeding.61 Other noted side effects include headache, gastrointestinal distress, headache, seizures in epileptics, and dizziness. With regard to dementia, the data is inconsistent and the cholinesterase inhibitors and memantine are preferred.62

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA), a precursor hormone for estrogens and androgens, is available OTC. It is an abundantly produced adrenal steroid that has been evaluated as a treatment for psychiatric disorders since the 1950s.

Recent years have seen an interest in DHEA for improving cognition, depression, sex drive, and general well-being in elderly adults. Some reports63,64 suggest that DHEA in doses of 50–100 mg/day increases the sense of physical and social well-being in women 40–70 years of age. Reports also exist65 of androgenic effects, including irreversible hirsutism, hair loss, voice deepening, and other undesirable sequelae. In addition, DHEA has at least a theoretical potential of enhancing tumor growth in people with latent, hormone-sensitive malignancies, such as prostate, cervical, and breast cancers. Despite its significant popularity, there is a dearth of controlled data on the safety or efficacy of DHEA.

DHEA has become popular as an OTC drug that can enhance quality of life. Because of the fact that it is reputed to diminish fat, to increase muscle mass, to increase libido, to increase sense of well-being, and to decrease depression, as well as to prevent various diseases (heart disease, cancer, diabetes, Parkinson’s disease, and Alzheimer’s disease), it is highly used. A recent double-blind depression study66 showed some efficacy in the treatment of depression.

Conclusion: Herbal Medication

One out of every three people in the US will use at least one form of alternative medication. It is important to note that the FDA has no established definition for an herbal supplement. Although traditionally used as drugs, herbal products are generally unable to pass the stringent requirements imposed by the FDA for new molecular entities, such as new medications.

The Dietary Supplement Health and Education Act of 1994 prohibits the FDA from the regulation of dietary supplements as food additives.

An estimated 70% of patients do not inform their doctors about the use of alternative therapies, causing 15 million Americans to be at risk for potential drug-dietary supplement interaction. Many of these therapies may prove to be a valuable addition to the armamentarium of treatments available to psychiatrists in the future.

Overall, the jury is still out. Whether these agents will prove to be safe and effective and used appropriately for psychiatric indications or whether they will pass into history remains to be seen. PP

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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

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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.

 

Dr. Nakka is fellow in the Hematology/Oncology Division at Maimonides Medical Center in Brooklyn, New York, Dr. Miller is associate director of Continuing Day Treatment Services in the Department of Psychiatry at Maimonides Medical Center, and Dr. Astrow is director of the Division of Hematology/Medical Oncology, all at Maimonides Cancer Center in Brooklyn.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors wish to express their appreciation to Vijay Nakka, MSEE, for technical support.

Please direct all correspondence to: Alan B. Astrow, MD, Maimonides Cancer Center, 6300 8th Ave, Brooklyn, NY, 11220; Tel: 718-765-2653; Fax: 718-765-2654; E-mail: aastrow@maimonidesmed.org.


 

Focus Points

• It is necessary to address patients’ psychosocial health to deliver high-quality cancer care.
• Faith and spirituality are important factors in medical decision making, and if physicians do not account for it, the decision-making process may be unsatisfactory.
• Communication skills training is essential for cancer professionals.

 

Abstract

Numerous physicians find it difficult to relay emotionally charged diagnostic and prognostic information to patients. Poor communication leads patients to misunderstand the status of their disease and goals of treatment, which can both adversely impact their decision making and reduce their quality of life. Despite advances in medical science and technology, physicians find themselves face-to-face with anxiety, sadness, and human tragedy. Delivering information to patients in an understandable way that displays concern for the patient as a person is a difficult yet required assignment demanding study and practice. Informative and empathic communication of prognostic information contributes to enhanced patient satisfaction. The high prevalence of physician burnout in oncology community is worrisome, as patients often rely heavily on their physicians for empathy and support. Communication skills training allowing oncologists to practice giving emotionally charged information and to explore their responses to human suffering and tragedy may enhance both patient and physician satisfaction. The authors of this article discuss how varied personality and coping styles and spiritual/cultural values, play a role in the patient’s response to a cancer diagnosis. They describe tools and strategies that can equip physicians to incorporate their understanding of the patient as a person into clinical practice.

Introduction

Discussing cancer diagnosis and communicating with distressed patients are extremely important yet challenging tasks required of the medical profession. The benefits of good communication skills should be well known, but breaking bad news and dealing with human tragedy are never easy, regardless of how skilled one may be. While the natural response to human tragedy is sadness or compassion, another less desirable response is avoidance. Improved communication and a greater degree of connection between the physician and the seriously ill patient may provide the patient with practical knowledge and emotional support needed for informed decision making and the physician with greater work satisfaction and an enhanced sense of meaning and purpose. The authors of this article have reviewed several articles in the medical literature regarding patients’ and physicians’ perspectives on discussing diagnosis and prognosis as well as how a patient’s personality style and any underlying psychiatric illness may affect physicians’ approach to meeting the patients’ information needs. The proposed approach for discussing prognosis is based on negotiation and patient-centered communication as well as the available research on what patients want to know.1,2

 

Physicians’ Perspectives

The difficulties doctors face when discussing prognosis with their patients include their deciding whether to provide estimates and survival statistics, discussing life expectancy with patients with “poor” prognoses, conveying prognostic information with sensitivity and honesty, deciding whether and how to encourage hope, and meeting the needs of patients from various cultural backgrounds whose prognostic information needs may differ. Clinically, the challenge has been balancing these concerns with the complexities of making prognostic estimates while complying with legal requirements to provide patients with all necessary information. A recent survey3 of 604 Australian cancer physicians found that insufficient time to spend with the patient and patients refusing recommended treatment were perceived by these physicians as the leading barriers to engaging in shared decision-making, while a trusting relationship with the patient was seen as most helpful. Though there is a lack of explicit guidance for clinicians concerning the best way to approach prognostic discussion, an evidence-based literature is underway. Anecdotal reports in the literature document the difficulties that physicians face in this arena. A physician in training, for example, recently described a young patient dying from advanced cancer and the plight of the patient’s father who was distressed about not being told the truth of his son’s impending death.4 She outlines treating physicians’ own fear of death and the “unknown” and, in this case, is critical of physicians’ inability to face the truth.

Communications skills do not automatically improve with increasing physician experience. Formal training in communicating complex and emotionally charged information is needed. Until recently, traditional oncology training programs focused on the skills needed to treat a wide range of cancers but did not prepare oncologists for the responsibility of talking to patients about undesired outcomes. In 1998, at the annual meeting of the American Society of Clinical Oncology (ASCO), among 400 oncologists who attended a session on breaking bad news, 74% indicated that they did not have a specific approach planned for breaking bad news, and >90% felt that the most difficult aspect was handling emotions that arise during the interview.5

The oncology community has responded through workshops, sessions at annual meetings, and innovative communications skills modules incorporated into the curricula of oncology training programs. The strongest evidence for the benefit of communications skills training comes from randomized clinical trials offering face-to-face learning involving communication with the patient or simulated patient coupled with opportunities to practice skills and receive feedback in a learner-focused environment.6,7 A 6-step algorithm for breaking bad news with the acronym SPIKES (setting, perception, invitation, knowledge, emotion, strategy, and summary) has been shown to be easily learned and taught8 and mirrors what patients say they want from their physicians.9,10

SPIKES is a consistent strategy that helps oncologists relate bad news. It encourages them to both assess patient response as it occurs and respond flexibly and constructively. The keys are to allow sufficient time, choose a comfortable setting, minimize distractions and interruptions, avoid jargon and try using the patient’s language, resist the temptation to offer premature reassurance, acknowledge and then validate the patient’s emotional response to bad news, and close with a summary and strategy. This approach will likely leave the patient feeling satisfied and prepared to take the necessary steps following the news.

When the SPIKES strategy was presented at the 1998 ASCO workshop, >99% of the oncologists found it easy to understand and remember.5 At the University of Texas MD Anderson Cancer Center, the SPIKES protocol was used in interactive workshops for oncologists and oncology fellows. As an outcome measure, the researchers used a paper and pencil test before and after the workshop to assess physician confidence in carrying out the various skills associated with SPIKES. They found that SPIKES in combination with experiential techniques (eg, role play) can increase the confidence of faculty and fellows in applying SPIKES.11 Undergraduate teaching experience also showed that the protocol increased medical students’ confidence in formulating a plan for breaking bad news.12 The SPIKES protocol has been tried and accepted in both academic and community settings. It may be a valuable tool for numerous medical specialties.5

Bach and colleagues describe the communication skills program, “Oncotalk,” developed for medical oncology fellows with funding from the National Cancer Institute.13 This program uses educational, evidence-based techniques with content tailored to medical oncology fellows. This structured curriculum includes the SPIKES protocol for breaking bad news, simulated clinical situations, trained actors functioning as patients, and other successful programs. The efficacy of Oncotalk was evaluated by measuring changing observable communication behaviors among participants.8 The primary outcomes were observable participant communication skills. These skills were measured during standardized patient encounters before and after a workshop on bad news and discussing transitions to palliative care. Compared with pre-workshop standardized patient encounters, post-workshop encounters showed that participants acquired a mean of 5.4 bad news skills and a mean of 4.4 transitions skills. This behavioral change leads to increased patient centeredness on the part of the physician and improves patient satisfaction.

Whether training in communication skills enhances professional satisfaction and lessens “burnout” is a ripe area for empirical study. Prevalence of burnout in the oncology community of the United States is >60%. The signs of burn-out are frustration, emotional exhaustion, depersonalization, and a sense of low personal accomplishment, all leading to decreased effectiveness at work.14 Burnout and distress can also lead to cynicism, which undermines physicians’ empathy and their relationships with patients. This erosion of compassion is especially troublesome in the field of oncology, as cancer patients often rely heavily on their physicians for emotional support.15 Recently, various causes for burnout were explored in detail. The prevalence of burnout was approximately 60% in a survey of primarily medical oncologists and hematologists. Number of hours spent on patient care and having colleagues with burnout were among the most critical positive associations with burnout, whereas attendance at educational meetings and number of days away from the office were highly significantly associated with less burnout.16

It is important to understand what makes an oncologist feel successful, what coping strategies help combat burnout, and what adds to the process of renewal. The doctor-patient relationship plays an important role for numerous oncologists in this regard, and communication skills are increasingly recognized for their importance in this arena. Clinical encounters that have shown to be especially stressful for oncologists include breaking bad news, discussing transitions in care, discussing/offering end-of-life care, suggesting participation in investigational studies, disclosing error, suggesting complementary and alternative medicine, addressing spirituality, entering family discussions, and approaching cross-cultural issues.17 Communication skills workshops offer simulated patient encounters wherein physicians can explore their responses to sadness and tragedy in a structured and supportive environment. This might lead to a reduction in oncology physician burnout. One small study supports this hypothesis. In a pilot workshop, medical oncology fellows were invited to present cases including a challenging psychosocial component. The purpose was to highlight both the patients’ psychosocial needs and the fellows’ personal responses to them. The program showed high satisfaction among the participants.18 Additional prospective studies are needed to see if these sorts of programs help in preventing burnout among oncologists in the long run.

Patient’s Perceptions and Preferences

Bad news has a direct impact a patient’s life. Each patient has a unique life history and psychological make-up. Therefore, he or she responds to bad news in a unique manner. Some patients seem to prefer less disclosure or at least a gradual unveiling of troubling prognostic information. Two cases suggesting the range of different perceptions that a medical oncologist must be prepared for are discussed below.

An 86-year-old woman with metastatic cancer of the vulva was referred by her gynecologist for evaluation and treatment recommendations. She underwent initial resection 8 years prior, followed by “re-resection” for disease recurrence 4 years prior, followed by additional surgery and radiation for a new recurrence 1 year prior. When seen at her initial visit to the medical oncologist, she presented with widespread painful abdominal wall skin and subcutaneous metastasis. Her son and daughter accompanied her to the medical oncology consultation and were visibly distressed because of their mother’s suffering. The patient, an intelligent woman living independently, had limited knowledge about the nature of her illness, despite the clearly visible metastases, one of which was open and draining. The son and daughter, also intelligent and concerned about their mother, displayed little understanding regarding their mother’s diagnosis and prognosis, despite her extensive medical history and numerous medical and surgical procedures and visits to physicians. The immediate issues at hand for the oncologist to address at this initial consultation were the patient’s severe pain, her profound psychological distress, and her foul smelling and draining cutaneous ulcer. At the same time, the oncologist needed to explain the diagnosis, prognosis, and reasonable treatment options to a patient and family with whom he had no prior relationship and in whom it appeared that some degree of denial was at play. Where does the physician begin?

A 52-year-old flight attendant had stage-3 ovarian cancer, sub-optimally debulked. She had a good initial response to standard chemotherapy but then had an extensive unresectable intra-abdominal recurrence within 6 months. The disease progressed despite multiple attempts at chemotherapy. Throughout, the patient’s main concern was that she continue working. She expressed a strong desire not to receive treatment that would cause hair loss. She made it clear that she did not want to hear bad news and that she wanted to focus only on the positive. Her sister, who accompanied her to several visits, insisted that the patient not be informed of her grave prognosis. The patient continued to work albeit with occasional absences for treatment and for therapeutic palliative paracentesis. Eventually, her condition worsened; she developed fevers, abdominal bloating, and inability to eat and was hospitalized for terminal care. The patient, though clearly dying, showed no interest in discussing what lay ahead. What is the oncologist’s obligation in this setting?

Empirical studies are beginning to give some evidence-based guidance to these questions. Understanding the patients values appears to help determine how to speak to a patient and what information to provide. Attention to the spiritual needs of patients can be considered an important aspect of health care that is not necessarily based on therapeutic benefit but that instead stems from a commitment to respecting patients as whole people.19 Faith is an important factor in medical decision making and plays an important role in how some patients decide on treatment.20 If physicians do not account for it, the decision-making process may be unsatisfactory to all involved. In a study21 of urban patients’ views about spirituality and health care, patients whose spiritual needs were not met reported lower ratings of quality and satisfaction with care.

Other studies have shown that factors predicting satisfaction among patients included making the environment comfortable, giving the patient adequate time to digest troubling news, and attempting to empathize with the patient’s experiences.9 Patients’ preferences for how they would like to be told news regarding their cancer can be grouped into three categories, namely content (what and how much information is told), facilitation (setting and context variables), and support (emotional support during the interaction). In a study of 351 patients with a variety of cancers, women and patients with higher education had signficantly higher scores on the content scale; women had higher scores on the support scale. In other words, women and patients with more education wanted more detailed information; female patients wanted more emotional support. Younger patients and those with more education had higher scores on the message facilitation scale. Medical variables were not associated with patients’ ratings of the importance of the three categories.10

There is growing evidence that psychological interventions can positively affect quality of life of cancer patients,22 prolong life,23,24 and possibly even affect the immune system.25 Maximizing hope during disclosure of a diagnosis is one way clinicians can contribute to psychological adjustment early in the treatment process. Patients look to their physicians for knowledge, expertise, skill, and human concern. By appearing confident and empathic while still realistic, a physician helps give patients hope. In contrast, being negative and maintaining a distant affect takes hope away.26 In a British survey of 2,331 patients with cancer, 98% indicated that they wished to have “all information” about their cancer.27 A more recent survey of 126 cancer patients found that almost all patients wanted their doctor to be realistic, provide an opportunity to ask questions, and acknowledge them as an individual when discussing prognosis. In addition to physicians’ knowledge on up-to-date treatment about patients’ cancer, they found that “saying that pain will be controlled” is one of the most hope-giving behaviors.28

Depression as a Barrier to Effective Oncologist-Patient Communication

Depression is common in the general population, as well as in adults and children with cancer, frequently coexisting with anxiety and pain. Unsuspected depression and/or anxiety can frustrate the oncologist’s efforts to communicate effectively with patients.29 The Psychosocial Collaborative Oncology Group determined that approximately 47% of hospitalized and ambulatory adult cancer patients had clinically apparent psychiatric disorders and 68% with depressed or anxious mood. A higher percentage of patients with a psychiatric diagnosis experienced significant pain compared to those who did not receive a psychiatric diagnosis.30 Cancer types highly associated with depression include oropharyngeal (22%–57%), pancreatic (33%–50%), breast (1.5%–46%), and lung (11%–44%).29 Depression is less prevalant in patients with cancers, such as colon (13%–25%), gynecologic (12%–23%), and lymphoma (8%–19%).29 It is important to note that the prevalence of depression varies with age, gender, where the individual stands in the course treatment, geographic location,31 and the presence of pain. It is difficult for the clinician to reliably predict the potential for depressed affect in an individual patient. Perhaps a more effective predictor of clinical depression is physical performance as measured by the Karnofsky scale.32 In one study, among patients with a Karnofsky score of ≤40, 77% met the criteria for major depressive disorder (MDD). Of those with scores >60, only 23% met the criteria for MDD.29

In addition, there was variance in screening and referral for depression based on the location. A study reported from New York City33 found that 44% of patients scoring ≥13 on Hospital Anxiety and Depression Scale were referred for evaluation. Another study34 from South Africa found that only 14% of patients identified as depressed had been identified and treated for depression. Pascoe and colleagues34 found that the majority of cancer patients with psychological distress were not receiving counseling or psychological treatment.

Hoffman and Weiner35 described strategies to enhance the oncologists’ ability to detect and diagnose depression in his or her patients. First, oncologists should expand their differential diagnosis of somatic symptoms to include depression. Second, the observatoins of people close to the patient should be obtained. Third, oncologists should follow the patient’s mood longitudinally. Fourth, the patient’s responses should be compared with normative responses. Lastly, the oncologists should be aware of disease phases associated with patient distress. The oncologist is typically under much time pressure during an average visit. If a patient has mild-to-moderate symptoms sugggestive of depression, the oncologist can space his or her evaluation over two meetings (Figure 1).36   

 

 

Coping Style and Prognostic Disclosure

Personality, spirituality/culture, and adaptation style collectively play a role in the patient’s response to a cancer diagnosis. The physician who knows his or her patient and acknowledges these key variables can most effectively engage in guiding the patient throughout the illness cycle (Figure 2).37,38

 

 

Personality

To be most thoroughly informed, the physician must begin by examining the building blocks38 informing the patient’s view of himself, others, and the world. These are formed early in childhood, and initially introduced by one’s parents. They are elaborated on through one’s learning and contact with other individuals, including teachers, clergy, friends, and family. With a sense of community and embedded national belief systems, the templates an individual utilizes to interpret events in his or her life are established.

Spirituality/Culture

It is essential to elucidate the patient’s spiritual/cultural beliefs with respect to a higher power and death/dying. While physicians are best informed of these by asking the patient formally and directly, informal conversation with and observation of the patient and his or her family are just as useful in informing physicians of the patient’s views.

Adaptation Style

Watson and Greer37 offer a practical and illuminating way to perceive the manner in which patients approach coping with serious medical conditions. A summary of a sample of those views is illustrated in Table 1,37 where an attempt is made to categorize them as they inform the physician of the patient’s likely adaptation style. Through an elucidation of the patient’s adaptation style, it is possible to anticipate and predict the specific coping strategies most likely to be employed throughout the illness cycle. Numerous studies have examined these coping strategies, concluding that active coping styles are much more effective in minimizing the emotional distress associated with serious medical illnesses.39 Approaching serious illness with a sense of helplessness/hopelessness has yielded depressive disorders while anxious preoccupation is likely to result in anxiety-related illnesses.

 

 

 

Synthesis: The Informed Physician

The physician who utilizes these building blocks develops insight into the patient’s likely adaptation style and is in the best position to establish a treatment approach best suited to his patient. For example, those who believe their fate is in God’s hands and have a fatalistic adaptation approach are less likely to ask questions or seek a great deal of attention/assistance from family/friends. However, those with a more hopeless or preoccupied approach may require the intervention of a psychiatric consult to help them cope with their emotional pain. Overall, the physician is now most thoroughly and appropriately informed with respect to the best manner in which to communicate/intervene with his patient.

Practical Application

Recalling the two case scenarios presented earlier, the emerging evidence base offers practical suggestions. For the 86-year-old woman with advanced vulvar cancer, the key initial issues include ascertaining patient and family’s understanding of the nature of her illness. Given her severe pain and distress at the foul smell of her metastatic lesions, offering a practical strategy to address these would be crucial at an initial visit. Confronting the patient and family’s denial would likely prove counter-productive. At subsequent visits, the physician would want to explore the patient and family’s wishes regarding how they want information to be related, try to get a sense of what the patient’s “coping style” might be and how her spiritual beliefs and values might influence attitudes toward continued treatment, explore the patient’s emotional reaction to the presence of visible and disfiguring metastases and offer empathic support. Once a trusting relationship has been established, the physician could move on to discussion of realistic treatment alternatives, including hospice referral. If there was evidence of underlying depression or anxiety, a psychiatric referral or pharmacologic treatment might be offered.

Regarding the second patient with advanced ovarian cancer who only wanted to hear good news and whose sister insisted that she not be told of her grave prognosis, patients may choose to allow others to be the primary recipients of diagnostic and prognostic information. This patient’s coping style appears to best fit the category of “avoidance/denial,” and attempts to engage in realistic discussion are likely to be rejected by the patient. However, it would be important to explore the patient’s reasons for not wishing to participate in crucial decisions about her care, offer her opportunites over the course of the relationship to change her approach, and explore the sister’s reasons for wishing to keep the patient uninformed. Requests for non-disclosure are common. Table 2 summarizes the priniciples of a suggested approach to such a scenario.40

 

Conclusion

Communication skills do not necessarily improve solely with years of medical practice.41 In recent years a variety of resources have emerged, highlighting the importance of communication skills training for cancer professionals. Evidence for the efficacy of formal training in communicating diagnosis and prognosis is beginning to emerge. Recognition of co-existing psychiatric illness and elucidation of each patient’s unique coping style may facilitate oncologist-patient communication. Additional studies of the impact of improved communication on patient and professional satisfaction need to be conducted. PP

References

1.    Back AL, Arnold RM. Discussing prognosis: “how much do you want to know?”: talking to patients who do not want information or who are ambivalent. J Clin Oncol. 2006;24(25):4214-4217.
2.    Back AL, Arnold RM. Discussing prognosis: “how much do you want to know?”: talking to patients who are prepared for explicit information. J Clin Oncol. 2006;24(25):4209-4213.
3.    Shepherd HL, Tattersall MH, Butow PN.  Physician-identified factors affecting patient participation in reaching treatment decisions. J Clin Oncol. 2008;26(10):1724-1731.
4.    Rockwell LE. Truthtelling. J Clin of Oncol. 2007;25(4):454-455.
5.    Buckman RA. Breaking bad news: the S-P-I-K-E-S strategy. Community Oncology. 2005;2(2):138-142.
6.    Fallowfield L, Jenkins V, Farewell V, et al. Efficacy of Cancer Res UK communication skills training model for oncologists: a randomized controlled study. Lancet. 2002;359(9307):650-656.
7.    Razavi D, Delvaux N, Marchal S, et al. Does training increase the use of more emotionally laden words by nurses when talking with cancer patients? A randomized study. Br J Cancer. 2002;87(1):1-7.
8.    Back AL, Arnold RM, Baile WF, et al. Efficacy of communication skills training for giving bad news and discussing transitions to palliative care. Arch Int Med. 2007;167(5):453-460.
9.    Ptacek JT, Ptacek JJ. Patients’ perceptions of receiving bad news about cancer. J Clin Oncol. 2001;19(21):4160-4164.
10.    Parker PA, Baile WF, de Moor C, Lenzi R, Kudelka AP, Cohen L. Breaking bad news about cancer: patients’ preferences for communication. J Clin Oncol. 2001;19(7):2049-2056.
11.    Baile WF, Lenzi R, Kudelka AP, et al. Improving physician-patient communication in cancer care: outcome of a workshop for oncologists. J Cancer Educ. 1997;12(3):166-173.
12.    Garg A, Buckman R, Kason Y. Teaching medical students how to break bad news. CMAJ. 1997;156(8):1159-1164.
13.    Back AL, Arnold RM, Tulsky JA, Baile WF, Fryer-Edwards KA. Teaching communication skills to medical oncology fellows. J Clin Oncol. 2003;21(12):2422-2426.
14.    Whippen DA, Cannelos GP. Burnout syndrome in the practice of oncology: results of a random survey of 1,000 oncologists. J Clin Oncol. 1991;9(10):1916-1920.
15.    Shanafelt T, Chung H, White H, Lyckholm LJ. Shaping your career to maximize personal satisfaction in the practice of oncology. J Clin Oncol. 2006;24(24):4020-4026.
16.    Allegra CJ, Hall R, Yothers G. Prevalence of burnout in the U.S. oncology community: results of a 2003 survey. J Oncol Pract. 2005;1(4):140-147.
17.    Armstrong J, Holland J. Surviving the stresses of clinical oncology by improving communication. Oncology (Williston Park). 2004;18(3):363-368.
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