Dr. Kim is director of the Hennepin Women’s Mental Health Program at Hennepin County Medical Center in Minneapolis, Minnesota, and clinical assistant professor of psychiatry at the University of Minnesota Medical School in Minneapolis. Dr. Kolpe is staff psychiatrist at the Hennepin Women’s Mental Health Program and clinical assistant professor of psychiatry at the University of Minnesota Medical School.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Helen Kim, MD, Hennepin Women’s Mental Health Program, S110 Clinic, Hennepin County Medical Center, 900 S 8th St, Minneapolis, MN 55404; Tel: 612-347-6851; Fax: 612-373-1859; E-mail: kimxx237@umn.edu.





What should a clinician consider in selecting a psychotropic medication for pregnant and lactating women with psychiatric symptoms? While postpartum depression is increasingly recognized as a public health priority, vulnerability to depression and anxiety begin in pregnancy. Clinicians are often called upon to counsel pregnant and postpartum patients about the risks and benefits of psychotropic medication. Patients generally overestimate the risks of psychotropic drugs and underestimate the impact of untreated psychiatric illness on themselves and their families. This article reviews recent studies and treatment considerations in selecting psychotropic medications for perinatal women with mood and anxiety symptoms.



The perinatal period can be a high-risk time for worsening mood and anxiety symptoms. While postpartum depression has been identified as a major public health concern,1 vulnerability to depression clearly begins before delivery and continues into the postpartum.2-6 A systematic review of perinatal depression found that the point of prevalence of major depressive disorder (MDD) and minor depression during pregnancy ranged from 6.5% to 12.9%, while another study of >3,000 pregnant patients found that 20% had significant depressive symptoms.7 Many factors have been implicated in worsening mood and anxiety symptoms during pregnancy, including psychosocial risk factors as well as physiologic changes associated with the perinatal period.8-11 Disrupting a maintenance antidepressant may also lead to worsening symptoms in pregnancy as demonstrated in a recent study by Cohen and colleagues,12 in which 68% of women with a history of recurrent MDD relapsed with depression after discontinuing antidepressants compared to 26% who maintained treatment.

With the high prevalence of MDD among women of reproductive age, clinicians are often called upon to help patients weigh the benefits and risks of psychotropic medications during pregnancy and lactation. Recent studies have highlighted both the potential risks of antidepressants in pregnancy as well as the effects of untreated psychiatric symptoms during and after pregnancy. Several studies from the renowned Motherisk Program in Toronto have examined the tendency of pregnant patients to underestimate this risk of untreated depression and anxiety13,14 and overestimate the risk of medication. For example, though the baseline rate of malformations in the general population is approximately 3% to 4%, women exposed to known nonteratogens assigned themselves a risk of 24% for major malformation before hearing about relevant medical studies, and then 14.5% thereafter.15 This misperception of risk can lead patients and physicians to avoid or terminate otherwise wanted pregnancies or avoid needed pharmacotherapy. Clinicians can help put the risks of medication into context by reminding patients that pregnancy itself carries many risks including spontaneous abortion and congenital defects. Many studies have documented the fact that untreated psychiatric illness can compound these risks by contributing to poor self care, decreased prenatal compliance, increased nicotine and substance misuse,16,17 poor obstetrical outcomes,18,19 and increased risk of postpartum depression.20 Given the potential risks of medication during pregnancy, patients often feel like they must not put their own need for symptom relief ahead of the well-being of the pregnancy. Clinicians can help patients realize that these two priorities are inextricably tied since emotional distress also impacts the pregnancy.

Routine formalized screening for major Axis I diagnoses both prenatally and postnatally can assist clinicians in identifying patients with psychiatric symptoms.21,22 Risk factors for depression and anxiety during and after pregnancy are also readily identifiable and include prior history of depression, young age, poverty, stressful life events, and limited social support.23,24 After screening for these risk factors, evaluating current symptoms, and ruling out possible medical conditions (eg, anemia or thyroid dysfunction) that may be contributing to mood, anxiety, and neurovegetative symptoms, clinicians must then direct patients toward the most appropriate course of treatment. This process involves careful review of the risks of untreated illness versus the risks and benefits of available treatment including medication, therapy, and supportive interventions. As Stowe and colleagues25 eloquently articulated, perinatal patients must be guided toward minimizing not only exposure to medication but exposure to illness as well. This article reviews recent studies and focuses on treatment considerations in selecting psychotropic medications for perinatal women with mood and anxiety symptoms.


Pharmacologic Considerations in Pregnancy


Congenital Malformations
Medications taken during pregnancy are considered teratogenic if they increase the risk of congenital malformations above the baseline risk of 3% to 4%. Most studies of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are reassuring and show no increased risk of major congenital malformations.26,27 However, while previous studies have shown no association between paroxetine and congenital malformations,28-30 the manufacturer of paroxetine issued a warning in 2005 that two studies found a possible association between first-trimester paroxetine exposure and increased risk for cardiac defects, particularly atrial and ventral septal in nature.31 Subsequently, the Food and Drug Administration issued a similar warning that first-trimester paroxetine use was associated with an increased risk of major malformations (4% versus 3%), particularly cardiac defects (2% versus 1%), and changed the pregnancy labeling from category C to D, which indicates that controlled or observational studies in pregnant women have demonstrated a risk to the fetus. In addition, the American College of Obstetricians and Gynecologists has recommended avoiding paroxetine use in pregnant women unless the benefits outweigh the risks of discontinuing the medication.32

While there have been fewer reported cases of prenatal exposures to non-SSRIs, the limited data available have not shown an increased risk of congenital malformations with venlafaxine,33 mirtazapine,34 nefazodone, or trazodone.35 In an admirable attempt to prospectively assess reproductive risk, the drug manufacturer of bupropion established a postmarketing epidemiologic surveillance registry in 1997. This registry reported a preliminary finding of a possible association between bupropion exposure and increased risk of birth defects involving the heart and great vessels. In the most recent report from this registry spanning September 1997 through August 2006, 1,443 prospectively registered pregnancies involved exposure to bupropion.36 Among this group, 483 were lost to follow up and 134 pregnancies were pending. Among the remaining 833 prospectively reported pregnancy outcomes, the Bupropion Pregnancy Registry Advisory Committee found no evidence of increased risk of birth defects; however, they warned that the relatively small sample size and large percentage of patients lost to follow up make it impossible to draw definitive conclusions about the possible teratogenic risk of bupropion. These findings are consistent with other studies including a prospective study of 136 women exposed to bupropion in the first trimester of pregnancy that found no increased risk of major malformations,37 and a claims-based, retrospective cohort study using the United Healthcare database which found no consistent pattern of birth defects associated with prenatal exposure to bupropion.38 To register pregnancies in women on bupropion, clinicians can call the GlaxoSmithKline Pregnancy Registry at 800-336-2176.

Perinatal Effects Following Late-Pregnancy Antidepressant Exposure
In utero exposure to antidepressants has been associated with transient symptoms of possible medication withdrawal or toxicity in neonates. These symptoms have been described with many SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) and include irritability, tremulousness, insomnia, poor feeding, temperature dysregulation, increased or decreased muscle tone, and/or respiratory distress.39,40 Using a formal screening tool, one study found that 30% of newborns exposed to SSRIs in late pregnancy developed neonatal abstinence symptoms.41 Although these neonatal syndromes are generally transient and not life threatening, in 2004 antidepressant manufacturers and the FDA decided to modify their drug labeling to include a recommendation to consider tapering antidepressants in the last part of pregnancy. For women with recurrent depression or anxiety conditions, this strategy may not be prudent since it would withdraw treatment just as patients are transitioning to the postpartum, a time of increased risk for affective instability.

Another recent study highlighted another concerning finding regarding antidepressant use in pregnancy. In 2006, Chambers and colleagues42 published a study that found a possible association between SSRI exposure after 20 weeks’ gestation and persistent pulmonary hypertension of the newborn (PPHN), a serious and rare condition with a baseline rate of 1–2 out of 1,000 live births and mortality rate of 10% to 20%. Although this study was retrospective in design and involved only a small number of affected infants, its findings are concerning and highlight the uncertainty that patients and providers must assume in choosing to use antidepressants or any psychotropic medications during pregnancy.

Long-Term Neurobehavioral Effects

It remains to be seen whether in utero antidepressant exposure is associated with any long-term neurologic or behavioral effects. In a cohort of children 4–5 years of age exposed in utero to SSRIs, levels of internalizing and externalizing behavior did not differ significantly between children who were (N=22) or were not (N=14) exposed prenatally to SSRIs.43,44 In another study, Nulman and colleagues45 compared a cohort of mother-child pairs exposed throughout gestation to TCAs (N=46) or fluoxetine (N=40) to a nondepressed comparison group (N=36). Children between 15 and 71 months of age were assessed and compared in terms of intelligence quotient (IQ), language, behavior, and temperament, with adjustment for severity of maternal depression, maternal IQ, socioeconomic status, maternal smoking, and alcohol history. Children exposed in utero to TCAs or fluoxetine were found to have no difference in temperament, language, or cognitive development compared to nonexposed children. In fact, it was exposure to maternal depression and not medication itself that was associated with less language and cognitive achievement.


Mood Stabilizers

Lithium use during pregnancy has been associated with perinatal toxicity, including case reports of lethargy, hypotonia, cyanosis, respiratory distress, and diabetes insipidus.46 In addition, lithium use during the first trimester has been associated with an increased risk of a serious congenital heart defect known as Ebstein’s anomaly and occurs in approximately 1 out of 1,000 live births. For women with moderate-to-severe bipolar disorder with recurrent episodes of mania or depression, the relatively small risk of these adverse pregnancy outcomes may be far overshadowed by the much greater risk of relapse. Maintenance lithium treatment for these patients during pregnancy may be the most prudent treatment option. For women with less severe bipolar disorder who have had significant periods of stability, slowly tapering off lithium and reintroducing it after the first trimester or just after delivery may help lower medication exposure while also minimizing risk of relapse during the postpartum, a time of known high risk in women with bipolar disorder.47

Lamotrigine is another highly effective mood stabilizer, particularly for bipolar depression. As with bupropion, the manufacturer of lamotrigine took a very proactive step in 1992 and established a pregnancy registry to assess the reproductive safety risk of lamotrigine. In January 2007, the Lamotrigine Pregnancy Registry reported its most recent update spanning the time period from September 1992 through September 2006 during which there were 1,539 prospectively registered pregnancies involving lamotrigine exposure.48 Among this group 908 outcomes involved first-trimester lamotrigine exposure with 26 (2.9%) major birth defects. This is similar to the baseline frequency of malformations reported in cohorts of women using antiepileptic monotherapy. Of note, in the 133 pregnancy outcomes involving polytherapy with lamotrigine and valproate, plus or minus another anticonvulsant, there was an alarming 11.3% rate of major congenital defects. Overall, the findings for lamotrigine monotherapy have been reassuring and consistent with other reports.49 However, the North American Antiepileptic Drug Pregnancy Registry recently found that infants who are exposed to lamotrigine as monotherapy during pregnancy have a much higher risk of oral cleft defects.50 In this study, 564 children exposed to lamotrigine monotherapy had a prevalence rate of major malformations of 2.7%; however, five infants had oral cleft lip/palate, yielding a prevalence rate of 9 out of 1,000 births compared to a baseline prevalence of 0.5–2.0 per 1,000 in unexposed infants. A larger sample size is needed to confirm this finding. Even if future prospective studies also find this association between first-trimester lamotrigine use and oral cleft lip and palate, the overall risk appears to be low and may be overshadowed by the high risk of recurrent illness in women with moderate-to-severe forms of bipolar disorder. Clinicians can help expand the available database of lamotrigine exposures by registering all pregnant patients on lamotrigine with the Lamotrigine Pregnancy Registry by calling 800-336-2176, or having patients enroll themselves in the North American AED Pregnancy Registry by calling 888-233-2334.

Valproic acid and carbamazepine have well-established risks of neural tube defects of 1.0% to 5.0% and 0.5% to 1.0%, respectively.51,52 In utero valproate exposure has also been associated with a higher frequency of major anomalies53,54 as well as neurodevelopmental delay in exposed children.55,56 Neonatal complications associated with valproate include irritability, jitteriness, and feeding problems.57 Liver toxicity has also been described following valproate and carbamazepine use during pregnancy.58,59 Less is known about the reproductive safety of newer anticonvulsants such as gabapentin, oxcarbazepine, and topiramate. While these newer anticonvulsants would not be the first choice in pregnancy, they may be indicated for pregnant women with refractory bipolar illness and a history of good response to these medications. Providers should encourage pregnant women who elect to continue any mood stabilizer to take high-dose folate (4 mg/day) for the theoretical benefit of reducing risk of neural tube defects. In addition, pregnant women should undergo a second trimester Level II ultrasound to screen for major congenital anomalies.



Untreated psychosis can be harmful in pregnancy, as demonstrated by one study that found a two-fold increase in adverse pregnancy outcomes (eg, stillbirth, preterm delivery, low birth weight) in women diagnosed with schizophrenia during pregnancy.60 Psychotic symptoms can also lead to disorganized behavior, increased paranoia, avoidance of prenatal care, increased drug and alcohol use, and other high-risk behaviors. First-generation antipsychotics with high and midpotency (eg, haloperidol, perphenazine) are generally considered to be the antipsychotics of choice during pregnancy since they have not consistently demonstrated teratogenic risk.57 Low-potency phenothiazines (eg, chlorpromazine) have shown increased risk of congenital malformations and should be avoided.61 Case reports of neonatal toxicity following in utero exposure to typical antipsychotics have been described and include motor restlessness, tremor, feeding difficulties, increased muscle tone, and abnormal motor movements.62,63

Studies of the reproductive safety of atypical antipsychotics have been limited to small case reports and case series. Olanzapine was not associated with major malformations in a manufacturer-sponsored study of 23 prospectively ascertained pregnancies.64 McKenna and colleagues65 reported on 151 pregnancy outcomes following exposure to olanzapine (N=60), risperidone (N=49), quetiapine (N=36), and clozapine (N=6). Among this total group there were 110 (approximately 73%) live births, 22 (approximately 15%) spontaneous abortions, 15 (approximately 10%) therapeutic abortions, four (approximately 3%) stillbirths, and one (approximately 1%) infant with major malformations. There was no statistically significant difference in pregnancy outcomes between this group and a comparison group of pregnant women except for a higher rate of low birth weight in exposed babies (approximately 10% versus 2%). Given the small sample sizes and the notable differences between the exposed and comparison group (eg, differences in socioeconomic background and rates of elective abortion), no definitive conclusions can be drawn about the reproductive safety of atypical antipsychotics in general. However, one theoretical concern with these medications is their propensity to cause significant weight gain that in pregnancy can lead to or exacerbate pre-existing hypertension and diabetes. This must be considered along with the potentially hazardous consequences of discontinuing an antipsychotic that is effectively treating a pregnant woman with a history of psychotic symptoms.

Based on the available evidence, experts have supported the use of typical antipsychotics for acute treatment of mania or psychosis during pregnancy.57 Others have suggested that the risk with high-potency typical antipsychotics may be less than the risks associated with available mood stabilizers,61 and that they offer a reasonable treatment alternative for women with bipolar disorder with recurrent symptoms during pregnancy.57



Benzodiazepine use during pregnancy has been associated with case reports of perinatal toxicity, including temperature dysregulation, apnea, depressed APGAR scores, hypotonia, and poor feeding. In addition, early studies revealed an elevated risk of oral cleft palate defects compared to the baseline risk in the general population.66 However, more recent studies have shown that the overall risk of cleft lip and palate with benzodiazepine use in pregnancy is likely quite low.67,68 In considering the risks and benefits of benzodiazepines, clinicians should also consider the risks of untreated insomnia and anxiety in pregnancy, which may lead to physiologic effects as well as diminished self care, worsening mood, and impaired functioning. Given the consequences of untreated psychiatric symptoms and the limited and controversial risks associated with benzodiazepine use, some women with overwhelming anxiety symptoms or sleep disturbance may find that the benefits outweigh any theoretical risks.


Pharmacologic Considerations in the Postpartum

Women can experience a range of emotional and psychological symptoms following delivery. Heightened emotional sensitivity, anxiety, and sleep disturbance can affect 80% of women after delivery in the form of the postpartum blues, a normal and self-limited syndrome that usually begins 2–3 days postpartum and resolves in 7–14 days. Approximately 10% to 20% of all postpartum women experience a more serious condition called postpartum depression (PPD). The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision,69 classifies PPD as MDD that occurs within 4 weeks postpartum; however, many new mothers develop symptoms more than 2–3 months after delivery. Postpartum anxiety syndromes are also extremely common and can include panic attacks, intense anxiety about not getting enough sleep, obsessive worry about the baby’s health or safety, and intrusive thoughts or mental images of hurting the baby.70 New mothers with intrusive thoughts are often ashamed of these ego-dystonic images and may develop behaviors to diffuse some of their anxiety and fear, such as avoiding sharp objects or compulsively checking their infants’ breathing. Postpartum patients can be reassured that though intrusive thoughts are common, violently acting them out is very uncommon. Postpartum psychosis is a serious and rare condition that occurs in 1–2 of every 1,000 postpartum women. Postpartum psychosis can begin acutely within the first 48–72 hours after delivery and may include delirium, agitation, irritability, and mood lability. Psychosis can also occur in new mothers with a history of a chronic psychotic disorder or as part of a major depressive or manic episode. Psychotic symptoms in any postpartum woman require immediate intervention in order to protect both mother and infant from harm.


Evaluation of Postpartum Women with Psychiatric Risk Factors or Symptoms

Evaluation of postpartum psychiatric symptoms includes assessment for medical conditions such as anemia or thyroid disorders that can contribute to low mood, anxiety, fatigue, and sleep disturbance. Systematic screening for psychosocial risk factors as well as current symptoms facilitates prevention, detection, and treatment of postpartum psychiatric syndromes. The Edinburgh Postnatal Depression Scale (EPDS) is a widely recommended, cost-effective means of screening for PPD.71 The EPDS is a 10-item self-rating scale that has been validated in Spanish and English and asks about depressive symptoms in the preceding week, including crying spells, decreased interest and pleasure, increased guilt, anxiety, sleeping problems, and thoughts of self harm.72 To improve prevention interventions, clinicians can also screen for risk factors both during and after pregnancy. These risk factors include a personal history of mood or anxiety disorder, psychiatric symptoms during pregnancy, limited social support, interpersonal conflicts, and negative life events during and after pregnancy.73-75 In addition, a history of extreme premenstrual irritability may be a possible marker for increased vulnerability during times of hormone fluctuation, such as the dramatic hormone shifts after delivery.76



Despite the high prevalence of postpartum psychiatric illness, there are only a limited number of medication treatment studies. In small open studies, venlafaxine (N=15),77 bupropion (N=8),78 fluvoxamine (N=6),79 and sertraline (N=26),80 have shown efficacy in treating PPD. Paroxetine alone (N=16) or in combination with 12 sessions of cognitive-behavioral therapy (CBT; N=19) improved mood and anxiety symptoms in a group of women with PPD and anxiety symptoms.81 In small randomized trials, sertraline has shown benefit in both preventing82 and treating83 PPD. In another controlled study of 61 women with PPD, fluoxetine was significantly more effective than placebo in treating PPD.84 Combining fluoxetine with six sessions of CBT did not produce additional improvement. Of note, 101 out of 188 eligible patients refused to enter the trial, mainly because of ambivalence about being randomized to take an antidepressant. Furthermore, the trial excluded nursing mothers as well as women with a history of severe or chronic depression. All these factors limit the generalizability of the findings and underscore the difficulty in carrying out randomized trials in this population. Clearly, more studies are needed with larger sample sizes and longer follow-up periods to compare different antidepressants and other psychosocial interventions.85

The choice of an antidepressant is largely guided by a patient’s depressive symptoms and past history of medication response. If a patient plans to breastfeed, clinicians must facilitate a careful risk-benefit discussion about taking psychotropic medication during lactation (see below). In addition, patients must consider the risks of untreated maternal depression which can lead to impaired mother-infant attachment.86-88 and higher risk of cognitive and behavioral problems.89,90 Women at increased risk for postpartum depression should consider initiating prophylactic antidepressants either in late pregnancy or early postpartum. Alternatively, women may elect a wait-and-see approach; however, patients, their loved ones, and psychiatrists should be vigilant for early signs of recurrence in order to institute prompt treatment.


Hormone Therapy

To temper the tremendous changes in estrogen and progesterone following birth, some studies have looked at hormone therapy. In one study, women with PPD who received transdermal estrogen had significantly lower mean EPDS scores at 4 weeks of treatment compared to placebo.91 However, in another study a single dose of synthetic progestogen administered within 48 hours after delivery was significantly more likely than placebo to be associated with increased depressive symptoms at 6 weeks postpartum.92 Given the limited data available, no specific recommendations can be made regarding the use of hormone therapy for PPD.93,94



All psychotropic medications are secreted into breast milk. Mothers on psychotropic medications require a thorough discussion of the risks and benefits of breastfeeding while taking medication to treat psychiatric symptoms.

A recent analysis of the available studies of antidepressants during lactation revealed that sertraline, paroxetine, and nortriptyline are the least likely to lead to accumulation in the infant.95 Other studies of TCAs and SSRIs have been reassuring and show no consistent association between any particular antidepressant and problems in nursing newborns. There have been isolated case reports of elevated infant levels and toxicity with breastfeeding mothers taking doxepin or fluoxetine.96 Little is known about the safety of other antidepressants during lactation, such as venlafaxine, bupropion, or mirtazapine.

Mood Stabilizers
For women with bipolar disorder, the choice to nurse while on a mood stabilizer is even less clear cut than with antidepressants. Lithium can quickly accumulate in the nursing infant and lead to levels exceeding 50% of the maternal level. Given this risk of lithium toxicity in the nursing infant, breastfeeding while on lithium is generally not recommended,97,98 however, a recent case series of 10 mother-infant pairs noted low infant lithium levels in nursing infants.99 The authors of this article encourage reassessment of general recommendations against lithium during breastfeeding and suggest that nursing on lithium may be appropriate for mothers with bipolar disorder who have healthy infants and who can reliably work with a pediatrician to monitor the infant and obtain infant lithium level, thyroid-stimulating hormone, blood urea nitrogen, and creatinine in the immediate postpartum, at 4–6 weeks postpartum, and then every 8–12 weeks thereafter.

Although not absolutely contraindicated in nursing mothers, valproate has been associated with infant anemia and thrombocytopenia, and carbamazepine has been associated with transient hepatic dysfunction.97 Mothers should be informed of signs of hepatic dysfunction or anemia, such as sedation or poor feeding. Among the few available reports, breastfed infants of mothers on lamotrigine have been shown to have serum levels that are approximately 30% of the mothers’ level.100,101 Though no adverse effects were noted in these infants, the severe life-threatening rash associated with lamotrigine in children and adults may also be a concern for infants exposed to lamotrigine through breastmilk.97

In general, clinicians should advise nursing women on psychotropic medications to monitor infants for behavioral changes, such as excessive sedation, jitteriness, or inconsolable crying. Infants who develop these symptoms should be evaluated by their pediatricians for possible drug toxicity. In the meantime, mothers can consider temporarily pumping and storing/discarding their breastmilk and using formula to see if their infants’ symptoms resolve. In infants who are preterm or have any medical problems, mothers on psychotropic medication could also consider pumping and storing/discarding breastmilk and introducing nursing later when the infant is healthy and can presumably metabolize medication more efficiently.


Supportive Interventions

Although a detailed discussion is beyond the scope of this article, it is important to note that nonpharmacologic interventions such as education, support services, and psychotherapy can be invaluable alternatives or adjuncts to medication for women with perinatal psychiatric symptoms. Establishing a therapeutic alliance; exploring feelings about the pregnancy and motherhood; and taking inventory of strengths, supports, and stressors can help target interventions. Studies have demonstrated that depressed pregnant and postpartum women can also benefit greatly from interpersonal psychotherapy, a time-limited therapy focused on certain areas of particular relevance to pregnant women such as role transitions and interpersonal disputes.102-105 Supportive therapy and CBT have also been shown anecdotally to help with perinatal depression and anxiety as well as referrals to mothers’ groups, childcare resources, and financial assistance agencies. Clinicians can also refer women to Postpartum Support International, an organization with many local chapters that offers support and resources for women with postpartum psychiatric illness.



The perinatal period can be a high-risk time for significant psychiatric symptoms. In treating pregnant and postpartum patients, clinicians must adopt an individualized treatment approach that incorporates an up-to-date discussion of the risks and benefits of medication and psychosocial interventions as well as the impact of untreated psychiatric symptoms on mothers and families. Several recent studies have highlighted the fact that reproductive psychiatry is a dynamic field with treatment recommendations that continue to evolve and currently can only serve as general guides rather than absolute mandates. Ultimately, clinicians must help patients reflect on these guidelines in the context of their own experience of illness as well as their own perception of the risks and benefits of different treatment options. PP



1. Wisner KL, Chambers C, Sit DK. Postpartum depression: a major public health problem. JAMA. 2006;296(21):2616-2618.
2. Stowe ZN, Hostetter AL, Newport DJ. The onset of postpartum depression: implications for clinical screening in obstetrical and primary care. Am J Obstet Gynecol. 2005;192(2):522-526.
3. Evans J, Heron J, Francomb H, Oke S, Golding J. Cohort study of depressed mood during pregnancy and after childbirth. BMJ. 2001;323(7307):257-260.
4. Andersson L, Sundstrom-Poromaa I, Wulff M, Astrom M, Bixo M. Depression and anxiety during pregnancy and six months postpartum: a follow-up study. Acta Obstet Gynecol Scand. 2006;85(8):937-944.
5. Eberhard-Gran M, Tambs K, Opjordsmoen S, Skrondal A, Eskild A. Depression during pregnancy and after delivery: a repeated measurement study. J Psychosom Obstet Gynaecol. 2004;25(1):15-21.
6. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol. 2005;106(5 Pt 1):1071-1083.
7. Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetric settings. J Womens Health (Larchmt). 2003;12(4):373-380.
8. Hendrick V, Altshuler LL, Suri R. Hormonal changes in the postpartum and implications for postpartum depression. Psychosomatics. 1998;39(2):93-101.
9. Parry BL, Sorenson DL, Meliska CJ, et al. Hormonal basis of mood and postpartum disorders. Curr Womens Health Rep. 2003;3(3):230-235.
10. Kammerer M, Taylor A, Glover V. The HPA axis and perinatal depression: a hypothesis. Arch Womens Ment Health. 2003;9(4):187-196.
11. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157(6):924-930.
12. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.
13. Bonari L, Koren G, Einarson TR, Jasper JD, Taddio A, Einarson A. Use of antidepressants by pregnant women: evaluation of perception of risk, efficacy of evidence based counseling and determinants of decision making. Arch Womens Men Health. 2005;8(4):214-220.
14. Koren G. The way women perceive teratogenic risk. Can J Clin Pharmacol. 2007;14(1):e10-6.
15. Koren G, Bologa M, Long D, Feldman Y, Shear NH. Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester. Am J Obstet Gynecol. 1989;160(5 Pt 1):1190-1194.
16. Zhu SH, Valbo A. Depression and smoking during pregnancy. Addic Behav. 2002;27(4):649-658.
17. Hanna EZ, Faden VB, Dufour MC. The motivational correlates of drinking, smoking, and illicit drug use during pregnancy. J Substance Abuse. 1994;6(2):155-167.
18. Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O. Depression and anxiety in early pregnancy and risk for preeclampsia. Obstet Gynecol. 2000;95(4):487-490.
19. Chung TK, Lau TK, Yip AS, Chiu HF, Lee DT. Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosom Med. 2001;63(5):830-834.
20. Beck CT. Postpartum depression predictors inventory–revised. Adv Neonatal Care. 2003;3(1):47-48.
21. Stowe ZN, Hostetter AL, Newport DJ. The onset of postpartum depression: implications for clinical screening in obstetrical and primary care. Am J Obstet Gynecol. 2005;192(2):522-526.
22. Spitzer RL, Williams JB, Kroenke K, Hornyak R, McMurray J. Validity and utility of the PRIME-MD patient health questionnaire in assessment of 3000 obstetric/gynecologic patients: the PRIME-MD Patient Health Questionnaire Obstetric-Gynecology Study. Am J Obstet Gynecol. 2002;183(3):759-769.
23. Robertson E, Grace S, Wallington T, Stewart DE. Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry. 2004;26(4):289-295.
24. Altshuler LL, Hendrick V, Cohen LS. An update on mood and anxiety disorders during pregnancy and the postpartum period. Prim Care Companion J Clin Psychiatry. 2000;2(6):217-222.
25. Stowe ZN, Calhoun K, Ramsey C, Sadek N, Newport DJ. Mood disorders during pregnancy and lactation: defining issues of exposure and treatment. CNS Spectr. 2001;6(2):150-166.
26. Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol. 2003;188(3):812-815.
27.  Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol. 2005;106(6):1289-1296.
28. Ericson A, Kallen B, Wiholm B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol. 1999;55(7):503-508.
29. Kulin NA, Pastuszak A, Sage S, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279(8):609-610.
30. Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf. 2005;14(12):823-827.
31. December 08, 2005. GSK changes Paroxetine Prescribing Information. Available at: www.gsk.com/media/archive.htm#nolink. Accessed August 27, 2007.
32. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy. Obstet Gynecol. 2006;108(6):1601-1603.
33. Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001;158(10):1728-1730.
34. Djulus J, Koren G, Einarson TR, et al. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. J Clin Psychiatry. 2006;67(8):1280-1284.
35. Einarson A, Bonari L, Voyer-Lavigne S, et al. A multicentre prospective controlled study to determine the safety of trazadone and nefazadone use during pregnancy. Can J Psychiatry. 2003;48(2):106-110.
36. GlaxoSmithKline GlaxoSmithKline Pregnancy Registries. Bupropion Pregnancy Registry Interim Report. Available at: http://pregnancyregistry.gsk.com/documents/bup_report_spring2007.pdf. Accessed August 27, 2007.
37. Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol. 2005;192(3):932-936.
38. Cole JA, Modell JG, Haight BR, Cosmatos IS, Stoler JM, Walker AM. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol and Drug Saf. 2007;16(5):474-484.
39. Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005;293(19):2372-2383.
40. Kallen B. Neonate characteristics after maternal use of antidepressants late in pregnancy. Arch Pediatr Adolesc Med. 2004;158(4):312-316.
41. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med. 2006;160(2):173-176.
42. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Eng J Med. 2006;354(6):579-587.
43. Misri S, Reebye P, Kendrick K, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry. 2006;163(6):1026-1032.
44. Oberlander TF, Reebye P, Misri S, Papsdorf M, Kim J, Grunau RE. Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med. 2007;161(1):22-29.
45. Nulman I, Rovet J, Stewart DE, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159(11):1889-1895
46. Newport DJ, Viguera AC, Beach AJ, Ritchie JC, Cohen LS, Stowe ZN. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry. 2005;162(11):2162-2170.
47. Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry. 2000;157(2):179-184.
48. The Lamotrigine Pregnancy Registry. Interim Report. 1 September 1992 through 31 March 2007. Available at: http://pregnancyregistry.gsk.com/documents/lam_report_spring2007.pdf. Accessed September 3, 2007.
49. Cunnington M, Tennis P, International lamotrigine pregnancy registry scientific advisory committee. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005;64(6):955-960.
50. Holmes LB, Wyszynski DF, Baldwin EJ, et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. Birth Defect Research Part A: Clinical and Molecular Teratology. 2006;76(5):318.
51. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med. 1991;324:674-677.
52. Perucca E. Birth Defects after prenatal exposure to antiepileptic drugs. Lancet Neurol. 2005;4(11):781-786.
53. Kaplan PW. Reproductive health effects and teratogenicity of antiepileptic drugs. Neurology. 2004;63(10 suppl 4):S13-S23.
54. Kini U, Adab N, Vinten J, Fryer A, Clayton-Smith J; Liverpool and Manchester Neurodevelopmental Study Group. Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed. 2006;91(2):F90-95.
55. Vinten J, Adab N, Kini U, et al. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology. 2005;64(6):949-954.
56. Eriksson K, Viinikainen K, Monkkonen A, et al. Children exposed to valproate in utero: population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Res. 2005;65(3):189-200.
57. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. 2004;161(4):608-620.
58. Frey B, Schubiger G, Musy JP. Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breastfeeding. Eur J Pediatr. 1990;150(2):136-138.
59. Felding I, Rane A. Congenital liver damage after treatment of mother with valproic acid and phenytoin. Acta Paediatr Scand. 1984;73(4):565-568.
60. Nilsson E, Lichtenstein P, Cnattingius S, Murray RM, Hultman CM. Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophre Res. 2002;58(2-3):221-229.
61. Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry. 1996;153(5):592-606.
62. Tamer A, McKey R, Arias D, Worley L, Fogel BJ. Phenothiazine-induced extrapyramidal dysfunction in the neonate. J Pediatr. 1969;75(3):479-480.
63. Auerbach JG, Hans SL, Marcus J, Maeir S. Maternal psychotropic medication and neonatal behavior. Neurotoxicol Teratol. 1992;14(6):399-406.
64. Goldstein D. Olanzapine-exposed pregnancies and lactation: early experience. J Clin Psychopharmacol. 2000;20(4):399-403.
65. McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry. 2005;66(4):444-449.
66. Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. Br Med J Clin Res Ed. 1998;317(7162):839-843.
67. Lin AE, Peller AJ, Westgate MN, Houde K, Franz A, Holmes LB. Clonazepam use in pregnancy and the risk of malformations. Birth Defects Res A Clin Mol Teratol. 2004;70(8):534-536.
68. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv. 2002;53(1):39-49.
69. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
70. Brandes M, Soares CN, Cohen LS. Postpartum onset obsessive-compulsive disorder: diagnosis and management. Arch Womens Ment Health. 2004;7(2):99-110.
71. Wisner KL, Parry BL, Piontek CM. Clinical practice. Postpartum depression. N Engl J Med. 2002;347:194-199.
72. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987;150:782-786.
73. Robertson E, Grace S, Wallington T, Stewart DE. Antenatal risk factors for postpartum depression: A synthesis of recent literature. Gen Hosp Psychiatry. 2004;26(4):289-295.
74. O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental and hormonal variables. J Abnorm Psychol. 1991;100(1):63-73.
75. Stowe ZN, Nemeroff CB. Women at risk for postpartum-onset major depression. Am J Obstet Gynecol. 1995;173(2):639-645.
76. Stewart DE, Boydell KM. Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med. 1993;23(2):157-162.
77. Cohen LS, Viguera AC, Bouffard SM, et al. Venlafaxine in the treatment of postpartum depression. J Clin Psychiatry. 2001;62(8):529-596.
78. Nonacs RM, Soares CN, Viguera AC, Pearson K, Poitras JR, Cohen LS. Bupropion SR for the treatment of postpartum depression: a pilot study. Int J Neuropsychopharmacol. 2005;8(3):445-449.
79. Suri R, Burt VK, Altshuler LL, Zuckerbrow-Miller J, Fairbanks L. Fluvoxamine for postpartum depression [letter]. Am J Psychiatry. 2001;158(10):1739-1740.
80. Stowe ZN, Casarella J, Landry J, Nemeroff CB. Sertraline in the treatment of women with postpartum onset major depression. Depression. 1995;3:49-55.
81. Misri S, Reebye P, Corral M, Milis L. The use of paroxetine and cognitive-behavioral therapy in postpartum depression and anxiety: a randomized controlled trial. J Clin Psychiatry. 2004;65(9):1236-1241.
82. Wisner KL, Perel JM, Peindl KS, et al. Prevention of postpartum depression: a pilot randomized clinical trial. Am J Psychiatry. 2004;161(7):1290-1292.
83. Wisner KL, Hanusa BH, Perel JM, et al. Postpartum depression: a randomized trial of sertraline versus nortriptyline. J Clin Psychopharmacol. 2006;26(4):353-360.
84. Appleby L, Warner R, Whitton A, et al. A controlled study of fluoxetine and cognitive-behavioural counseling in the treatment of postnatal depression. BMJ. 1997;314(7085):932-936.
85. Hoffbrand S, Howard L, Crawley H. Antidepressant treatment for post-natal depression. Cochrane Database Syst Rev. 2001;(2):CD002018.
86. Brockington IF, Oates J, George S, et al. A screening questionnaire for mother-infant bonding disorders. Arch Womens Ment Health. 2001;3(4):133-140.
87. Moehler E, Brunner R, Wiebel A, Reck C, Resch F. Maternal depressive symptoms in the postnatal period are associated with long-term impairment of mother-child bonding. Arch Womens Ment Health. 2006;9(5):273-278.
88. Righetti-Veltema M, Conne-Perreard E, Bousquet A, Manzano J. Postpartum depression and mother-infant relationship at 3 months old. J Affect Disord. 2002;70(3):291-306.
89. Brennan PA, Hammen C, Andersen MJ, et al. Chronicity, severity, and timing of maternal depressive symptoms: relationships with child outcomes at age 5. Dev Psychol. 2000;36(6):759-766.
90. Murray L, Hipwell A, Hooper R, Stein A, Cooper P. The cognitive development of 5-year-old children of postnatally depressed mothers. J Child Psychol Psychiatry. 1996;37(8):927-935.
91. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal estrogen for the treatment of severe postnatal depression. Lancet. 1996;347(9006):930-933.
92. Lawrie T, Hofmeyr G, De Jager M, et al. A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynaecology. 1998;105(10):1082-1090.
93. Lawrie TA, Herxheimer A, Dalton K. Oestrogens and progestins for preventing and treating postpartum depression. Cochrane Database Syst Rev. 2000;(2):CD001690.
94. Gentile S. The role of estrogen therapy in postpartum psychiatric disorders: an update. CNS Spectr. 2005;10(12):944-952.
95. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078.
96. Lester BM, Cucca J, Andreozzi L, Flanagan P, Oh W. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry. 1993;32(6):1253-1255.
97. Chaudron LH, Jefferson JW. Mood stabilizers during breastfeeding: a review. J Clin Psychiatry. 2000;61(2):79-90.
98. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and chemicals into human milk. Pediatrics. 2001;108(3):776-789.
99. Viguera AC, Newport J, Ritchie J, et al. Lithium in breast milk and nursing infants: clinical implications. Am J Psychiatry. 2007;164(2):342-345.
100. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia. 1997;38(9):1039-1041.
101. Ohman I, Tomson T, Vitols S. Lamotrigine levels in plasma and breast milk in nursing women and their infants. Epilepsia. 1998;39(suppl 2):21.
102. O’Hara MW, Stuart S, Gorman LL, Wenzel A. Efficacy of interpersonal psychotherapy for postpartum depression. Arch Gen Psychiatry. 2000;57(11):1039-1045.
103. Zlotnick C, Johnson SL, Miller IW, Pearlstein T, Howard M. Postpartum depression in women receiving public assistance: pilot study of an interpersonal-therapy-oriented group intervention. Am J Psychiatry. 2001;158(4):638-640.
104. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry. 2003;160(3):555-562.
105. Reay R, Fisher Y, Robertson M, et al. Group interpersonal psychotherapy for postnatal depression: a pilot study. Arch Womens Ment Health. 2006;9(1):31-39.


Levels of Active Brain Response to Facial-Expressed Emotion in Alcoholism

Many social and physiologic factors can lead recovering alcoholics to relapse, including anxiety disorders, anger, and social pressure. According to a new study, the brains of alcoholics may have a significantly diminished ability to recognize and process certain emotions such as fear or disgust, which may explain a propensity for alcohol relapse.

The study used functional magnetic resonance imaging (fMRI) to examine the blood-oxygen level dependent (BOLD) responses of 11 male alcoholics who were subjected to a variety of facial emotions in emotion-decoding tests. Lead author, Jasmin B. Salloum, PhD, of the National Institute on Alcohol Abuse and Alcoholism, has published other studies on fMRI imaging and emotional-recognition.

The alcoholic patients’ responses to facial expressions of happiness, sadness, anger, fear, and disgust were compared to the responses of 11 male, non-alcoholic controls. Alcoholic patients and non-alcoholic controls both identified the intensity of emotions accurately during a non-complicated emotional decoding task. The two groups, however, showed significantly different BOLD responses during a facial emotion recognition task. Brain activation for the alcoholic patients was generally lower than that of the non-alcoholic group and varied most during the decoding of facial-expressed emotions of fear and disgust. For example, the affective division of the anterior cingulate cortex (ACC), which has been associated with autonomic cognitive processing and emotional processing, showed decreased activity in alcoholic patients. Anger was the only facial-expressed emotion that caused significant ACC activation in alcoholic patients; those BOLD results were not significantly different than those of controls.

According to the authors of this study, the “blunted” ACC activation demonstrated by alcoholic patients may affect their ability to recognize dangerous situations, such as bars or social scenes where drinking behavior occurs. In turn, there may be an increased possibility of alcohol relapse. In addition, the failure to properly interpret facial-expressed emotions of others can lead to social disregard, or to indifference to interventions by clinicians or loved ones.

Several limitations to this study include a small sample size as well as comorbid pathology and substance use in the alcoholic patient group. The authors acknowledge that alcoholic patients with no serious comorbidities could show different results.

Funding for this research was provided by the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Mental Health. (Alcohol Clin Exp Res. 2007;31(9):1490-504). —LS


Coronary Artery Disease is More Significant in Patients Suffering from Incident MDD

Coronary artery disease (CAD) is the world’s most common form of heart disease. It can result in heart attack and angina and can contribute to heart failure and arrhythmias. Recent research has found high rates of recurrent and incident major depressive disorder (MDD) in this patient population.

Karina Davidson, PhD, from Columbia University College of Physicians and Surgeons in New York City, and colleagues, investigated 88 patients to assess CAD severity in patients suffering from incident and recurrent MDD. The authors assessed history of depression and current depressive symptoms through patient interviews. They evaluated CAD severity via coronary angiography within 1 month of the aforementioned interviews. CAD severity was defined as: 0=no vessels significantly affected; 1=only one vessel affected; 2=two vessels affected; and 3=three vessels affected and/or left main obstruction.

Davidson and colleagues found that approximately 24% of acute coronary syndrome patients have comorbid MDD. Of these patients, approximately 67% had recurrent MDD and 33% had incident MDD. However, the authors found that the patients suffering from incident MDD had more severe types of CAD compared to patients with recurrent MDD patients. The mean CAD severity scores for incident MDD patients was 2.4 while the mean CAD severity scores for recurrent MDD patients was 1.6 (P=.043).

Due to these findings, Davidson and colleagues believe that patients with incident MDD should be differentiated from patients with recurrent MDD via two distinct subtypes. They propose using angiograms as a means of determining CAD severity. Future studies should explore the mechanisms underlying these differences. (J Psychiatr Res. In Press.) —CN


Effects of Mania and Depression on Functional Impairment and Disability

Bipolar disorder is a disabling condition that affects both moods and daily functioning. Gregory E. Simon, MD, MPH, at the Center for Health Studies in Seattle, Washington, and colleagues, reviewed data from 441 patients in a randomized trial of a care management and psychoeducational intervention in order to measure the relationship between changes in mood symptoms and changes in functioning in patients treated for bipolar disorder.

Symptom severity was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, structured clinical interview, and functional status was measured with the social subscale of the 36-item Short-form Health Survey (SF-36). Patients were enrolled between August 1999 and October 2000, and follow-up data were collected until October 2001. Patients were assessed at baseline and every 3 months during the 12-month follow-up period.

Four measures of impairment and disability were utilized and included the SF-36 Role-Emotional score, SF-36 Social Function score, days unable to perform household duties, and days disabled from performing other activities (P<.001 for all comparisons). Severity of depressive symptoms were strongly and consistently associated with all measures, even after adjustment for co-ocurring manic symptoms. Compared to patients in remission, patients with a depressive episode scored approximately 60 points lower on the SF-36 scales and were unable to participate in daily activities for an additional 15 days. Severity of mania and hypomania symptoms showed significant association with all measures as well (P<.001 for all comparisons); however, associations were weaker after factoring in co-ocurring depressive symptoms. Compared with patients in remission, patients with mania or hypomania scored approximately 30 points lower on the SF-36 scale and reported 9 additional days of disability.

“Our study shows that symptoms of bipolar disorder have a significant impact on daily functioning and disability,” Dr. Simon said. “When symptoms of bipolar disorder improve, daily functioning improves as well.”

Dr. Simon added that this relationship was stronger and more consistent for symptoms of depression than for symptoms of mania or agitation.

The study was limited in that it was an observational study as opposed to a randomized trial.

“We can show that improvement in depression is followed by improvement in disability,” Dr. Simon said, “but we cannot absolutely prove that the improvement in depression caused the improvement in disability.”

Funding for this research was provided by the National Institute of Mental Health. (J Clin Psychiatry. 2007;68:1237-1245) —DC


Possible Genetic Link Found for Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD) is more than just a severe case of premenstrual syndrome. Affecting approximately 8% of women, PMDD is characterized by a noticeably depressed mood, anxiety, and/or irritability in the week leading up to a woman’s menstrual cycle. In order to receive an official diagnosis, the symptoms must also be severe enough to cause impairment in daily life. Though not included in the main text of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, PMDD is listed as an area requiring further study.

Though researchers have suspected that the underlying cause of PMDD is hormonal, a new study by Liang Huo, MD, at the National Institutes of Mental Health, and colleagues, was the first to link PMDD to an estrogen receptor gene. The study included 91 women with PMDD and 56 women without PMDD or any history of mood disorders linked to their menstrual cycle. The women had an average age of 40 years and were Caucasian with similar demographic and socioeconomic backgrounds. Blood samples from each woman were analyzed. Researchers looked specifically at numerous single nucleotide polymorphisms (SNPs) in three specific genes: ESR1, ESR2 and COMT.

ESR1 and ESR2 are two types of estrogen receptors while COMT is involved in the process of metabolizing estrogen. The results showed that four SNPs located on the ESR1 were significantly more prominent in the PMDD group. Even after removing 29 women with a history of major depressive disorder from the PMDD group, the results were still significant. David R. Rubinow, MD, a study co-author, noted that while this study suggests the involvement of specific genes linked to estrogen, the patients had normal levels of estrogen. The problem, therefore, may lie in the abnormal response to a normal level of hormones.

Huo and colleagues also note that the absence of the SNPs in the control group could be as telling as their presence in the PMDD group. The control group may have some sort of protective factor against menstrual-related mood disorders. However, further research is needed given the relatively small sample size of the current study.

Funding for this research was provided by the Intramural Research Program at the National Institute of Mental Health.

(Biol Psychiatry. 2007; June 26; Epub ahead of print.) —VJ

Psychiatric Dispatches is written by Dena Croog, Virginia Jackson, Christopher Naccari, and Lonnie Stoltzfoos.


Dr. Kornstein is professor of Psychiatry and Obstetrics/Gynecology, executive director of the Institute for Women’s Health, and executive director of the Mood Disorders Institute at Virginia Commonwealth University in Richmond.

Disclosure: Dr. Kornstein is on the advisory boards of or receives honoraria from Biovail, Bristol-Myers Squibb, Eli Lilly, Forest, Neurocrine, Pfizer, Sepracor, and Wyeth; and receives research support from AstraZeneca Boehringer-Ingelheim, Bristol-Myers Squibb, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health,  Novartis, Sanofi-Synthelabo, Sepracor, and Wyeth.

Please direct all correspondence to: Susan G. Kornstein, MD, Dept of Psychiatry, Virginia Commonwealth University, PO Box 980710, Richmond, VA 23298-0710; Tel: 804-828-5637; Fax: 804-828-5644; E-mail: skornste@vcu.edu.


In March 2008, clinicians, researchers, policymakers, and advocates from across the world will convene in Melbourne, Australia for the 3 rd International Congress on Women’s Mental Health. This occasion will celebrate the remarkable progress that has been made in the field of women’s mental health since the last Congress in 2004. This progress includes advances in our understanding of sex and gender differences in mental illness and treatment efficacy, our knowledge of the etiology and treatment of psychiatric conditions related to the reporoductive cycle, and our appreciation of the role of not only biologic but social and cultural influences on women’s mental health and well-being.

This issue of Primary Psychiatry provides a sampling of topics from the field of women’s mental health across the life span. Nancy C. Raymond, MD, and Jennifer B. Beldon, MD, present an overview of the evaluation and management of eating disorders, which are among the most serious illnesses affecting young women. Diagnostic classification of anorexia nervosa, bulimia nervosa, and binge-eating disorder is reviewed. The authors underscore the importance of clinicians’ awareness of the warning signs of these disorders, since patients themselves are typically not forthcoming about their symptoms and often hide their abnormal eating and purging behaviors from family, friends, and healthcare professionals. In addition, patients with eating disorders may develop medical complications that can become life threatening. The authors highlight the effectiveness of a multidisciplinary approach to the treatment of eating disorders, including medication, psychotherapy, nutritional evaluation, and general medical monitoring.

One aspect of treating female patients that many clinicians find challenging is decisions regarding the use of psychotropic medications during pregnancy and the postpartum period. Recent studies suggesting possible associations of paroxetine and lamotrigine with congenital malformations have heightened the controversies in this arena. Helen G. Kim, MD, and Manasi Kolpe, MD, discuss the risks and benefits of pharmacologic treatment of perinatal women with mood and anxiety disorders. They emphasize that clinicians and patients must weigh in their decision-making process the risks of medications against the risks of untreated illness on the health and safety of both mother and infant.

Another area that has shown great progress in research over the last several years is psychiatric aspects of the menopausal transition. There is now improved clarity in defining the phases of the transition with the development of the Stages of Reproductive Aging Workshop criteria. In addition, several major studies have recently been published showing that the menopausal transition is associated with an increased risk for depression in women both with and without a previous history of mood disorder. Susan G. Kornstein, MD, and Larry Culpepper, MD, MPH, review the biologic, psychologic, and social factors that may contribute to depression during the menopausal transition along with strategies to evaluate and treat depression in midlife women.

The field of women’s mental health is advancing at a rapid pace. In addition to progress in research and clinical practice, there is an increasing recognition of the public health importance of women’s mental health. There is more discussion of the need to improve access to services, screening, and prevention, and there is a greater awareness of the impact of women’s health on children, families, and communities.

It is hoped that the articles in this issue will enable clinicians to better understand, evaluate, and manage mental health problems in their female patients. Perhaps some of the readers will be inspired to come to Melbourne to learn more. PP


Dr. Raymond is professor in the Departments of Psychiatry and Family Medicine and the director of the Center of Excellence in Women’s Health at the University of Minnesota Medical School in Minneapolis. Dr. Beldon is staff psychiatrist at Boynton Health Service at the University of Minnesota.

Disclosures: Dr. Raymond has received grant support from the Department of Health and Human Services and the National Institute of Mental Health. Dr. Beldon reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Nancy C. Raymond, MD, Department of Psychiatry, University of Minnesota Medical School, F282/2A West, 2450 Riverside Ave, Minneapolis, MN 55454; Tel: 612-273-9808; Fax: 612-273-9779; E-mail: raymo002@umn.edu; Web site:  www.womenshealth.umn.edu.



Eating disorders are potentially severe and life threatening, affecting primarily adolescents and young women. Anorexia nervosa and bulimia nervosa have their onset in young adults; illness during this period can significantly affect both physical and psychological development. Since these women are fearful of having their disorders discovered, they are unlikely to seek psychiatric care. Therefore, it is important for primary care physicians, obstetricians, gynecologists, and even dentists or any clinician who works with young women to be able to identify, assess, refer, or treat young women with eating disorders. This article identifies common clinical presentations of women with eating disorders, how to assess these patients, and the best settings and methods for treatment.



Eating disorders are potentially severe or life threatening and predominately affect young women. These disorders can take an irreversible toll on both the physical and mental health of young women. Onset of bulimia nervosa and anorexia nervosa often occurs at a critical time of development, during the early adolescent to young adult years. Both physical and psychological development can be adversely affected. The onset of binge-eating disorder occurs somewhat later, but the obesity that is typical of the disorder can also have negative physical and psychological effects on those who suffer from it.

Approximately 33% of women with anorexia and 6% of those with bulimia are treated by mental health professionals.1 Therefore, it is essential that primary care physicians, obstetrician/gynecologists, and all other healthcare providers that offer care to young women screen their patients for eating disorders. They must be able to determine if an eating disorder is present, the severity of the problem, whether the patient is medically and psychiatrically stable, what they can provide in the way of treatment, and when to refer the patient to a comprehensive care team.


Prevalence, Incidence, and Mortality

It is estimated that the incidence rate of anorexia is 8 per 100,000 people and the rate for bulimia is 13 per 100,000.1 However, in young women the prevalence rates are 0.3% for anorexia and 1% for bulimia.1 Binge-eating disorder was found in approximately 2% of a community sample and 30% of subjects in a weight loss sample.2 Approximately 95% to 97% of those with anorexia and 80% to 85% of those with bulimia are women.3 However, only approximately 66% of those suffering from binge-eating disorder are women.2,4

A large number of women do not meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),3 criteria for an eating disorder but still have significant morbidity related to disordered eating behavior and cognitions. These women would be diagnosed with eating disorder not otherwise specified (ED NOS). Women in this category are thought to represent approximately 60% of patients presenting for clinical treatment of eating disorders compared to 14.5% presenting with anorexia and 25.5% with bulimia.5 The true prevalence of ED NOS is uncertain. Studies indicate that the morbidity and mortality associated with these subthreshold cases of eating disorders are, in many cases, equivalent to the morbidity associated with anorexia or bulimia; however, little research has been done on the prevalence, course of illness, symptomatology, or treatment of ED NOS.

Among patients with anorexia, mortality is estimated to be 0.56% per year.6 The suicide mortality rate for those with eating disorders is higher than for any of the other major psychiatric disorders including major depressive disorder (MDD) and bipolar disorder, and the rate is approximately three times greater than the suicide rate for those with opiate use, alcohol abuse, and schizophrenia.7 The mortality rate from all natural and unnatural causes for those with eating disorders is second only to opiate abuse, and those with eating disorders have a higher rate than those with alcohol abuse, schizophrenia, MDD, and bipolar disorder.8



The assessment of women with eating disorders consists of a physical exam as well as a psychiatric and mental-status exam. A simple set of screening questions has been suggested by Powers (Table 1).9 In addition to reviewing the specific criteria for eating disorders (Tables 2–4),10-12 it is important to obtain a weight, eating behavior, and nutritional history. Menstrual history is critical since absence of menses is one of the diagnostic criteria for anorexics and menstrual irregularity often occurs in women with bulimia. While obesity is not one of the diagnostic criteria for binge-eating disorder, it is common in women with binge-eating disorder and, therefore, they too can suffer from menstrual irregularity. Regardless of the particular eating disorder in question, all patients must be assessed for excessive use of diuretics, laxatives, diet pills, and ipecac. A dental history to assess for sensitive teeth is important since recurrent vomiting can cause thinning of tooth enamel. Patients often complain of feeling bloated after eating, a symptom which may be due to delayed gastric emptying. Patients may also complain of muscle weakness that can be caused by metabolic abnormalities and palpitations that can be caused by hypokalemia. Patients with severe anorexia often complain of cold intolerance.13





Women with anorexia and binge-eating disorder are predisposed to other psychiatric disorders and substance abuse disorders, so it is important to assess patients for these disorders. Psychiatric disorders that are often associated with eating disorders include depression, anxiety disorders, and obsessive-compulsive disorders.14 Even though the body image disturbance and odd beliefs about food and weight may seem to be of psychotic proportions, psychotic disorders are rare in patients with eating disorders.

The review of systems needs to include questions to help rule out other potential medical problems that can present with similar symptoms to eating disorders or complicate the treatment of the eating disorder, such as thyroid abnormalities, diabetes mellitus, cystic fibrosis, and inflammatory bowel disease.9

On physical exam, special emphasis should be placed on height, weight, and state of hydration. The latter can be evaluated by examining for orthostatic hypotension. Patients with anorexia are often bradycardic but can be tachycardiac due to dehydrations. Thorough cardiac and abdominal exams are indicated. An examination of the teeth to look for signs of erosion of the enamel secondary to vomiting is important. Hair loss, lanugo-like hair, and easy bruising due to possible thrombocytopenia may be seen in later stages of anorexia.13

Screening laboratory tests that should be administered include complete blood count and differential (to screen for leukopenia, anemia, and thrombocytopenia); basic electrolytes (to screen for hypokalemia, hyponatremia, and metabolic alkalosis with a high sodium bicarbonate level in patients who vomit or metabolic acidosis and low sodium bicarbonate levels in patients who abuse laxatives)15; calcium, magnesium, and phosphorous levels (to screen for deficiencies); and blood urea nitrogen and creatinine (to assess kidney function).13 If abnormalities in electrolytes are not present at baseline, these levels can become abnormal during refeeding. Particularly during refeeding, patients can experience profound or even lethal hypophosphatemia. Electrolytes often initially need to be monitored daily during the refeeding process. An electrocardiogram should be obtained because of the possibility of arrythmias and corrected Q-T interval prolongation in both anorexia and bulimia. In addition, especially in low-weight anorexic patients with long-standing disease, a bone-mineral density should be obtained to determine the level of osteopenia or osteoporosis.


Clinical Presentation

Anorexia Nervosa

By definition, patients with anorexia must be underweight. Their body weight must be less than what is expected for their height (the DSM-IV suggests <85% of normal weight) or they must be failing to make expected weight gain during a period of growth.10 According to the diagnostic criteria, they must have an intense fear of gaining weight or becoming fat even though they are underweight. Some patients may be knowledgeable enough about the diagnostic criteria to deny this symptom but behaviorally will show a great deal of difficulty in eating the food necessary to gain weight. Additionally, amenorrhea is a criterion for women who are postmenarchal and are not taking oral contraception or other hormones. Clinical presentation often includes an adamant denial of the illness. Patients often exhibit hyperactivity and like to be in constant motion as this burns calories. Often they prefer standing to sitting. Sleep disturbance is common. Irritability and social isolation are also very common. Patients often complain of constipation, though physical exam and x-rays may not indicate this as a problem. Instead, patients may be eating too little to have normal bowel movements. Cold intolerance, dizziness, and fainting spells are also quite common. On examination, patients will often present with low body temperature, bradycardia, hypotension, and dehydration; in end-stage disease, edema secondary to hypoproteinemia is not unusual. Patients will also be noted to have dry skin, brittle hair, brittle nails, and sometimes loss of hair.


Bulimia Nervosa

In contrast to anorexia, most women with bulimia are of normal weight. However, due to their episodes of binge eating and purging they may exhibit a number of physiologic abnormalities. Binge-eating episodes involve eating a large quantity of food in a short period of time with the sense that one cannot control what or how much one is eating. The most common method of purging to counteract the binge-eating behavior is self-induced vomiting, although this may be combined with or substituted by misuse of laxatives, diuretics, or enemas. Ipecac is a particularly dangerous way to induce vomiting as repeated use can cause severe cardiac damage. In the nonpurging subtype of bulimia, patients use behaviors such as fasting or excessive exercise to compensate for binge eating but do not regularly engage in the purging behavior. Other common symptoms are abdominal pain, constipation, and edema of the hands or feet. Important physical signs of bulimia are swollen parotid glands, erosion of the dental enamel on the inside of the teeth making the disorder diagnosable by dentists, and calluses on the back of the finger from the effects of gastric hydrochloride acid hitting the finger during self-induced vomiting. However, many patients with bulimia appear quite healthy during an initial inspection. Women with bulimia typically engage in the bulimic behaviors in secrecy. Because of this, the disorder can escape detection for many years. It is often 8–10 years after the initiation of the bulimic behavior before a patient seeks help and the diagnosis is made.


Binge-Eating Disorder

Patients with binge-eating disorder frequently present requesting diet advice and with weight concerns. Unless they are asked directly, patients will often not report that they have binge-eating behavior (ie, eating large quantities of food in a short period of time with a sense of loss of control). Since women with binge-eating disorder are more likely to fail traditional weight-loss programs and since they are more likely to regain weight after dieting, it is very important to screen all obese patients for binge-eating disorder.16 The majority of symptoms that patients with binge-eating disorder have are related to complications of obesity. Obese individuals with binge-eating disorder are more likely to have depression than non-binge eating obese women, so it is important to screen for other psychiatric disorders.



Anorexia Nervosa

The preferred approach to treating eating disorders is within the context of a multidisciplinary team, and this particularly holds true for anorexia. The gold standard is to involve the patient in a structured treatment program including a nutritionist, individual and family therapy, close medical monitoring by a physician, and, if needed, a psychiatrist. Ultimately, the best treatment for anorexia is restoring weight through adequate dietary intake. However, achieving this can be quite difficult and sometimes requires a combination of medications and intensive psychotherapy. A day treatment program or even inpatient hospitalization is often required to achieve weight gain. It is generally accepted that hospitalization is necessary in very low-weight patients who are experiencing cardiac sequelae (eg, hypotension, bradycardia, arrhythmia) or electrolyte abnormalities, and in patients who are deemed unlikely to improve without a closely monitored refeeding environment. Because of the deeply-held cognitive distortions about their appearance, and ambivalence about treatment, it is sometimes necessary to hospitalize patients against their wishes. Follow-up studies have reported that inpatient treatment is still beneficial in these cases, and patients often report that they later recognized the need for hospitalization.17

Few good medication trials for the treatment of anorexia exist, and many trials inadequately characterize the phase of the illness during which the patients were treated (ie, early or late), which can have an impact on outcome. Of note, the anorexic patient can be viewed as fitting into two subtypes. The first type is the acutely ill patient, suffering physical consequences of the disorder (eg, amenorrhea, osteoporosis) as well as other effects of starvation. The effects of starvation have been documented and include low mood, mental and physical apathy, difficulties with concentration, obsession with food, and anxiety.18 The treatment for this phase is weight restoration, which will often ameliorate or eliminate the comorbid mood or anxiety symptoms. There are no double-blind, placebo-controlled trials of any medication that demonstrate efficacy in promoting weight restoration in low-weight patients with anorexia. Two studies (one double-blind and one open-label) in which fluoxetine was administered at target doses of up to 60 mg showed no benefit.19,20 It is possible that the relative lack of dietary precursors necessary for the synthesis of catecholamines is part of the reason for the lack of efficacy during this phase of the illness.21 Recent case studies have shown atypical antipsychotics may help to reduce obsessive thoughts, improve body image, and improve anxiety in patients with anorexia. According to reports, risperidone 0.5–1.5 mg/day and olanzapine 2.5–15.0 mg/day have been suggested to be beneficial.21 Though double-blind, placebo-controlled studies need to be conducted, these reports appear promising. It is important that the distorted body image and odd beliefs about food, weight, and appetite found in patients with anorexia are nonpsychotic symptoms in all but the exceptional patient. There are no studies of benzodiazepines; however, it has been suggested that a small dose of lorazepam 0.5–1.0 mg just prior to meals can help lower anxiety surrounding the eating process. This should only be used on a short-term basis in the initial phases of treatment to decrease anticipatory anxiety.

For the second type of anorexic patient, the weight-restored patient, antidepressants may be helpful in maintaining weight. Most studies have been on the use of fluoxetine, and while there are conflicting outcomes in the literature, it appears some patients may benefit from the use of a selective serotonin reuptake inhibitor (SSRI) to help prevent relapse.21 In one such study dosages of fluoxetine 20–60 mg were administered with the average dose being approximately 40 mg.22 However, others have found no benefit from fluoxetine 60–80 mg over a 1-year period in weight-recovered anorexic patients.23 Patients that continue to struggle with depression, obsessions, or anxiety despite weight-restoration should be treated as with any other patient and may benefit from an antidepressant. There are no studies of the efficacy of antidepressants in treating comorbid diagnosis such as depression in patients with anorexia.

Certainly attention must be given to all the various medical complications. One of particular importance is early-onset osteoporosis seen in patients with anorexia. Again, adequate nutrition is the best treatment, but one must consider use of vitamin supplements to treat osteoporosis in young anorexic women.24 The Society for Adolescent Medicine recommends treating anorexic patients with 1,200 mg of calcium and 400 IU of vitamin D daily. Studies have been conducted to evaluate the use of hormone-replacement therapy in these patients, but as yet no clear benefit on bone density has been shown.25


Bulimia Nervosa

Bulimia is most effectively treated with a combination of outpatient psychotherapy and medications. Much research supports the use of cognitive-behavioral therapy (CBT) as an effective treatment for bulimia.26,27 There is some evidence that interpersonal therapy is a useful treatment.28 A combination of CBT and medications have been found to be more efficacious than medications alone.27,29 There is good evidence that SSRIs are helpful in reducing binge eating and purging behavior, and, in fact, fluoxetine has Food and Drug Administration approval for the treatment of bulimia. SSRIs appear to be effective in the treatment of bulimic symptoms regardless of the presence of comorbid mood or anxiety disorders. Patients with no reported depression or anxiety symptoms can still respond to fluoxetine 60 mg with a significant reduction in binge eating and purging episodes; however, 20 mg has been found to be ineffective.30,31 These doses are similar to those that would be given to patients with obsessive-compulsive disorder. Many SSRIs have been studied, and there is evidence that other SSRIs such as sertraline 100–200 mg/day32,33 and citalopram34 are helpful as well. The SSRIs seem to decrease preoccupation with food and weight, and to help with impulse control over urges to binge eat.

Bupropion is specifically contraindicated in patients with bulimia. There is an increased risk of seizures as a result of administration of bupropion in patients with electrolyte abnormalities, often found in patients with bulimia and anorexia.35 Some evidence supports the use of ondansetron in the treatment of bulimia.36,37 In published studies, patients were instructed to take up to 24 mg/day of ondansetron in 4 mg dosages when they felt the urge to binge or 30 minutes before they were to eat a meal that might lead to a binge.37 Topiramate in a dosage range of 25–400 mg/day has been shown in case studies and one small controlled trial to decrease the tendency to binge, with secondary decreases in compensatory behaviors (ie, purging).38 However, topiramate has side effects that sometimes make it intolerable, particularly fatigue, flu-like symptoms, and paresthesias.38 There is minimal but intriguing evidence that opiate antagonists such as naltrexone in doses of ≥100 mg might be helpful in treating bulimia.39,40 However, in these dosages liver function must be monitored and patients cannot take nonsteroidal anti-inflammatory medications while on naltrexone.41,42

Ultimately, the majority of patients treated with medications alone do not become completely abstinent from binge eating and purging. Long-term studies indicate that abstinence is necessary for recovery.43 Even studies of combination treatment with psychotherapy and medications show there is still room to improve upon the treatment of this disorder.


Binge-Eating Disorder

Fewer clinical trials study the treatment of binge-eating disorder. Medications alone are not found to be highly efficacious. However, there is some evidence that SSRIs help control bingeing behavior in binge-eating disorder as in bulimia. Doses of fluoxetine 60–80 mg/day and citalopram 60 mg/day in comparison to placebo were found to be effective in reducing binge frequency. Topiramate 25–600 mg/day (mean dose=250 mg/day) has also been used to treat binge-eating disorder and has been found to be efficacious in reducing binge-eating episodes.44 CBT has also been successfully used in the treatment of binge-eating disorder.45 Treatment tends to decrease binge eating but does not lead to weight loss. Fluoxetine may offer some advantage over behavioral modification alone. In one study, obese women with or without binge-eating disorder receiving behavioral treatment lost more weight when on fluoxetine (as opposed to placebo).46 Atomoxetine, a selective norepinephrine reuptake inhibitor that is prescribed to induce weight loss when given in doses of 40–120 mg/day (mean=106 mg/day) was found to reduce binge-eating episodes in women with binge-eating disorder in a double-blind, placebo-controlled study.47



Eating disorders represent one of the most serious illnesses among young women. The disorders can have serious long- and short-term mental and physical manifestations for young women who suffer from them. Aggressive treatment that leads to remission of symptoms is critical in order to minimize the long-term health risks of the disorders. Medications may help to reduce the symptoms of bulimia and binge-eating disorder but seldom are sufficient for treating anorexia. Even if medications are helpful in reducing symptoms, they often do not bring about complete remission of symptoms. Maintenance of a healthy weight and good nutrition are essential for recovery and prevention of long-term sequelae. Often an interprofessional team that includes a dietician, therapist, general physician, and/or psychiatrist is necessary for recovery. For some patients, structured self-help manuals may also be useful in helping patients with bulimia or binge-eating disorder to reduce binge eating.48 Additional information on the diagnosis, assessment, and management of eating disorders can be found in the American Psychiatric Association treatment guidelines, which were updated in 2006.49 PP



1. Hoek HW. Incidence, prevalence and mortality of anorexia nervosa and other eating disorders. Curr Opin Psychiatry. 2006;19(4):389-394.
2. Spitzer RL, Devlin MJ, Walsh BT, Hasin D, Wing R, Marcus MD. Binge eating disorder: a multisite field trial of the diagnostic criteria. Int J Eat Dis. 1992;11:191-203.
3. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
4. Spitzer RL, Yanovski S, Wadden T, et al. Binge eating disorder: its further validation in a multisite study. Int J Eat Dis. 1993;13(2):137-153.
5.  Fairburn CG, Bohn K. Eating disorder (NOS (EDNOS): an example of the troublesome ‘not otherwise specified’ (NOS) category in DSM-IV. Behav Res Ther. 2005;43(6):691-701.
6. Sullivan PF. Mortality in anorexia nervosa. Am J Psychiatry. 1995;152(7):1073-1074.
7. Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry. 1997;170:205-228.
8. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-53.
9. Powers PS. Initial assessment and early treatment options for anorexia nervosa and bulimia nervosa. Psychiatr Clin North Am. 1996;19(4):639-655.
10. Diagnostic and Statistical Manual of Mental Disorders. 4th ed rev. Washington, DC: American Psychiatric Association; 2000:589.
11. Diagnostic and Statistical Manual of Mental Disorders. 4th ed rev. Washington, DC: American Psychiatric Association; 2000:594.
12. Diagnostic and Statistical Manual of Mental Disorders. 4th ed rev. Washington, DC: American Psychiatric Association; 2000:787.
13. Carney CP, Andersen AE. Eating disorders, guide to medical evaluation and complications. Psychiatr Clin North Am. 1996;19(4):657-679.
14. Mitchell JE. Medical complications of anorexia nervosa and bulimia. Psychiat Med. 1983;1(3):229-255.
15. Powers PS, Coovert DL, Brightwell DR, Stevens BA. Other psychiatric disorders among bulimic patients. Compr Psychiatry. 1988;29(5):503-508.
16. Raymond NC, de Zwaan M, Mitchell JE, Ackard D, Thuras P. Effect of a very low calorie diet on the diagnostic category of individuals with binge eating disorder. Int J Eat Disord. 2002;31(1):49-56.
17. Guarda AS, Pinto AM, Coughlin JW, Hussain S, Haug NA, Heinberg LJ. Perceived coercion and change in perceived need for admission in patients hospitalized for eating disorders. Am J Psychiatry. 2007;164(1):108-114.
18. Keys A, Henschel A, Mickelsen O, Taylor HS, eds. Biology of Human Starvation. Vol I. Minneapolis, MN: University of Minnesota Press; 1950.
19. Attia E, Schroeder L. Pharmacologic treatment of anorexia nervosa: where do we go from here? Int J Eat Disord. 2005;37(Suppl):S60-S69.
20. Strober M, Pataki C, Freeman R, DeAntonio M. No effect of adjunctive fluoxetine on eating behavior or weight phobia during the inpatient treatment of anorexia nervosa: an historical case-control study. J Child Adolesc Psychopharmacol. 1999;9(3):195-201.
21. Steffen KJ, Roerig JL, Mitchell JE, Uppala S. Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006;11(2):315-336.
22. Kaye WH, Nagata T, Weltzin TE, et al. Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-purging-type anorexia nervosa. Biol Psychiatry. 2001;49(7):644-652.
23. Walsh BT, Kaplan AS, Attia E, et al. Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial. JAMA. 2006;295(22):2605-2612. Erratum in: JAMA. 2006;296(8):934.
24. Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol. 2002;15(3):135-143.
25. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab. 1995;80(3):898-904.
26. Fairburn CG, Jones R, Peveler RC, et al. Three psychological treatments for bulimia nervosa. A comparative trial. Arch Gen Psychiatry. 1991;48(5):463-469.
27. Walsh BT, Wilson GT, Loeb KL, et al. Medication and psychotherapy in the treatment of bulimia nervosa. Am J Psychiatry. 1997;154(4):523-531.
28. Fairburn CG, Jones R, Peveler RC, Hope RA, O’Connor M. Psychotherapy and bulimia nervosa. Longer-term effects of interpersonal psychotherapy, behavior therapy, and cognitive behavior therapy. Arch Gen Psychiatry. 1993;50(6):419-428.
29. Agras WS, Rossiter EM, Arnow B, et al. Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled comparison. Am J Psychiatry. 1992;149(1):82-87.
30. Goldstein DJ, Wilson MG, Ascroft RC, al-Banna M. Effectiveness of fluoxetine therapy in bulimia nervosa regardless of comorbid depression. Int J Eat Disord. 1999;25(1):19-27.
31. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa. A multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry. 1992;49(2):139-147.
32. Leombruni P, Amianto F, Delsedime N, Gramaglia C, Abbate-Daga G, Fassino S. Citalopram versus fluoxetine for the treatment of patients with bulimia nervosa: a single-blind randomized controlled trial. Adv Ther. 2006;23(3):481-494.
33. Milano W, Petrella C, Sabatino C, Capasso A. Treatment of bulimia nervosa with sertraline: a randomized controlled trial. Adv Ther. 2004;21(4):232-237.
34. Leombruni P, Piero A, Brustolin A, et al. A 12 to 24 weeks pilot study of sertraline treatment in obese women binge eaters. Hum Psychopharmacol. 2006;21(3):181-188.
35. Horne RL, Ferguson JM, Pope HG Jr, et al. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988;49(7):262-266.
36. Faris PL, Eckert ED, Kim SW, et al. Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms. J Affect Disord. 2006;92(1):79-90.
37. Faris PL, Kim SW, Meller WH, et al. Effect of decreasing afferent vagal activity with ondansetron on symptoms of bulimia nervosa: a randomised, double-blind trial. Lancet. 2000;355(9206):792-797.
38. Hedges DW, Reimherr FW, Hoopes SP, et al. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 2: improvement in psychiatric measures. J Clin Psychiatry. 2003;64(12):1449-1454.
39. Mitchell JE, Laine DE, Morley JE, Levine AS. Naloxone but not CCK-8 may attenuate binge-eating behavior in patients with the bulimia syndrome. Biol Psychiatry. 1986;21(14):1399-1406.
40. Marrazzi MA, Bacon JP, Kinzie J, Luby ED. Naltrexone use in the treatment of anorexia nervosa and bulimia nervosa. Int Clin Psychopharmacol. 1995;10(3):163-172.
41. Kim SW, Grant JE, Adson DE, Remmel RP. A preliminary report on possible naltrexone and nonsteroidal analgesic interactions. J Clin Psychopharmacol. 2001;21(6):632-634.
42. Kim SW, Grant JE, Yoon G, Williams KA, Remmel RP. Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients. Clin Neuropharmacol. 2006;29(2):77-79.
43. Olmsted MP, Kaplan AS, Rockert W. Rate and prediction of relapse in bulimia nervosa. Am J Psychiatry. 1994;151(5):738-743.
44. McElroy SL, Hudson JI, Malhotra S, Welge JA, Nelson EB, Keck PE Jr. Citalopram in the treatment of binge-eating disorder: A placebo-controlled trial. J Clin Psychiatry. 2003;64(7):807-813.
45. Devlin MJ, Goldfein JA, Petkova E, et al. Cognitive behavioral therapy and fluoxetine as adjuncts to group behavioral therapy for binge eating disorder. Obes Res. 2005;13(6):1077-1088.
46. Marcus MD, Wing RR, Ewing L, Kern E, McDermott M, Gooding W. A double-blind, placebo-controlled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and non-binge-eaters. Am J Psychiatry. 1990;147(7):876-881.
47. McElroy SL, Guerdjikova A, Kotwal R, et al. Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2007;68(3):390-398.
48. Stefano SC, Bacaltchuk J, Blay SL, Hay P. Self-help treatments for disorders of recurrent binge eating: a systematic review. Acta Psychiatr Scand. 2006;113(6):452-459.
49. Yager J, Devlin MJ, Halmi KA, et al. Practice Guideline for the Treatment of Patients with Eating Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 2006.


Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York. Dr. Feldman is senior medical director at the Care Management Organization at Montefiore Medical Center in Bronx, New York, and clinical professor of internal medicine at Albert Einstein College of Medicine in New York City.

Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer. Dr. Feldman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.




Depression is a leading cause of disability-adjusted life years lost and projected to be more so within a generation. Mood disorders were implicated in 10% of all hospitalizations in 2004. Despite major advances in depression-care management, there is little expectation that health policy will generate the necessary number of mental health providers to meet the need. Moreover, only 50% of patients with major depressive disorder (MDD) fully respond to initial antidepressant treatment. At best, an additional 33% will recover when the antidepressant is switched to another agent or augmented with a second antidepressant or psychotherapy. For those who do recover, 40% to 60% will experience recurrence depending on the severity of the initial episode. As a result, the need to prevent depression is imminent and numerous studies suggest that the means may be at hand.


How Has Prevention Terminology Evolved?

A review of prevention terminology will allow an appreciation of how the goal of depression prevention might be attained. The Table1-3 defines the concepts and terms used in the text to follow. Whyte and Rovner1 have summarized the range of risk indicators and their definitions. Although epidemiologic studies often find cross-sectional associations between illness and potential risk factors, true indicators of risk precede the development of the disorder. A genuine indicator of risk predicts who is more or less likely to develop the disorder, but the prediction is more often relative than absolute, and may be neither necessary nor sufficient to produce illness. Some individuals exposed to the risk never fall ill; some ill individuals were never exposed. A fixed indicator of risk is not changeable and thus not a target of intervention, although it may delimit the vulnerable population as in male gender and prostate cancer. A fixed indicator such as ethnicity may also identify a subset of the vulnerable population at heightened risk as in older white males and suicide. A variable indicator (eg, age, weight, alcohol intake) may be changeable either through intervention or spontaneously. Variable risk indicators that cannot be manipulated or have no effect on the emergence of a disorder when manipulated are variable risk markers which are important to reduce the potential population for prevention without defining what intervention should be applied. A variable indicator is determined to be a causal risk factor if an intervention targeting the indicator truly reduces the incidence of the disorder. 



A genuine indicator of risk may or may not be causative and may itself be a proxy for an unrecognized biomedical or psychosocial pathologenic agent. Whyte and Rovner1 cite two studies to demonstrate the complexity of risk identification-preventive outcomes and late-life depression. Bereavement in late life is a fixed marker for the incidence of depression and an unchangeable event (death of a loved one) as well as the status of the bereaved. However, the self-imposed social isolation that too often follows bereavement is a behavior subject to change. Since intervening to help the bereaved sustain an active rhythm of social engagement reduces the incidence of late-life depression,4 it is the abandonment of social rhythms that is the causative risk factor, and not bereavement itself.

If loss of social rhythm during bereavement is a proven psychosocial causal risk factor for depression, then high-dose interferon-a therapy for melanoma represents a compelling example of a biomedical casual factor.5 Interferons are cytokines known to induce self-protective illness behaviors in animals during periods of inflammation, thus reducing their vulnerability to predation while ill. High-dose interferon-a also reliably precipitates MDD in 25% of exposed individuals. However, MDD can be prevented in the majority of exposed people who receive prophylactic antidepressant treatment prior to the administration of interferon-α.

These two examples demonstrate an added critical element in prevention. Once individual research studies prove the efficacy of the preventive intervention, an added step is required to demonstrate broad-scale applicability across diverse health systems where limited resources, organizational constraints, and patient preferences my present serious obstacles. Incorporating an antidepressant regimen into the chemotherapy protocol for all melanoma patients scheduled to receive interferon therapy seems relatively simple and inexpensive if a generic antidepressant is prescribed. However, identifying bereaved individuals and providing a social rhythms therapist is a different matter. Similarly, offering prophylactic antidepressant therapy immediately after delivery to non-depressed women with a single prior episode of postpartum depression reduces the likelihood of a second postpartum episode. However, knowing that the probability of remaining depression free following the second delivery is 3 out of 4, may make some new mothers opt to take their chances with recurrence rather than taking medication.6 In summary, the characterization of risk indicators is only the first step toward establishing where and when preventive efforts should begin.


Where and When Should Depression Prevention Begin?

The provision of depression care has evolved substantially with important implications for prevention. The choice of medications singly, in combination, and in sequence; modifications of psychotherapy; and the integration of mental health services within primary care provide an evidence base upon which to establish both where and how depression prevention should begin. Numerous studies suggest that the detection of a depressive prodrome answers the question of when to begin.

Smit and colleagues2 followed a population-based cohort of 2,200 adults 55–85 years of age to detect the incidence of clinically significant symptoms of depression over the course of 3 years. They also collected data on any array of demographic, functional, biomedical, and psychosocial characteristics thought to predict the incidence of depression among community residents. In addition, to account for the effect of baseline levels of depressive symptoms not reaching clinical significance, they limited the definition of a case of depression to respondents whose depression score passed the threshold for significance by ≥5 points. People with a baseline score <5 were considered to be free of depressive symptoms. Those scoring 5–15 were considered to have depressive symptoms but not at the clinically significant level. This allowed them to construct a parsimonious predictive model of variables including female gender, low education, ≥2 chronic conditions, functional limitations, small social network, and baseline depressive symptoms. The model accounted for >80% of the attributable risk fraction with baseline depressive symptoms accounting for 50%. As a result, the calculated number needed to treat to prevent depressive symptoms from resulting in one clinically significant case of depression would be 16. However, when the group with baseline depressive symptoms was further restricted to those with functional limitations and small social networks as well, the number needed to treat dropped to 5.

Schoevers and colleagues7 used the same population sample as Smit and colleagues2 but restricted their longitudinal analyses to people 64–84 years of age. In addition, they employed a categorical diagnostic measure which grouped respondents into not depressed, subsyndromal depressed but not meeting diagnostic criteria, and MDD. This allowed the investigators to explore two models of risk for the development of MDD. The selective prevention model characterized people at elevated risk for the development of MDD but who had little if any depressive symptomatology at baseline. The indicated model incorporated those with subsyndromal depression. In the selective model, spousal death and chronic illness for those without depressive symptoms at baseline substantially elevated the risk for depression. In contrast within the indicated model, subsyndromal depression accounted for 40% of the risk for a depressive incident. The number needed to treat based on the single subsyndromal depression risk factor was 5.8, accounting for 24% of the new cases.  Adding other subject characteristics elevated the risk to 49%, resulting in a lower number needed to treat. The investigators concluded that focusing depression prevention on older people with symptoms not yet meeting diagnostic criteria identifies a subset of the population with a depressive prodrome. In addition, subsyndromal symptoms may reflect vulnerability to relapse or recurrence among those with a prior depressive episode. As a result, choosing the single risk factor of depressive symptoms minimizes wasted effort directed at people whose symptoms will remit spontaneously.

Yet, the identification of additional indicators of risk is necessary to reduce the number needed to treat. Mast and colleagues8 examined risk factors for cerebrovascular disease, including diabetes, hypertension, and heart disease and their relationship to depression and impaired executive dysfunction at baseline, and 18 months thereafter among older patients admitted to a rehabilitation hospital. People with lower executive function scores at baseline were more likely to develop depressive symptoms as they accumulated cerebrovascular risk factors. Among those with average or above executive function scores at baseline, the addition of risk factors did not lead to greater levels of depression. Thus, the causal risk factor was executive dysfunction, with diabetes, hypertension, and heart disease being variable markers. However, the exposure rate of primary older care patients to diabetes, hypertensions, and heart disease is substantial.  


Intervention and the Depressive Disorder Prodrome

Although the characterization of risk has advanced substantially, prevention in practice remains problematic. The characterization of a depressive prodrome remains a challenge. In randomized controlled trials of interventions for minor depression or dysthymia in primary care settings, neither problem-solving therapy nor paroxetine were superior to placebo in helping patients achieve remission.9 The majority of people who had received medication or psychotherapy and experienced remission discontinued the intervention at the end of the trial, yet were considered recovered 25 weeks after starting the study.10 However, the response rate among the placebo group was greater than expected. It may well be that the added but nonspecific attention given the placebo group functioned as low dose supportive therapy. In contrast, among people with MDD complicated by executive dysfunction, Alexopoulos and colleagues11 found problem-solving therapy superior to supportive therapy in domains of decision making and generation of alternative solutions to personal problems.

Allart-van Dam and colleagues12 found no difference in the incidence of MDD between control groups and a series of educational sessions known as the Coping with Depression course for primary care patients with subclinical depressive symptoms. However, patients with a lower initial level of depressive symptoms benefited more than controls. Definitions of “subclinical,” “subsyndromal,” and “minor” depression can be confusing,13 but each is associated with as much as a 5-fold risk for the subsequent development of a major depressive episode. Yet, a substantial number of patients in each category will experience a remission of symptoms without intervention. As a result, it becomes important to identify associated cross-sectional patient characteristics that predict trajectory. Self-assessed health and perceived lack of social support may be the simplest and most reliable measures to predict the less benign course.14 As an alternative to developing a more reliable indicated prevention model, a stepped care approach is underway, which entails watchful waiting to determine persistence of symptoms followed by educational therapy, problem-solving therapy, and medication.15 Finally, an array of acute medical events or conditions including macular degeneration,1 stroke,1 and myocardial infarction16,17 are markers which have proven to the reliable indicators of depression risk.

Because of increased incidence and mortality of myocardial infarction associated with depression, there has been interest in preventive protocols with theses patients. However, randomized interventions employing antidepressants (Sertaline AntiDepressant Heart Attack Randomized Trial [SADHART]16) and psychotherapy (Enhancing Recovery in Coronary Heart Disease [ENRICHD]17) have not consistently demonstrated the hypothesized prevention in mortality and adverse cardiac events despite reductions in depressive symptoms. In contrast, cardiac patients who received antidepressants either from their primary care provider or a psychiatrist, and either before or after randomization to psychotherapy in the ENRICHD study, experienced significantly less morbidity and mortality.17 

Several findings argue for depression prophylaxis among all post-myocardial infarction patients rather than those with depressive symptoms only. The first finding is suggestions that both antidepressant and psychological treatments in the SADHART and ENRICHD trials were started too late to show robust effects. The second finding that is evidence that the failure to reduce mortality in the intervention groups may be the result of the frequency with which routine care patients also received antidepressants. The third finding is the availability of non-sedating antidepressants that inhibit platelet aggregation do not promote arrhythmias and are relatively free of dangerous drug interactions. A strategy of “antidepressants for all” is imminently feasible, but methodologic advances in risk stratification and outcomes measures will be required to prove its value. A similar approach to the prevention of post-stroke depression is already yielding benefits.18 


Financing the Model

Studies of the costs compared to benefits of depression care are informative for efforts to finance a model of depression prevention. Gilbody and colleagues19 compared costs and benefits of randomized studies of depression care in primary practices. The authors found uniformly superior outcomes for collaborative care and case management. However, incremental improvements in depression care were associated with increments in costs. A collaborative, interdisciplinary approach to depression in primary care settings was cost effective but did not reduce the total costs of care.

Both the President’s New Freedom Commission on Mental Health20 and the National Business Group on Health21 have recommended that public and private payers reimburse the collaborative, interdisciplinary model of depression care. Bachman and colleagues22 have proposed numerous financing methods and find the prospects of improved funding favorable. Concerns for the economic impact of parent care on younger adults in the work force add to the incentive for the prevention of depression in late life.23 In addition, the Children’s Health and Medicare Protection (CHAMP) Act H.R. 3162 passed by the House of Representatives on August 1, 2007 would authorize preventive screening of mental disorders as a billable service at the discretion of the Secretary of Health and Human Services.24 CHAMP stipulates that preventive services must be recognized, as is depression screening, by the United States Preventive Services Taskforce.25 Of note, the Taskforce finds depression screening effective if it is directly linked to the availability of treatment.

In 2004, the Center for Medicare and Medicaid Services (CMS) instituted a hierarchical condition categories (HCC) model to adjust payments to private health plans participating in the Medicare Advantage program (Medicare managed care, previously titled “M+C”).3 CMS pays private health plans a monthly capitation rate to provide services to enrolled beneficiaries. Initially, the capitation rates were based on fee-for-service expenditures categorized by geographic area with payments set at 95% of the locally adjusted average per capita costs of care. However, because of concerns that heath plans were leaving Medicare Advantage for lack of profitability due to higher than expected costs, and conversely, because some plans were “cherry picking” the healthiest seniors who would be least expensive to serve and generate more profits, CMS adopted the risk adjustment model.

To construct the model, close to 12,000 diagnoses from the International Classification of Diseases: Clinical Modification, Ninth Edition,26 were collapsed into diagnostic groups, then clinical conditions, and finally into 158 HCCs incorporating >3,000 diagnoses and the range of illness severity. This allows CMS to generate cost coefficients (multipliers), which could be used to justify an increase or decrease in the annual premium paid to the private health plan based on the number of conditions and risk of expenditures. Most importantly, the HCCs are additive such that as the number of chronic conditions increases so does the total risk calibration. Age, gender, and locality adjustments are also factored into the equation.3 The capitation (estimated basic premium payment) is based on the adjusted average per capita cost of care and is recalibrated annually to reach unity or a value of 1.00. In theory, the recalibration is meant to lessen the impact of accumulating HCCs. The practical effect is to introduce a degree of uncertainty into the calculations and financial risk to the Medicare Advantage carriers. Nonetheless, a reasonable estimate of the premium to be paid in the subsequent year can be ascertained. 

For example, HCC number 55 covers the disease group including “Major Depressive, Bipolar and Paranoid Disorders” with a factor loading of 0.370.27 HCC 95 covers the disease group “Cerebral Hemorrhage” with a factor of 0.366.  HCC 18, “Diabetes without Complication,” factors at 0.181, and HCC 77, “Respirator Dependence/Tracheostomy Status,” factors at 1.860. In practical terms, when the provider documents “Diabetes without Complication” based on a face-to-face encounter with the Medicare Advantage patient, the annual premium in the following year may increase as much as 18% although various adjustments may reduce the actual payment. In contrast, “Major Depressive, Bipolar and Paranoid Disorders” or “Cerebral Hemorrhage” would increase the premium by 33%, and “Respirator Dependence/Tracheostomy Status” by 186%. The examples of cerebral hemorrhage and respirator dependency are provided only to give a sense of the relative impact HCCs may have. But with comparisons in mind it becomes clear that detection of one case of MDD is worth twice the detection of one case of uncomplicated diabetes.

More to the point, if the monthly per member payment rate approximates $700 and is multiplied by 0.370 because MDD has been documented, the monthly rate would increase by as much as $259 ($700 X 0.370=$259) in the next year. In as much as depressive disorders are prevalent but often unrecognized in primary care settings, a considerable reservoir of income remains untapped that could be used to provide for depression screening and treatment but also for carefully constructed, modest prevention efforts. Although the annual amount may seem generous, Katon and colleagues28 found the excess costs of MDD or minor depression were at least $1,045 per person per 6 months, or better than $2,000 annually. In addition, Gallo and colleagues29 found that depression is as predictive of mortality as diabetes or coronary heart disease in primary care settings.  



A confluence of factors suggests that prevention strategies must be added to treatment protocols if the worldwide burden of depressive illness is to be substantially reduced. First, despite advances in antidepressant compounds only a slight majority of older patients in randomized, placebo-controlled trials achieve recovery. A significant minority will experience recurrence due to premature cessation of treatment. Second, disabling somatic conditions, most notably stroke, heart attack, and loss of sight, are associated with a predictable prevalence of depressive symptoms and MDD. Third, medications such as interferon-a treat physical illness but reliably induce a depressive syndrome. Fourth, bereavement, executive dysfunction, and trauma place the older person at increased risk for MDD. Finally, anticipated improvements in therapeutics and access to treatment for depression will continue to be incremental rather than dramatic, leaving a considerable burden of disability in their wake. Thus, in populations selected for screening because of events which place them at elevated risk, and particularly among those with subsyndromal depression, prophylactic antidepressants or psychotherapy30 may be genuinely preventive. Screening to document and reduce the prevalence of MDD may generate the income to offset the costs of efforts to reduce the incidence as well. If either or both approaches result in a reduced rate of hospitalization due to somatic illnesses that increase the risk of depression, the coupling of screening, treatment and prevention might prove essential to the financial viability of managed Medicare programs. PP



1. Whyte EM, Rovner B. Depression in late-life: shifting the paradigm from treatment to prevention. Int J Geriatr Psychiatry. 2006;21(8):746-751.
2. Smit F, Ederveen A, Cuijpers P, Deeg D, Beekman A. Opportunities for cost-effective prevention of late-life depression: an epidemiological approach. Arch Gen Psychiatry. 2006;63(3):290-296.
3. Pope GC, Kautter J, Ellis RP, et al. Risk adjustment of Medicare capitation payments using the CMS-HCC model. Health Care Financ Rev. 2004;25(4):119-141.
4. Prigerson HG, Monk TH, Reynolds CF III, et al. Lifestyle regularity and activity level as protective factors against bereavement-related depression in late-life. Depression. 1995/1996;3:297-302.
5. Musselman D, Lawson D, Gumnick J, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Eng J Med. 2001;344(13):961-966.
6. Wisner KL, Perel JM, Peindl KS, Hanusa BH, Piontek CM, Findling RL. Prevention of postpartum depression; A pilot randomized clinical trial. Am J Psychiatry. 2004;161(7):1290-1292.
7. Schoevers RA, Smit F, Deeg DJ, et al. Prevention of late-life depression in primary care: do we know where to begin? Am J Psychiatry. 2006;163(9):1611-1621.
8. Mast BT, Yochim B, MacNeill SE, Lichtenberg PA. Risk factors for geriatric depression: The importance of executive functioning within the vascular depression hypothesis. J Gerontology: Medical Science. 2004;59A(12):1290-1294.
9. Frank E, Rucci P, Katon W, et al. Correlates of remission in primary care patients treated for minor depression. Gen Hosp Psychiatry. 2002;24(1):12-19.
10. Oxman T, Barrett JE, Sengupta A, et al. Status of minor depression or dysthymia in primary care following a randomized controlled treatment. Gen Hosp Psychiatry. 2001;23(6):301-310.
11. Alexopoulos GS, Raue P, Areán PA. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11(1):46-52.
12. Allart-van Dam E, Hosman CM, Hoogduin CA, Schaap CP. Prevention of depression in subclinically depressed adults: follow-up effects on the ‘Coping with Depression’ course. J Affect Disord. 2007;97(1-3):219-228 .
13. Lyness JM, Kim J, Tang W, Tu X, Conwell Y, King D, Caine ED. The clinical significance of subsyndromal depression in older primary care patients. Am J Geriatr Psychiatry. 2007;15(3):214-223.
14. Lyness JM, Heo M, Datto CJ, et al. Outcomes of minor and subsyndromal depression among elderly patients in primary care settings. Ann Intern Med. 2006;144(7):496-504.
15. van ‘t Veer-Tazelaar N, van Marwijk H, van Oppen P, et al. Prevention of anxiety and depression in the age group of 75 years and over: a randomized controlled trial testing the feasibility and effectiveness of a generic stepped care programme among elderly community residents at high risk of developing anxiety and depression versus usual care. BMC Public Health. 2006;18;6:186.
16. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288(6):701-709. Erratum in: JAMA. 2002;288(14):1720.
17. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patient after myocardial infarction. Arch Gen Psychiatry. 2005;62(7):792-798.
18. Whyte EM, Mulsant BH, Rovner BW, Reynolds CF. Preventing depression after stroke. Int Rev Psychiatry. 2006;18(5):471-481.
19. Gilbody S, Bower P, Whitty P. Costs and consequences of enhanced care for depression; systematic review of randomized economic evaluations. Br J Psychiatry. 2006;189:297-308.
20. The President’s New Freedom Commission on Mental Health Report. Available at: www.mentalhealthcommission.gov/reports/reports.htm. Accessed August 15, 2007.
21. National Business Group on Health. Available at: www.businessgrouphealth.org/prevention/depression.cfm. Accessed August 15, 2007.
22. Bachman J, Pincus HA, Houtsinger JK, Unutzer J. Funding mechanisms for depression care management: opportunities and challenges. Gen Hosp Psychiatry. 2006;28(4):278-288.
23. MetLife Mature Market Institute and the National Alliance for Caregiving. The MetLife Caregiving Cost Study: Productivity Losses to U.S. Business. Available at: www.maturemarketinstitute.com. Accessed August 15, 2007.
24. H.R. 3162, Title II, Section 201, pg 96-102 (PDF version). Available at: http://thomas.loc.gov/cgi-bin/query/z?c110:H.R.3162.EF. Accessed August 15, 2007.
25. U.S. Preventive Services Task Force. Screening for Depression: Recommendations and Rationale. May 2002. Agency for Healthcare Research and Quality, Rockville, MD. Available at: www.ahrq.gov/clinic/3rduspstf/depression/depressrr.htm. Accessed August 15, 2007.
26. International Classification of Diseases: Clinical Modification. 9th ed. Chicago, IL: American Medical Association; 2006.
27. Announcement of Calendar Year (CY) 2007 Medicare Advantage Capitation Rates and Medicare Advantage and Part D Payment Policies Available at: www.cms.hhs.gov/MedicareAdvtgSpecRateStats/Downloads/Announcement2007.pdf. Accessed August 15, 2007.
28. Katon WJ, Lin E, Russo J, Unützer J. Increased medical costs of a population based sample of depressed elderly patients. Arch Gen Psychiatry. 2003;60(9):897-903.
29. Gallo JJ, Bogner HR, Morales KH, Post EP, Ten Have T, Bruce M. Depression, cardiovascular disease, diabetes and 2-year mortality among older primary care patients. Am J Geriatr Psychiatry. 2005;13(9):748-755.
30. Rovner BW, Casten RJ, Hegel MT, Leiby BE, Tasman WS. Preventing depression in age-related macular degeneration. Arch Gen Psychiatry. 2007;64(8):886-892.


This interview took place on May 2, 2007, and was conducted by Norman Sussman, MD.


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

Disclosure: Dr. Wray receives grant support from the Australian National Health and Medical Research Council, the National Institutes of Health, and Sequenom, Inc.


Dr. Wray is a statistical geneticist specializing in the genetics of complex diseases. She is senior research officer at Queensland Institute of Medical Research in Brisbane, Australia, where she leads the Anxiety and Depression Study of the Genetic Epidemiology Laboratory. The study represents a powerful design to identify a large cohort of individuals for genetic analysis for whom comorbidity between depression and anxiety subtypes is fully documented.


There are so many terminologies used in genetics that many may be unfamiliar with. Can you provide an overview of the jargon associated with genomes?

An individual’s genome is their complete deoxyribonucleic acid (DNA) sequence which is found in 22 pairs of chromosomes, plus the sex chromosomes. A high proportion of the DNA sequence is identical between people as well as between species. It is commonly noted that humans are related to apes in that they share a lot of the same DNA. However, there are sites throughout the genome called genetic polymorphisms which can vary. The variation at these sites can cause the differences between individuals. Similarly, they can cause similarities between relatives as a proportion of shared genetic material is passed from parent to offspring.

Different versions of polymorphisms are called alleles. A single-nucleotide polymorphism (SNP) is the simplest form of a genetic polymorphism, where a single nucleotide in the DNA strand can vary. Because each person has two sets of chromosomes, people carry two versions of each DNA strand. Thus, each SNP site has two versions of the nucleotides that may be either the same (homozygous) or different (heterozygous). The two copies that a person carries makes up their genotype. Within a population there are three possible types of genotypes at each SNP position that can exist. A gene is a chunk of DNA that codes for a particular protein. If an SNP within a section that codes for a gene is different, it might end up with placement of a different amino acid into that protein chain. However, the vast majority of these genetic polymorphisms do not alter the protein product, though it is believed that they are very likely to be involved in regulation of genes.

In a genetic association study, allele frequencies at a polymorphic site are examined in a set of cases and controls. If the allele frequency differs between the cases and controls, the polymorphism may be a causal risk factor for a disease. There are millions of genetic polymorphisms within the human genome, although some are very rare, and others almost always occur together. In fact, the majority of the variation in the human genome can be investigated by studying approximately 500,000 of these SNPs. The forefront of genetic research currently consists of genome-wide association studies where, in very large sets of cases and controls, half a million SNPs are genotyped. This should make groudbreaking progress in relation to complex diseases such as psychiatric disorders.

Semaphorins are molecular cues that have been implicated in the development of the nervous system and, in particular, in the guidance of axonal projections and neuronal migration. Semaphorins were only discovered approximately 13 years ago; thus, understanding their function is relatively new. The role of semaphorins and their receptors in the developing nervous system has been examined mostly in mice studies. As new axons made in the developing brain reach their target, they do not appear to be normal in mice who have defective genes-encoding semaphorins. These differences are very subtle, which makes them very interesting as potential candidate genes to study in relation to psychiatric disorders.1,2 Plexins are receptors for semaphorins. Interestingly, whereas the expression of semaphorins occur throughout the brain during development, in adults this expression is limited to the motor system and the olfactory-hippocampal pathway.


Are there certain areas of the brain where neurogenesis is more prevalent than others?

Current literature indicates that neurogenesis in adults is confined to the olfactory hippocampal pathway. There used to be a well-entrenched dogma that no new neurones were laid down post-puberty. Only recently was it recognized that neurogenesis is not restricted to the developing brain, and does occur in adults. Although the rate of neurogenesis is not high, it is significant when accumulated over time.


Are neurogenesis and neurodegeneration likely to be involved in the onset of mood disorders and anxiety?

At the moment there is a theory that something precipitates a reduction in neurogenesis in the adult brain which results in a depression that is alleviated when neurogenesis returns to normal levels. When this theory was first introduced the evidence simply came from the fact that brain volume in depressed patients is less common than in normal controls. This finding has been replicated in many studies. More recently, work with mouse and rat models show that the commonly prescribed mood-stabilizing drug lithium enhances hippocampal neurogenesis. Specifically, it was discovered that neurogenesis is a requirement for the behavioral responses in order for lithium to be effective. Further research suggests that all major pharmacologic treatments result in enhanced hippocampal neurogenesis.

The theory about adult neurogenesis complements other theories. Many factors associated with depression, such as changes in neurotransmitters, hormones, and physical exercise enhance neurogenesis, whereas factors such as age, stress, and other stimuli for the pituitary-adrenal axis reduce neurogenesis.Thus, the theory does not stand on its own. It is complementary. However, it is unclear whether changes in neurogenesis cause depression or whether another mechanism precipitates depression and, as a result, causes a reduction in neurogenesis.


What methodology was used in your study examining the possible association between genetic polymorphisms and anxiety and depression?

Our study3 was conducted after a study by Mah and colleagues4 in which 25,000 SNPs were genotyped in a set of schizophrenia cases and controls. This was the first study to use so many variants. From the discovery case-control set, they identified 62 SNPs that had a different allele frequency between the cases and controls. Certainly, when studying so many SNPs, some differences between cases and controls are expected to occur by chance. Thus, Mah and colleagues used these 62 SNPs and genotyped them on several additional case-control samples. One of the 62 SNPs—a SNP in the gene encoding plexin A2 (PLXNA2)—showed a difference in allele frequency between cases and controls across most of their replication samples. By replicating the result, it is quite unlikely that the difference in allele frequency was by chance.

One of the replication samples was genotyped in our lab at the Queensland Institute of Medical Research. We decided to study PLXNA2 in an anxiety-depression study sample. Although schizophrenia, anxiety, and depression are considered distinct disorders, there is a growing school of thought that there may be underlying risk variants in common. It did not seem too far fetched to think that something which was associated with schizophrenia might also be associated with anxiety and depression.

There is some background to the development of our study. In the early 1980s, Nick Martin, PhD, who heads the lab at the Queensland Institute of Medical Research, started to collect measurements on monozygotic and dizygotic twins as well as their siblings and parents. This classic twin family design can provide measurements to help understand the genetic basis of disease or, in fact, any phenotype. By comparing groups of identical and non-identical twins, we can tease apart the relative importance of common genetic factors versus common environmental factors. The collection of these records started way before the genomics revolution. The foresight of Martin has resulted in a collection of participants, which is a hugely valuable resource for the sorts of studies we can do today. Our laboratory has investigated genetic contribution to an amazing array of factors, including, for example, body mass index, sexual orientation, susceptibility to mosquito bites, and alcohol and nicotine addiction.

In a study conducted between 1980 and 1989, >18,000 people completed the Eysenck Personality Questionnaire (EPQ) to identify the personality trait of neuroticism.5 It has been frequently validated that people who score highly on the neuroticism scale are likely to have clinical disorders of anxiety and depression. The questions on the EPQ probe for anxious and depressive behaviors. We analyzed the results and identified sibling pairs who had extreme measures for neuroticism; siblings either both scored extremely high, both scored extremely low, or one scored extremely high and one scored extremely low. We invited these people to participate in another study on anxiety and depression.3 This kind of study design is called an extreme discordant and concordant design, and it is a very powerful way of trying to extract the maximum amount of information that was present in the original cohort of 18,000 people by investigating a much smaller subset. This large quantity of data and good consistency of quality is quite superior to what is usually available from clinical settings.

More than 3,000 participants in this anxiety depression study retook the EPQ and also completed the complete international diagnostic interview (CIDI) which was devised and validated by psychiatrists. It is possible to allocate Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition6 diagnoses of anxiety or depression based on the answers to this self-report questionnaire. High scorers on the EPQ were more often allocated diagnoses of anxiety and/or depression than low scorers. Six hundred and twenty four people met the criteria for diagnosis of anxiety or depression. Participants could be allocated more than one diagnosis and anxiety could be be broken down to the more specific diagnoses of phobias and obsessive compulsive disorder.

In the study sample, we genotyped variants of PLXNA2 and found an association with anxiety and depression. In our study samples we were able to probe to see exactly who was contributing to that association. We found they were people who showed anxiety either with or without depression, but not the people who had depression only. Our original result was really hypothesis testing, and this post-hoc analysis is really hypothesis generating. We hope others in the scientific community will replicate our results so that we can be truly confident.

The interesting thing was that the PLXNA2 gene lies within a homologous region, ie, the same region, from the mouse genome, which has been shown to be related to anxiety traits in mice. Large-scale mouse studies can produce powerful and much more certain results. Thus, the fact that we found the association with anxiety only in the CIDI study seemed to fit with the result from the mice study.


How do these results connect to the results of Caspi and Kendler?

Caspi and colleagues7 looked at the genetic polymorphism 5-HTTLPR which is in the serotonin transporter. (This study was later replicated by Kendler and colleagues.8) 5-HTTLPR is an insertion-deletion polymorphism, meaning  some people have a chunk of the DNA strand missing (deletion) and others have it present (insertion). The deletion form has been shown to reduce the transcription efficiency of the serotonin transporter gene. Caspi then examined stressful life events (SLE) and found that people with both SLE and the short form of 5-HTTLPR more likely to succumb to depression than others. This result for genotype-environment interaction is appealing because it fits with our knowledge about the relationship between stress and psychiatric disorders. A combination of the stress and genetic factors are more likely to predispose a person to depression.

Replication studies of the original Caspi study have had mixed results. However, these studies generally do not have the power to detect what they are trying to detect. The problem is that the necessary study samples are expensive and time-consuming to collect. Information on stressful life events, depression, or psychiatric disorders have to be collected from each participant. The, blood must be drawn in order to conduct a DNA study. Thus, I tend to look more toward animal models to really understand the interaction between genotype and environment.


Do your findings fit in with any studies on brain-derived neurotropic factor (BDNF)?

There are parallels between the studies. However, I do not think anyone has pieced them together. BDNF is a gene that is involved in neuronal survival and differentiations in synaptic plasticity. It also has a role in brain development and is expressed in the adult brain, particularly in the hippocampus, which is parallel to PLXNA2. There has been mixed success in the association studies regarding whether or not there are variants of the gene-encoding BDNF which directly have an effect on psychiatric disorders. However, I think the information coming from mouse studies is quite convincing that BDNF does play a role. In addition, BDNF levels are lower in patients with depression, and treatment with antidepressants increases BDNF levels in the adult hippocampus and increases adult neurogenesis. I would not be surprised if PLXNA2 and BDNF are related. However, studies are necessary to determine this.


If validated, what are the practical implications of your findings?

I think we are kidding ourselves if we think the brain is simple. There are many interacting factors. Part of the research will serve to help others to eventually understand more about the metabolic pathway. That is a long way from clinical input. However, it is interesting that our genetic research has found a small increase in risk for anxiety disorders. As we study more genes we are finding more variants, which each individually have a small effect on risk. I think we are coming to a point where we will realize that the people who are at higher risk of succumbing to a disease are those who actually harbor many of these risk variants. The sorts of studies which are currently underway will help us to produce interventions to help prevent disease from manifesting. Soon we will have a better understanding of the genetic architecture which underlies psychiatric disorders.

Not so long ago, psychiatric geneticists thought that for each psychiatric illness there was one or at most a few genetic variants. Now, the community is waking up to the fact that there are many variants. However, there is still debate in the literature. Two recent articles published in The British Journal of Psychiatry argued for very different spectrums of the genetic architecture.9,10 One argued for the fact that there would be very rare alleles or genetic loci underlying schizophrenia, so that families had private mutations that, if present, were very highly causal for the disease.9 Another article argued the complete opposite, that many genetic variants could be common, but individually they carried only a small increase in risk.10

The current era of genome-wide association studies, where very large, powerful studies look at many variants, will likely produce answers as to how many risk factors are involved. My personal thoughts are very much in line with the second article. Many simultaneous risk variants can cause the breakdown of metabolic pathways, thus causing disease to manifest itself. I think this a very exciting time for psychiatric genetics. PP



1. Morris D, Runker A, O’Tuathaigh CMP, et al. Animal knockout and human studies identify SEMA6A and PLXNA2 as schizophrenia candidate genes [abstract]. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(7):737.
2. Suto F, Tsuboi M, Kamiya H, et al. Interactions between Plexin-A2, Plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron. 2007;53(4):535-547.
3. Wray NR, James MR, Mah SP, et al. Anxiety and comorbid measures associated with PLXNA2. Arch Gen Psychiatry. 2007;64(3):318-326.
4. Mah S, Nelson MR, Delisi LE, et al. Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Mol Psychiatry. 2006;11(5):471-478.
5. Kirk KM, Birley AJ, Statham DJ, et al. Anxiety and depression in twin and sib pairs extremely discordant and concordant for neuroticism: prodromus to a linkage study. Twin Res. 2000;3(4):299-309.
6. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
7. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5HTT gene. Science. 2003;301(5631):386-389.
8. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry. 2005;62(5):529-535.
9. McClellan JM, Susser E, King MC. Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:194-199.
10. Craddock N, O’Donovan MC, Owen MJ. Phenotypic and genetic complexity of psychosis. Invited commentary on… schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:200-203. Erratum in: Br J Psychiatry. 2007;190:365.


e-mail: ns@mblcommunications.com


Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

Disclosures: Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.



One of the most important needs in clinical medicine is improved post-marketing surveillance of adverse drug reactions. Headlines in the popular press have recently highlighted an increasing number of drugs that have been in use for years that suddenly are withdrawn from the market or are tagged with a so-called “back-box warning” of a potentially life-threatening treatment-emergent event. Yet, there are numerous side effects of psychotropic drugs that are undesirable or that impact quality of life, that go unrecognized by prescribers.

As some readers may notice, letters to the editor are infrequently published in Primary Psychiatry. In part, it is because the journal does not typically print clinical trial results, which are the most common triggers for correspondence in journals. Readers, in those cases, question the design, analysis, or conclusions of a study. When a letter is published, it is usually to share a thoughtful opinion by a reader or to increase awareness of a possible benefit or risk of a treatment modality.

In publishing “Lithium-Induced Sialorrhea” by Johnny Lops, DO, I wanted to remind prescribers that there are rare side effects that may be overlooked among commonly prescribed medications. Lithium has been used as a treatment for bipolar disorder for >60 years. However, other than a 1982 case report of sialorrhea by Donaldson,1 there have been no published reports of patients experiencing prolonged, increased salivation with normal lithium levels. This letter caught my attention because 1 year ago a patient saw me in consultation for the same problem after finding no other expert psychopharmacologists who could explain why he was experiencing this problem. Like Dr. Lops, I could only find the single case report. Yet, it was clear that the patient I saw was in fact hypersalivating, and quite distressed by this symptom. It reminded me that there are many side effects associated with the commonly prescribed psychotropic drugs that go unrecognized by physicians.

A 2004 commentary in Journal of the American Medical Association (JAMA)2 railed about the shortcomings and failures of the current imperfect system for postmarketing surveillance. The mechanism for monitoring postmarketing adverse events is the Food and Drug Administration’s MedWatch program. This involves a passive collection of spontaneous reports of adverse drug reactions, where manufacturers of prescription medical products are required by regulation to submit adverse event reports to the FDA.3 According to the commentary in JAMA, this “results in an underreporting of adverse outcomes with capture of only a small fraction of adverse events that actually occur.” The system does not permit accurate calculation of rates of adverse events and makes it difficult to determine whether the adverse event resulted from the drug or the disease it was intended to treat.

Since we now recognize that preapproved clinical trials, which typically involve only several hundred patients, cannot detect all possible side effects of a drug, and that the FDA monitoring system is seriously flawed, it seems that the time has come for more innovative ways to capture the true incidence of drug safety and tolerability profiles. There should also be a mechanism for prescribers to have real-time access to any emerging database of unexpected events. Not only would this better serve the patient population, but a transparent picture of how a drug is performing might serve to indemnify pharmaceutical manufacturers from litigation claiming that they were withholding potentially unfavorable information about a product. To protect manufacturers against information derived from such a system being used to damage their commercial interests, it should be made clear that none of the data collected could be used in promotional information by competitors. PP



1. Donaldson SR. Sialorrhea as a side effect of lithium: a case report. Am J Psychiatry. 1982;139(10):1350-1351.
2. Fontanarosa PB, Rennie D, DeAngelis CD. Postmarketing surveillance—lack of vigilance, lack of trust. JAMA. 2004;292(21):2647-2650.
3. Postmarketing Surveillance Programs. Available at: www.fda.gov/cder/regulatory/applications/postmarketing/surveillancepost.htm. Accessed August 15, 2007.


Dr. Clark is associate professor and director of the Adolf Meyer Chronic Pain Treatment Programs in the Department of Psychiatry and Behavioral Sciences at The Johns Hopkins Medical Institution in Baltimore, Maryland.

Disclosure: Dr. Clark reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Michael R. Clark, MD, MPH, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Medical Institution, Osler 320, 600 N Wolfe St, Baltimore, MD 21287-5371; Tel: 410-955-2126; Fax: 410-614-8760; E-mail: mclark9@jhmi.edu.




Chronic pain is a common problem. Neuropathic pain, ranging from diabetic peripheral neuropathy and postherpetic neuralgia to less well understood conditions such as fibromyalgia, affects approximately 3% of the world’s population. The pathophysiology of these disorders, such as ion channel upregulation, spinal hyperexcitability, and descending facilitation, has been detailed through extensive research. Psychotropics such as antidepressants, anticonvulsants, and neuroleptics offer effective alternatives to conventional analgesics. Antidepressants typically block the reuptake of monoamines such as norepinephrine and serotonin. Increased amounts of these neurotransmitters are presumed to increase descending inhibition of nociception. Anticonvulsants possess more heterogeneity in their pharmacology. Many anticonvulsants block use-dependent sodium channels that are increased in number on damaged neurons. Other anticonvulsants modulate calcium channels required for the release of neurotransmitters at the synaptic cleft. Newer anticonvulsants affect other nociceptive components such as the g-aminobutyric acid receptor complex, N-methyl-D-aspartate receptors, and protect neurons from free radical damage. Atypical neuroleptics can augment other medications through their actions at dopamine and serotonin receptors that likely interact with the opioid- and adreno-receptor systems. Benzodiazepines, while widely prescribed, generally cause more problems, such as cognitive impairment and physicial dependence, than benefits. However, significant pain relief can be achieved in a select group of patients.



While the psychiatric comorbidities of chronic pain syndromes are well documented, a large body of research now supports the use of traditional psychiatric treatments in the management of chronic pain. Psychopharmacology is a broad term that encompasses the uses, effects, and actions of medications as they relate to the mind. With respect to chronic pain, almost any non-analgesic or adjunctive medication could be considered a psychopharmacologic treatment. However, a relatively small number of drug classes are employed in the treatment of chronic pain and usually the focus is on the treatment of neuropathic pain conditions, which affect 2% to 3% of the world’s population.1,2 Medications typically target pathophysiologic mechanisms of neuropathic pain such as sodium and calcium channel upregulation, spinal hyperexcitability, descending facilitation, and aberrant sympathetic-somatic nervous system interactions.3 Antidepressants and anticonvulsants remain the best studied and should be first-line therapies, particularly for painful polyneuropathies and postherpetic neuralgia.4,5

Unfortunately, medications are generally underutilized and underdosed. In one study of patients with neuropathic pain, 73% complained of inadequate pain control but 72% had never received anticonvulsants, 60% had never received tricyclic antidepressants (TCAs), 41% had never received opioids, and 25% had never received any of the above.6 The selection of a particular medication will depend on multiple factors. The disease itself may change over time such that the efficacy of a treatment is altered, one treatment may be selected over another based on the response to previous treatments, and combinations will be designed with the hope of pharmacologic synergies.

Neurobiology of Pain
The neurobiology of pain is complex and described in numerous studies.7 Complex interactions take place throughout the peripheral and central nervous systems.8 Changes in peripheral nerves, spinal cord structures, and supraspinal structures contribute to sensory/discriminative abnormalities such as hyperalgesia and allodynia as well as affective/limbic pathophysiology such as depression and suffering.9 Ongoing nociceptive or neuropathic stimulation cause sensory neurons to become electrically hyperexcitable and generate ectopic impulses manifested as spontaneous firing and abnormal responsiveness to a variety of stimuli in neuroma endbulbs, regenerating sprouts, the dorsal root ganglia, areas of demyelination, and local uninjured axons.

Pathophysiologic mechanisms include the remodeling of voltage-sensitive ion channels (primarily sodium channels), transducer molecules, receptors in the cell membrane, activation of intracellular second messenger systems, gene induction leading to changes in protein synthesis, long-term potentiation of synaptic transmission, and loss of inhibitory mechanisms as well as neurons due to apoptotic cell death.8,10 Continuing neurobiologic discoveries generate new ideas for the development of pharmacologic agents to treat pain. For example, more effective therapies could modulate synaptic transmission and membrane excitability using sodium channel subtype antagonists, selective N-methyl-D-aspartate (NMDA) receptor antagonists, adenosine A1 receptor antagonists, nitric oxide synthase inhibitors, cholecystokinin receptor antagonists, cannabinoids, protein kinase C inhibitors, aldose reductase inhibitors, lipoic acid, VR-1 receptor modulators, dronabinol, and cyclo-oxygenase-2 inhibitors.11

Psychopharmacologic Treatments
Pharmacologic Mechanisms of Antinociception
The neurobiology of pain suggests a potential efficacy for all antidepressants in the treatment of chronic pain.12 The analgesic effect of antidepressants is primarily mediated by the blockade of reuptake of norepinephrine and serotonin increasing the levels of these neurotransmitters to enhance the activation of descending inhibitory neurons. However, antidepressants may produce antinociceptive effects through a variety of pharmacologic mechanisms that include other types of monoamine modulation, interactions with opioid receptors, inhibition of ion channel activity, as well as inhibition of NMDA, histamine, and cholinergic receptors.13 TCAs such as nortriptyline, desipramine, and amitriptyline are potent blockers of Na(V)1.7 sodium channels implicated in neuropathic pain.14 Antidepressants may also interact with opioid receptors or stimulate endogenous opioid peptide release.

Clinical Applications
Tricyclic Antidepressants
The effectiveness of antidepressants for the treatment of major depressive disorder is well documented, but their analgesic properties are under-appreciated.15 In 1960, the first report of imipramine use for trigeminal neuralgia was published.16 Since then, antidepressants, particularly the TCAs, have been commonly prescribed for many chronic pain syndromes, including diabetic neuropathy, postherpetic neuralgia, fibromyalgia, irritable bowel syndrome (IBS), interstitial cystitis, chronic pelvic pain, central pain, post-stroke pain, tension-type headache, migraine, and oral-facial pain.17-22 TCAs have been most effective in relieving neuropathic pain and headache syndromes. Meta-analyses of randomized controlled trials concluded that TCAs are the most effective agents for the treatment of neuropathic pain based on calculations of number-needed-to-treat.23,24 Randomized controlled trials have not demonstrated consistent differences in efficacy between the TCAs, but nortriptyline is generally better tolerated than amitriptyline.25-27

Only 25% of patients in a multidisciplinary pain center were prescribed TCAs. However, 73% of treated patients were prescribed only the equivalent of ≤50 mg of amitriptyline, suggesting the potential for additional pain relief.28 The cost of TCAs is often <$5/month and analyses of cost effectiveness continue to support the use of TCAs.29 A variety of treatment studies of post-herpetic neuralgia and painful diabetic peripheral neuropathy have used TCAs with mean daily doses ranging from 100–250 mg.30,31 However, a study of a large United States health insurance claims database found that the mean daily dose of TCAs for the treatment of neuropathic pain in patients ≥65 years of age was only 23 mg.32 While analgesia usually occurs at lower doses and with earlier onset of action than expected for the treatment of depression, the results of investigations to determine drug concentrations needed for pain relief support higher serum levels but remain contradictory.33,34

Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) produce weak antinociceptive effects in animal models of acute pain.35 In human clinical trials, the efficacy of SSRIs in chronic pain syndromes has been variable and inconsistent.36 Fluoxetine significantly reduced pain in patients with rheumatoid arthritis and was comparable to amitriptyline.37 Treatment with fluoxetine also improved outcome measures in women with fibromyalgia.38 Citalopram improved IBS symptoms with therapeutic effects independent of those on anxiety, depression, and colonic sensorimotor function compared to placebo.39 A Cochrane review40 found SSRIs no more efficacious than placebo for migraine and significantly less efficacious than TCAs for tension-type headache. In depressed patients with neuropathic pain, improvements in pain were dependent on improvements in depressive symptoms if treated with fluoxetine but not fluvoxamine, which improved pain independent of antidepressant effects.41

Desipramine was superior to fluoxetine in the treatment of painful diabetic peripheral neuropathy, but paroxetine and citalopram have shown benefit in separate studies.42-44 In antidepressant-naïve patients with post-herpetic neuralgia, desipramine produced more meaningful pain relief and was better tolerated than fluoxetine.45 Despite better efficacy, the TCAs increase catecholamines, which increase glucose levels, decrease insulin release, and diminish insulin sensitivity. In contrast, increased serotonergic function improves sensitivity to insulin and reduces plasma glucose with subsequent weight loss, decreased fasting plasma glucose, and lower levels of HbA1c, making SSRIs an appropriate alternative for some diabetic patients.46 In addition, in a comparison study of gabapentin, paroxetine, and citalopram for painful diabetic peripheral neuropathy, patients reported greater satisfaction, compliance, and mood with SSRIs with similar efficacy for pain.47 Overall, SSRIs are not recommended as a first-line therapy for chronic pain.

Serotonin Norepinephrine Reuptake Inhibitors
Duloxetine and venlafaxine inhibit the presynaptic reuptake of both serotonin and norepinephrine and, to a lesser extent, of dopamine. Duloxetine more potently blocks serotonin (5-HT) and norepinephrine transporters both in vitro and in vivo when compared to venlafaxine.48 Evidence supports that serotonin norepinephrine reuptake inhibitors (SNRIs) produce better analgesic efficacy compared to SSRIs in combination with selective noradrenergic reuptake inhibitors.49

In animal models of neuropathic pain, venlafaxine attenuated thermal allodynia and mechanical hyperalgesia as well as prevented hyperalgesia.50,51 In patients with neuropathic pain, venlafaxine significantly decreased allodynia and hyperalgesia despite a lack of decrease in ongoing pain intensity.52 Average pain relief and maximum pain intensity were significantly lower with venlafaxine compared to placebo in a group of 13 patients with neuropathic pain following treatment of breast cancer.53 Response improved with higher doses of venlafaxine that may be attributable to increased reuptake inhibition of norepinephrine. In contrast, there was no correlation between serum concentration and response to treatment for patients with atypical facial pain receiving significant pain relief with venlafaxine.54 In a double-blind, randomized, placebo-controlled study of painful diabetic neuropathy, venlafaxine 150–225 mg/day produced a greater percentage reduction in pain than the 75 mg/day dosage.55 Venlafaxine has also been demonstrated as an effective agent for migraine prophylaxis.56

Duloxetine possesses analgesic efficacy in preclinical models and in clinical populations such as fibromyalgia and painful diabetic neuropathy.57-59 Guidelines for the treatment of neuropathic pain recommend duloxetine as an efficacious treatment indicated by the Food and Drug Administration for the treatment of diabetic peripheral neuropathic pain.4,5 In combination with ibuprofen, duloxetine produced additive effects for reversing mechanical allodynia and synergistic effects for reducing thermal hyperalgesia in rats with persistent, inflammation-related pain.60 The efficacy of duloxetine in the treatment of painful diabetic neuropathy has been shown to be greater in patients with more severe pain but not related to the severity of diabetes or neuropathy.61 Duloxetine did not cause significant QTc prolongation, increase in blood pressure, weight gain, elevation in hemoglobin A1c values, changes in lipid profiles or nerve function, or disease course in patients with diabetic peripheral neuropathic pain.62,63 While patients with depression and painful somatic symptoms experience relief when treated with duloxetine, research shows that the analgesic effects of this medication are independent of its antidepressant action.64

Novel Antidepressants
While there is little evidence to recommend the use of other antidepressants in the treatment of chronic pain, animal studies and pharmacologic data suggest a rationale. Mirtazapine has post-synaptic actions that enhance noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central α-, auto-, and hetero-adrenoreceptors. Animal models of acute, persistent, and neuropathic pain suggest a different antinociceptive profile than amitriptyline and duloxetine.35 Antinociceptive effects of mirtazapine involve μ- and k-opioid mechanisms combined with both serotonergic and noradrenergic receptors and may be specific to the R(-) enantiomer.65,66 Mirtazapine decreased duration and intensity of chronic tension-type headache in a small study of treatment refractory patients.67

Bupropion, a dopamine and norepinephrine reuptake inhibitor, attenuated mechanical allodynia in rat models of persistent and neuropathic pain.68 In patients with neuropathic pain but without depression, bupropion sustained release decreased pain intensity and interference of pain on quality of life.69 Monoamine oxidase inhibitors decrease the frequency and severity of migraine headaches.70 Nefazodone produced analgesia and potentiated opioid analgesia in the mouse hotplate assay.71 Trazodone is commonly prescribed for insomnia and anecdotal reports proposed efficacy for chronic pain. However, in higher-quality studies, trazodone was ineffective in decreasing pain of patients with chronic low back pain.72,73

Pharmacologic Mechanisms of Antinociception
Anticonvulsants inhibit excessive neuronal activity by blocking voltage-gated sodium and calcium channels, inhibiting excitatory amino acid (glutamine, aspartate) neurotransmission, or enhancing γ-aminobutyric acid (GABA)ergic-mediated inhibitory neurotransmission.74,75 Sodium channels are a critical component of excitable cells with considerable diversity in their subtypes and location that is a manifestation of gene expression that changes in response to a variety of conditions including nerve injury.76 The sodium channel is composed of a principal a subunit and two auxiliary β subunits that are differentially regulated in response to nerve injury and modify sodium channel kinetics, a subunit density, and factors that affect axonal growth and myelination.77 Blocking the activity of use-dependent sodium channels stabilizes the presynaptic neuronal membrane preventing the release of excitatory neurotransmitters and decreasing the spontaneous firing rate in damaged and regenerating nociceptive fibers.26,78,79

Clinical Applications   
First-Generation Anticonvulsants
Phenytoin was first reported in 1942 as a successful treatment for trigeminal neuralgia.80 Carbamazepine has been studied extensively with effectiveness treating multiple neuropathic pain conditions.81 Most anticonvulsants are now utilized in the treatment of chronic pain.82-84 Anticonvulsants are effective for trigeminal neuralgia, diabetic neuropathy, postherpetic neuralgia, and migraine recurrence.85,86 Reviews of efficacy for chronic pain treatment suggest that anticonvulsants may produce better compliance when compared to antidepressants because of lower rates of adverse effects.25-27,87

Valproic acid is most commonly used in the prophylaxis of migraine but is also effective in the treatment of neuropathic pain.88 Valproate produces minimal side effects such as nausea, dizziness, tremor, and rare instances of hepatotoxicity and bone marrow suppression.89 Improvement occurs in frequency of headache, duration or number of headache days per month, intensity of headache, use of other medications for acute treatment of headache, the patient’s opinion of treatment, and ratings of depression and anxiety.90-92 The mechanism of action of valproate is probably related to increased GABA levels by the inhibition of GABA transaminase-mediated metabolism and enhanced GABA synthesis.93 Analgesia may result from the suppression of neuronal activity in the cortex, perivascular parasympathetic fibers, nociceptive trigeminal neurons innervating the meninges, or the trigeminal nucleus caudalis. GABAA receptor-mediated mechanisms, altered levels of excitatory and inhibitory neurotransmitters, and direct stabilizing effects on neuronal membranes could also decrease neurogenic inflammation.94,95

Second-Generation Anticonvulsants
Gabapentin, a lipophilic GABA analog capable of crossing the blood-brain barrier, has been reported to reduce the pain of neuropathic states such as multiple sclerosis, migraine, postherpetic neuralgia, spinal cord injury, human immunodeficiency virus-related neuropathy, and reflex sympathetic dystrophy.96-99 The efficacy of gabapentin has been shown for diabetic peripheral neuropathy pain, postamputation phantom limb pain, and postherpetic neuralgia for which an FDA indication was received.100-106 A retrospective analysis found that patients with chronic pain were more likely to respond to treatment with gabapentin if they had experienced allodynia as a feature of their neuropathic pain.107 The antinociceptive effects of gabapentin are the result of inhibiting calcium currents in postsynaptic dorsal horn neurons through binding with the α2δ1 subunit of L-type voltage-dependent calcium channels, which are involved in the maintenance of mechanical hypersensitivity in neuropathic pain models.108

In animal models of allodynia and hyperalgesia with upregulation of spinal cord α2δ1 subunit levels, mechanical nerve injuries and diabetic neuropathy were sensitive to gabapentin.109 Gabapentin suppressed the release of excitatory amino acids (glutamate, aspartate, serine) in the spinal cord of rats given intraperitoneal acetic acid to induce visceral pain.110 Gabapentin blocks both static and dynamic allodynia and reverses cold and tactile allodynia as well as heat hyperalgesia.111,112 Gabapentin inhibited ectopic discharges and evoked dorsal horn neuronal responses more in spinal nerve ligated rats than sham rats but had no effect in naïve rats or normal afferent fibers. In humans, gabapentin decreased as well as prevented acute neuronal sensitization in the skin without changing thermal nociception in normal skin, suggesting a role in the prophylaxis of chronic neuropathic pain.113

Pregabalin is a 3-alkylated GABA analog similar to gabapentin but with greater potency that decreases tactile allodynia, thermal hyperalgesia, and the rate of ectopic discharges from partially ligated sciatic nerves in rats.114,115 Pregabalin also binds to the voltage-dependent calcium channel α2δ subunit and modulates the influx of calcium and subsequently the release of neurotransmitters in the brain and spinal cord.116,117 Evidence suggests that pregabalin exerts its antiallodynic effect in the spinal cord of rats with neuropathic pain.118 Pregabalin has primarily been studied and found effective for the treatment of painful diabetic neuropathy and post-herpetic neuralgia with rapid onset of action.119-121 FDA indications have now been obtained for painful diabetic neuropathy, post-herpetic neuralgia, and fibromyalgia.122 A cost-effectiveness trial found pregabalin preferable to gabapentin for the treatment of painful diabetic neuropathy and post-herpetic neuralgia.123 Other trials finding significant improvement in pain with pregabalin include central neuropathic pain associated with spinal cord injury.124

Despite inconsistent results, lamotrigine may be effective in reducing the pain of diabetic neuropathy, phantom limbs, neuroma hypersensitivity, trigeminal neuralgia, causalgia, central post-stroke pain, and post-herpetic neuralgia.125-127 A linear relationship has been reported to exist between lamotrigine serum level, drug activity, and clinical outcome.128 Doseages above 300 mg/day with serum levels below potentially dangerous serum levels of 15 mg/L were effective for the treatment of painful diabetic neuropathy.129 Lamotrigine produced analgesia that was correlated with serum drug concentrations and comparable to that obtained with phenytoin and dihydrocodeine.130 Lamotrigine decreased the pain of diabetic neuropathy without associated improvements in mood or pain-related disability.131 The primary mechanism of action of lamotrigine may be due to its ability to inhibit neuronal release of glutamate and decrease long-term excitatory effects mediated by NMDA receptors, but it also blocks use-dependent voltage-gated sodium channels, reduces calcium influx, and alters mechanisms of neurotransmitter release and reuptake.132

Next-Generation Anticonvulsants
Topiramate, oxcarbazepine, tiagabine, levetiracetam, and zonisamide are newer anticonvulsants with a spectrum of pharmacologic actions that include enhancing neuronal inhibition, decreasing neuronal excitability, and protecting neurons from free radical damage.133 Topiramate possesses several pharmacologic actions including the blockade of sodium channels, inhibition of high-voltage–activated L-type calcium channels, potentiation of GABA-mediated inhibition by facilitating the action of GABA receptors, and modulating the action of amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA)/kainate glutamate receptors.93 Topiramate offers the advantages of low protein binding, minimal hepatic metabolism and unchanged renal excretion, few drug interactions, a long half-life, and the unusual side effect of weight loss. In rats, topiramate delayed the onset of allodynia and decreased hyperalgesia induced by the chronic constriction injury model of neuropathic pain.134 Despite several negative trials for the treatment of diabetic peripheral neuropathic pain and trigeminal neuralgia, topiramate decreased pain from chronic lumbar radiculopathy and painful diabetic neuropathy but side effects were common.135-137 Topiramate has also been effective for migraine prophylaxis.138,139 In studies of chronic low back pain, subjects experienced improvements in pain but also several measures of anger processing, disability, and health-related quality of life.140

Oxcarbazepine was hoped to be as effective as carbamazepine but with an improved safety and tolerability profile.141 Mechanical and cold allodynia were reduced by oxcarbazepine in rats with neuropathic pain from spinal nerve ligation.142 Mechanical hyperalgesia was reduced by oxcarbazepine in guinea pigs with partial sciatic nerve ligation.143 In addition to sodium channel blockade, antihyperalgesic effects are probably mediated by activation of adrenergic α2 receptors.144 In an open trial of oxcarbazepine for post-herpetic neuralgia that had not responded to prior treatments, patients experienced pain relief with rapid onset of action and subsequent improvements in function and quality of life.145 A randomized, placebo-controlled trial for painful diabetic neuropathy found that approximately 35% of patients treated with oxcarbazepine experienced >50% improvement in their pain.146

In several animal models of acute and chronic pain, tiagabine produced antinociception that is attributed to the inhibition of GABA reuptake.147 A pilot study found that tiagabine improved pain symptoms and neuronal function assessed with quantitative sensory testing in patients with painful neuropathy.148 In an open-label, randomized trial of various chronic pain conditions, tiagabine reduced pain by comparable amounts to gabapentin in patients with similar diagnoses, but produced significantly greater improvements in sleep quality.149 Levetiracetam produces an antihyperalgesic effect in animal models of acute and neuropathic pain.150 Case reports have found it effective for the treatment of painful sensorimotor peripheral neuropathy.151 Zonisamide is reported to possess multiple mechanisms of action.152 A randomized, controlled trial for the treatment of painful diabetic neuropathy did not reach statistical significance and zonisamide was poorly tolerated.153

Combinations of anticonvulsants with complementary mechanisms of action may increase effectiveness and decrease adverse effects of treatment. Patients with multiple sclerosis or trigeminal neuralgia who had failed treatment with carbamazepine or lamotrigine at therapeutic doses due to intolerable side effects were given gabapentin as an augmentation agent.154 Gabapentin was titrated to pain relief with no new side effects with a maximum dose of 1,200 mg/day, at which time either carbamazepine or lamotrigine were tapered until side effects were no longer present. When anticonvulsants were combined with tramadol, synergistic effects were found for inhibiting allodynia and blocking nociception.155 Carbamazepine and oxcarbazepine combined with clonidine produced a synergistic anti-hyperalgesic effect in rats with inflammatory pain.144

Pharmacologic Mechanisms of Antinociception
Animal research has demonstrated antinociceptive effects of benzodiazepines induced by activation of GABA receptors in the spinal cord dorsal horn that affect the nitric oxide-cyclic guanosine monophosphate pathway and have synergistic effects with a2-adrenergic receptor agonists such as clonidine.156,157 Diazepam causes a reduction in the increased cerebral blood flow associated with acute pain localized to the temporal lobes (affective-emotional component of pain).158 Benzodiazepines may interact with several receptor classes to synergistically decrease nociception and sensitization processes such as wind-up mediated by NMDA and AMPA/kainate receptors.159 Benzodiazepines have been associated with exacerbation of pain and interference with opioid analgesia.160,161 These hyperalgesic effects appear to be the result of activating supraspinal GABAA receptors coupled with descending effects on NMDA receptors known to antagonize opioid analgesia.162 When used in combination, benzodiazepines may also increase the rate of developing tolerance to opioids.163

Clinical Applications
Benzodiazepines are commonly prescribed for insomnia and anxiety in patients with chronic pain, but no studies demonstrate any benefit for these target symptoms.164,165 Benzodiazepines decreased pain in only a limited number of chronic pain conditions such as trigeminal neuralgia, tension headache, and temporomandibular disorders.166 Clonazepam has been reported to provide long-term relief of the episodic lancinating variety of phantom limb pain.167 A recent extensive review failed to conclude that benzodiazepines significantly improved spasticity following spinal cord injury, and no evidence was found to support the analgesic efficacy of barbiturates.168,169 Benzodiazepines have been used for the detoxification of patients with chronic pain from sedative/hypnotic medications and were superior to barbiturates for minimizing symptoms of withdrawal.170

Not only are the benefits of benzodiazepines difficult to document, but the negative effects are well studied and extend beyond the usual concerns of abuse, dependence, withdrawal, and secondary effects on mood. The elderly are particularly sensitive to the adverse effects of benzodiazepines such as sedation.171,172 Benzodiazepines also cause cognitive impairment as demonstrated by abnormalities on neuropsychological testing and electroencephalograph.173,174 In patients with chronic pain, use of benzodiazepines and not opioids were associated with decreased activity levels, higher rates of healthcare visits, increased domestic instability, depression, and more disability days.175 Combining benzodiazepines with opioids may be particularly problematic. Studies of methadone-related mortality found high rates of benzodiazepine use with the cause of death being attributed to a combination of drug effects, especially in patients receiving methadone for chronic pain.176,177

Atypical Neuroleptics
Pharmacologic Mechanisms of Antinociception
While older neuroleptics showed some potential for analgesic activity, side effects and long-term toxicity have limited their utility.178,179 Continued study of haloperidol suggests antinoceptive effects in the formalin test may be related to interaction with sigma-1 receptors.180 Second-generation antipsychotics have pain-modulating effects in various experimental paradigms.181,182 The primary pharmacology of these agents involves lower affinity for blockade of dopamine (D)2 receptors compared to that of 5-HT2A receptors with varying degrees of secondary actions at muscarinic, histamine-1, and a-adrenoreceptors. However, the pharmacologic profiles of this medication class are very heterogeneous, particularly with respect to dopamine receptor subtypes and pre- versus post-synaptic actions. Risperidone, olanzapine, amisulpride, and clozapine have differing degrees of antinociceptive effect in the rat tail-flick assay antagonized by agents to varying extent suggesting different profiles of opioid, serotonin, and α2-adrenoreceptor-mediated mechanisms.183-185 The interaction with the opioid system is presumed to occur through the action of neuroleptics at D2 receptors, although noradrenergic and serotonergic receptors have also been implicated in antinociptive effects of these drugs.

Clinical Applications
In the clinical setting, atypical neuroleptics offer several advantages over traditional antipsychotics, including a broader therapeutic spectrum, lower rates of extrapyramidal side effects, and augmentation of antidepressants and mood stabilizers.186 These benefits have been offset by concerns about weight gain, new-onset diabetes, and cardiac arrhythmias. Neuroleptics have been tried in a variety of chronic pain conditions including diabetic neuropathy, postherpetic neuralgia, headache, facial pain, pain associated with acquired immunodeficiency syndrome and cancer, and musculoskeletal pain.187 Fishbain and colleagues181 reviewed 10 available reports and studies of the analgesic effects produced in patients with cancer, fibromyalgia, spinal pain, and headache by atypical neuroleptics (including tiapride, which is not available in the United States) and concluded that there is consistent evidence to support their effectiveness. Significant limitations were noted including small sample sizes, single dose designs, lack of placebo control, and open-label protocols.
Subsequent trials have focused on fibromyalgia because of limited evidence of D2 receptor hypersensitivity.188 An open-label study of the addition of quetiapine to patients’ existing but ineffective treatment regimen did not decrease pain but produced significant improvements on the Fibromyalgia Impact Questionnaire and Quality-of-Life measures.189 A case series with olanzapine as an add-on therapy for fibromyalgia resulted in ratings of much or very much improved on the Clinical Global Impression scale for six of 14 patients, but 11 patients discontinued the medication because of adverse events.190 A similar study of ziprasidone showed lower response rates, smaller beneficial effects, and poor tolerability.191 Results are difficult to interpret because of comorbid depressive, anxiety, and sleep disorders in patients with fibromyalgia who might respond to treatment with atypical neuroleptics.



Recent advances in the pharmacologic treatment of chronic pain include a growing number of adjuvant medications such as antidepressants, anticonvulsants, benzodiazepines, and neuroleptics. These medications are well known to psychiatrists because of their psychopharmacologic uses. The expertise of the psychiatrist in the care of patients with chronic pain should be expanded beyond diagnosis and treatment of psychiatric comorbidity and the development of interdisciplinary treatment programs, to include the design and application of psychopharmacologic regimens specific to mechanisms of chronic pain. PP

1.    Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007;12(1):13-21.
2.    Nitu AN, Wallihan R, Skljarevski V, Ramadan NM. Emerging trends in the pharmacotherapy of chronic pain. Expert Opin Investig Drugs. 2003;12(4):549-559.
3.    Gilron I, Watson CP, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006;175(3):265-275.
4.    Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 suppl):S12-S25.
5.    Attal N, Cruccu G, Haanpaa M, et al. EFNS Task Force. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13(11):1153-1169.
6.    Gilron I, Bailey J, Weaver DF, Houlden RL. Patients’ attitudes and prior treatments in neuropathic pain: a pilot study. Pain Res Manag. 2002;7(4):199-203.
7.    Clark MR, Treisman GJ. Neurobiology of pain. Adv Psychosom Med. 2004;25:78-88.
8.    Bolay H, Moskowitz M. Mechanisms of pain modulation in chronic syndromes. Neurology. 2002;59(5 suppl 2):S2-7.
9.    Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci. 2001;2(2):83-91.
10.    Zimmerman M. Pathobiology of neuropathic pain. Eur J Pharmacol. 2001;429(1-3):23-37.
11.    Gidal BE. New and emerging treatment options for neuropathic pain. Am J Manag Care. 2006;12(9 suppl):S269-78.
12.    Mattia C, Paoletti F, Coluzzi F, Boanelli A. New antidepressants in the treatment of neuropathic pain. A review. Minerva Anestesiol. 2002;68(3):105-114.
13.    Coluzzi F, Mattia C. Mechanism-based treatment in chronic neuropathic pain: the role of antidepressants. Curr Pharm Des. 2005;11(23):2945-2960.
14.    Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain. 2007;8(4):315-324.
15.    Barkin RL, Fawcett J. The management challenges of chronic pain: the role of antidepressants. Am J Ther. 2000;7(1):31-47.
16.    Paoli F, Darcourt G, Cossa P. Preliminary note on the action of imipramine in painful states [French]. Rev Neurol (Paris). 1960;102:503-504.
17.    Clark MR. Pharmacological treatments for chronic non-malignant pain. Int Rev Psychiatry. 2000;12:148-156.
18.    Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2005;(3):CD005454.
19.    Littlejohn GO, Guymer EK. Fibromyalgia syndrome: which antidepressant drug should we chose. Curr Pharm Des. 2006;12(1):3-9.
20.    Gerson MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132(1):397-414.
21.    Walker EA, Roy-Byrne PP, Katon WJ, Jemelka R. An open trial of nortriptyline in women with chronic pelvic pain. Int J Psychiatry Med. 1991;21(3):245-252.
22.    Phatak S, Foster HE. The management of interstitial cystitis: an update. Nat Clin Pract Urol. 2006;3(1):45-53.
23.    Dworkin RH, Schmader KE. Treatment and prevention of postherpetic neuralgia. Clin Infect Dis. 2003;36(7):877-882.
24.    Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289-305.
25.    Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20(6):449-458.
26. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83(3):389-400.
27.    Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology. 2000;55(7):915-920.
28. Richeimer SH, Bajwa ZH, Kahraman SS, Ransil BJ, Warfield CA. Utilization patterns of tricyclic antidepressants in a multidisciplinary pain clinic: a survey. Clin J Pain. 1997;13(4):324-329.
29. Cepeda MS, Farrar JT. Economic evaluation of oral treatments for neuropathic pain. J Pain. 2006;7(2):119-128.
30. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Annal Neurol. 1994;35(suppl):S50-S53.
31.    Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992;49(2):205-219.
32.    Berger A, Dukes EM, Edelsberg J, Stacey BR, Oster G. Use of tricyclic antidepressants in older patients with painful neuropathies. Eur J Clin Pharmacol. 2006;62(9):757-764.
33.    Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves post-herpetic neuralgia. Clin Pharm Ther. 1990;47(3):305-312.
34.    Sindrup SH, Ejlertsen B, Froland A, Sindrup EH, Brosen K, Gram LF. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Phar. 1989;37(2):151-153.
35.    Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent, and neuropathic pain. Neuropharmacology. 2005;48(2):252-263.
36.    Tokunaga A, Saika M, Senba E. 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain. 1998;76(3):349-355.
37.    Rani PU, Naidu MU, Prasad VB, Rao TR, Shobha JC. An evaluation of antidepressants in rheumatic pain conditions. Anesth Analg. 1996;83(2):371-375.
38.    Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191-197.
39.    Tack J, Broekaert D, Fischler B, Oudenhove LV, Gevers AM, Janssens J. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006;55(8):1095-1103.
40.    Mojo PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev. 2005;(3):CD002919.
41.    Ciaramella A, Grosso S, Poli P. Fluoxetine versus fluvoxamine for treatment of chronic pain. Minerva Anestesiol. 2000;66(1-2):55-61.
42.    Max M, Lynch S, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline and fluoxetine on pain in diabetic neuropathy. NEJM. 1992;326(19):1250-1256.
43.    Sindrup SH, Gram LF, Brosen K, Eshoj O, Magensen EF. The SSRI paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42(2):135-144.
44.    Sindrup SH, Bjerre U, Dejaard A, Brosen K, Aaes-Jorgensen T, Gram LF. The SSRI citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992;52(5):547-552.
45.    Rowbotham MC, Reisner LA, Davies PS, Fields HL. Treatment response in antidepressant-naïve postherpetic neuralgia patients: double-blind, randomized trial. J Pain. 2005;6(11):741-746.
46. Goodnick PJ. Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry. 2001;13(1):31-41.
47. Giannopoulos S, Kosmidou M, Sarmas I, et al. Patient compliance with SSRIs and gabapentin in painful diabetic neuropathy. Clin J Pain. 2007;23(3):267-269.
48.    Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.
49.    Jones CK, Eastwood BJ, Need AB, Shannon HE. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition. Neuropharmacology. 2006;51(7-8):1172-1180.
50.    Beyreuther B, Callizot N, Stohr T. Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy. Eur J Pharmacol. 2006;539(1-2):64-70.
51.    Lang E, Hord AH, Denson D. Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with an experimental mononeuropathy. Pain. 1996;68(1):151-155.
52.    Yucel A, Ozyalcin S, Koknel Talu G, et al. The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Eur J Pain. 2005;9(4):407-416.
53.    Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain. 2002;6(1):17-24.
54.    Forssell H, Tasmuth T, Tenovuo O, Hampf G, Kalso E. Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. J Orofac Pain. 2004;18(2):131-137.
55.    Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110(3):697-706.
56.    Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45(2):144-152.
57.    Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119(1-3):5-15.
58.    Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6(5):346-356.
59.    Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67(8):1411-1420.
60.    Jones CK, Peters SC, Shannon HE. Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents. Eur J Pain. 2007;11(2):208-215.
61.    Ziegler D, Pritchett YL, Wang F, et al. Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain. Diabetes Care. 2007;30(3):664-669.
62.    Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJ. Does treatment with duloxetine for neuropathic pain impact glycemic control. Diabetes Care. 2007;30(1):21-26.
63.    Raskin J, Wang F, Pritchett YL, Goldstein DJ. Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain Med. 2006;7(5):373-385.
64.    Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol. 2006;21(6):311-317.
65.    Freynhagen R, Vogt J, Lipfert P, Muth-Selbach U. Mirtazapine and its enantiomers differentially modulate acute thermal nociception in rats. Brain Res Bull. 2006;69(2):168-173.
66.    Schreiber S, Rigai T, Katz Y, Pick CG. The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms. Brain Res Bull. 2002;58(6):601-605.
67.    Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004;62(10):1706-1711.
68.    Pedersen LH, Nielsen AN, Blackburn-Munro G. Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain. Psychopharmacology. 2005;182(4):551-561.
69.    Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of buproprion SR for the treatment of neuropathic pain. Neurology. 2001;57(9):1583-1588.
70.    Merikangas KR, Merikangas JR. Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression. Biol Psychiatry. 1995;38(9):603-610.
71.    Pick CG, Paul D, Eison MS, Pasternak GW. Potentiation of opioid analgesia by the antidepressant nefazodone. Eur J Pharm. 1992;211(3):375-381.
72.    Goodkin K, Gullion C, Agras WS. A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. J Clin Psychopharmacol. 1990;10(4):269-278.
73.    Marek GJ, McDougle CJ, Price LH, Seiden LS. A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action. Psychopharmacology. 1992;109(1-2):2-11.
74.    Blackburn-Munro G, Erichsen HK. Antiepileptics and the treatment of neuropathic pain: evidence from animal models. Curr Pharm Des. 2005;11(23):2961-2976.
75.    Soderpalm B. Anticonvulsants: aspects of their mechanisms of action. Eur J Pain. 2002;6 suppl A:3-9.
76.    Waxman SG, Cummins TR, Black JA, Dib-Hajj S. Diverse functions and dynamic expression of neuronal sodium channels. Novartis Found Symp. 2002;241:34-51.
77.    Blackburn-Munro G, Fleetwood-Walker SM. The sodium channel auxiliary subunits beta1 and beta2 are differentially expressed in the spinal cord of neuropathic rats. Neuroscience. 1999;90(1):153-164.
78.    Baker MD, Wood JN. Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci. 2001;22(1):27-31.
79.    Waxman SG, Cummins TR, Dibhajj SD, Fjell J, Black JA. Sodium channels, excitability of primary sensory neurons and the molecular basis of pain. Muscle Nerve. 1999;22(9):1177-1187.
80.    Bergouignan M. Successful cures of essential facial neuralgias by sodium diphenylhydantoinate [French]. Rev Laryngol Otol Rhinol. 1942;63:34-41.
81.    Tanelian DL, Victory RA. Sodium channel-blocking agents: their use in neuropathic pain conditions. Pain Forum. 1995;4:75-80.
82.    Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conerence (EILAT VIII). Epilepsy Res. 2007;73(1):1-52.
83.    Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics. 2007;4(1):75-83.
84.    Stefan H, Feuerstein TJ. Novel anticonvulsant drugs. Pharmacol Ther. 2007;113(1):165-183.
85.    Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs. 2000;60(5):1029-1052.
86.    Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2000;(3):CD001133.
87.    Sindrup SH, Jensen TS. Pharmacotherapy of trigeminal neuralgia. Clin J Pain. 2002;18(1):22-27.
88.    Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 1994;44(4):647-651.
89.    Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex. Arch Neurology. 1995;52(3):281-286.
90.    Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol. 1997;54(9):1141-1145.
91.    Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997;17(2):103-108.
92.    Rothrock JF. Clinical studies of valproate for migraine prophylaxis. Cephalalgia. 1997;17(2):81-83.
93.    Cutrer FM. Antiepileptic drugs: how they work in headache. Headache. 2001;41(suppl 1):S3-10.
94.    Cutrer FM, Moskowitz MA. Wolff Avard 1996. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache. 1996;36(10):579-585.
95.    Cutrer FM, Limmroth V, Moskowitz MA. Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia. 1997;17(2):93-100.
96.    Houtchens MK, Richert JR, Sami A, Rose JW. Open label gabapentin treatment for pain in multiple sclerosis. Mult Scler. 1997;3(4):250-253.
97.    La Spina I, Porazzi D, Maggiolo F, Bottura P, Suter F. Gabapentin in painful HIV-related neuropathy: a report of 19 patients, preliminary observations. Eur J Neurol. 2001;8(1):71-75.
98.    To TP, Lim TC, Hill ST, et al. Gabapentin for neuropathic pain following spinal cord injury. Spinal Cord. 2002;40(6):282-285.
99.    Wetzel CH, Connelly JF. Use of gabapentin in pain management. Ann Pharmacother. 1997;31(9):1082-1083.
100.    Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831-1836.
101.    Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: a randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med. 2002;27(5):481-486.
102. Chandra K, Shafiq N, Pandhi P, Gupta S, Malhotra S. Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial – the GONIP Trial. Int J Clin Pharmacol Ther. 2006;44(8):358-363.
103. Mellegers MA, Furlan AD, Mailis A. Gabapentin for neuropathic pain: systematic review of controlled and uncontrolled literature. Clin J Pain. 2001;17(4):284-295.
104. Rice AS, Maton S, Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94(2):215-224.
105.    Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280(21):1837-1842.
106.    Serpell MG, Neuropathic pain study group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99(3):557-566.
107.    Gustorff B, Nahlik G, Spacek A, Kress HG. Gabapentin in the treatment of chronic intractable pain [German]. Schmerz. 2002;16(1):9-14.
108.    Alden KJ, Garcia J. Differential effect of gabapentin on neuronal and muscle calcium currents. J Pharmacol Exp Ther. 2001;297(2):727-735.
109.    Luo ZD, Calcutt NA, Higuera ES, et al. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther. 2002;303(3):1199-1205.
110.    Feng Y, Cui M, Willis WD. Gabapentin markedly reduces acetic acid-induced visceral nociception. Anesthesiology. 2003;98(3):729-733.
111.    Field MJ, McCleary S, Hughes J, Singh L. Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat. Pain. 1999;80(1-2):391-398.
112.    Xiao WH, Bennett GJ. Synthetic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats. J Pharmacol Exp Ther. 1995;274(2):666-672.
113.    Dirks J, Peterson KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology. 2002;97(1):102-107.
114.    Bryans JS, Wustrow DJ. 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev. 1999;19(2):149-177.
115.    Chen SR, Xu Z, Pan HL. Stereospecific effect of pregabalin on ectopic afferent discharges neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology. 2001;95(6):1473-1479.
116.    Field MJ, Cox PJ, Stott E, et al. Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A. 2006;103(46):17537-17542.
117.    Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150.
118.    Han DW, Kweon TD, Lee JS, Lee YW. Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain. Yonsei Med J. 2007;48(1):41-47.
119. Sonnett TE, Setter SM, Campbell RK. Pregabalin for the treatment of painful neuropathy. Expert Rev Neurother. 2006;6(11):1629-1635.
120. Tassone DM, Boyce E, Guyer J, Nuzum D. Pregabalin. A novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 2007;29(1):26-48.
121.    Van Seventer R, Feister HA, Young JP Jr, Stoker M, Versavel M, Rigaudy L. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin. 2006;22(2):375-384.
122. Crofford LJ, Rowbotham MC, Mease PJ, et al, Pregabalin 1008-105 Study Group. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):1264-1273.
123. Tarride JE, Gordon A, Vera-Llonch M, Dukes E, Rousseau C. Cost-effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a Canadian perspective. Clin Ther. 2006;28(11):1922-1934.
124. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67(10):1792-1800.
125. Frese A, Husstedt IW, Ringelstein EB, Evers S. Pharmacologic treatment of central post-stroke pain. Clin J Pain. 2006;22(3):252-260.
126. Jose VM, Bhansali A, Hota D, Pandhi P. Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. Diabet Med. 2007;24(4):377-383.
127. McCleane G. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomized, double-blind, placebo controlled trial. Pain. 1999;83(1):105-107.
128. Devulder J. The relevance of monitoring lamotrigine serum concentrations in chronic pain patients. Acta Neurol Belg. 2006;106(1):15-18.
129. Vinik AI, Tuchman M, Safirstein B, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain. 2007;128(1-2):169-179.
130. Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers. Pain. 1998;76(3):357-363.
131. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized controlled study. Neurology. 2001;57(3):505-509.
132. Coderre TJ, Kumar N, Lefebvre CD, Yu JS. A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain. J Neurochem. 2007;100(5):1289-1299.
133. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia. 1997;38(8):859-880.
134. Benoliel R, Tal M, Eliav E. Effects of topiramate on the chronic constriction injury model in the rat. J Pain. 2006;7(12):878-883.
135. Donofrio PD, Raskin P, Rosenthal NR, et al. Safety and effectivenss of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study. Clin Ther. 2005;27(9):1420-1431.
136. Khoromi S, Patsalides A, Parada S, Salehi V, Meegan JM, Max MB. Topiramate in chronic lumbar radicular pain. J Pain. 2005;6(12):829-836.
137. Vinik A. Clinical review: use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab. 2005;90(8):4936-4945.
138. Silberstein SD, Hulihan J, Karim MR, et al. Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study. Clin Ther. 2006;28(7):1002-1011.
139. Van Passel L, Arif H, Hirsch LJ. Topiramate for the treatment of epilepsy and other nervous system disorders. Expert Rev Neurother. 2006;6(1):19-31.
140. Meuhlbacher M, Nickel MK, Kettler C, et al. Topiramate in treatment of patients with chronic low back pain: a randomized, double-blind, placebo-controlled study. Clin J Pain. 2006;22(6):526-531.
141. Carrazana E, Mikoshiba I. Rationale and evidence for the use of oxcarbazepine in neuropathic pain. J Pain Symptom Manage. 2003;25(5 Suppl):S31-35.
142. Jang Y, Kim ES, Park SS, Lee J, Moon DE. The suppressive effects of excarbazepine on mechanical and cold allodynia in a rat model of neuropathic pain. Anesth Analg. 2005;101(3):800-806.
143. Fox A, Gentry C, Patel S, Kesingland A, Bevan S. Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig. Pain. 2003;105(1-2):355-362.
144. Vuckovic SM, Tomic MA, Stepanovic-Petrovic RM, Ugresic N, Prostran MS, Boskovic B. The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain. Pain. 2006;125(1-2):10-19.
145. Criscuolo S, Auletta C, Lippi S, Brogi F, Brogi A. Oxcarbazepine monotherapy in postherpetic neuralgia unresponsive to carbamazepine and gabapentin. Acta Neurol Scand. 2005;111(4):229-232.
146. Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain. 2005;9(5):543-554.
147. Laughlin TM, Tram KV, Wilcox GL, Birnbaum AK. Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception. J Pharmacol Exp Ther. 2002;302(3):1168-1175.
148. Novak V, Kanard R, Kissel JT, Mendell JR. Treatment of painful sensory neuropathy with tiagabine: a pilot study. Clin Auton Res. 2001;11(6):357-361.
149. Todorov AA, Kolchev CB, Todorov AB. Tiagabine and gabapentin for the management of chronic pain. Clin J Pain. 2005;21(4):358-361.
150. Ardid D, Lamberty Y, Alloui A, Coudore-Civiale MA, Klitgaard H, Eschalier A. Antihyperalgesic effect of levetiracetam in neuropathic pain models in rats. Eur J Pharmacol. 2003;473(1):27-33.
151. Price MJ. Levetiracetam in the treatment of neuropathic pain: three case studies. Clin J Pain. 2004;20(1):33-36.
152. Biton V. Zonisamide: newer antiepileptic agent with multiple mechanisms of action. Expert Rev Neurother. 2004;4(6):935-943.
153. Atli A, Dogra S. Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study. Pain Med. 2005;6(3):225-234.
154. Solaro C, Messmer Uccelli M, Uccelli A, Leandri M, Mancardi GL. Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis. Eur Neurol. 2000;44(1):45-48.
155. Codd EE, Martinez RP, Molino L, Rogers KE, Stone DJ, Tallarida RJ. Tramadol and several anticonvulsants synergize in attenuating nerve injury-induced allodynia. Pain. In press.
156. Nishiyama T, Hanaoka K. The synergistic interaction between midazolam and clonidine in spinally-mediated analgesia in two different pain models in rats. Anesth Analg. 2001;93(4):1025-1031.
157. Talarek S, Fidecka S. Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol. 2002;54(1):27-34.
158. Di Piero V, Ferracuti S, Sabatini U, et al. Diazepam effects on the cerebral responses to tonic pain: a SPET study. Psychopharmacology. 2001;158(3):252-258.
159.     Szekely JI, Torok K, Mate G. The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites. Curr Pharm Des. 2002;8(10):887-912.
160.     France RD, Kirshman KR. Psychotropic drugs in chronic pain. In: Chronic Pain. France RD, Kirshman KR, ed. Washington, DC: American Psychiatric Association; 1988.
161.     Sawynok J. GABAergic mechanisms of analgesia: an update. Pharmacol Biochem Behav. 1987;26(2):463-474.
162. Rady JJ, Fujimoto JM. Confluence of antianalgesic action of diverse agents through brain interleukin (1beta) in mice. J Pharmacol Exp Ther. 2001;299(2):659-665.
163. Freye E, Latasch L. Development of opioid tolerance – molecular mechanisms and clinical consequences. Anasthesiol Intensivmed Notfallmed Schmerzther. 2003;38(1):14-26.
164.    Hollister LE, Conley FK, Britt R, Shuer L. Long-term use of diazepam. JAMA. 1981;246(14):1568-1570.
165.    King SA, Strain JJ. Benzodiazepine use by chronic pain patients. Clin J Pain. 1990;6(2):143-147.
166.    Dellemijn PL, Fields HL. Do benzodiazepines have a role in chronic pain management? Pain. 1994;57(2):137-152.
167. Bartusch SL, Sanders BJ, D’Alessio JG, Jernigan JR. Clonazepam for the treatment of lancinating phantom limb pain. Clin J Pain. 1996;12(1):59-62.
168. McLean W, Boucher EA, Brennan M, Holbrook A, Orser R, Peachey J, Sellers E. Is there an indication for the use of barbiturate-containing analgesic agents in the treatment of pain? Guidelines for their safe use and withdrawal management. Canadian Pharmacists Association. Can J Clin Pharmacol. 2000;7(4):191-197.
169. Taricco M, Adone R, Pagliacci C, Telaro E. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev. 2000;(2):CD001131.
170. Sullivan M, Toshima M, Lynn P, Roy-Byrne P. Phenobarbital versus clonazepam for sedative-hypnotic taper in chronic paian patients. A pilot study. Ann Clin Psychiatry. 1993;5(2):123-128.
171.    Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988;38(9):1427-1432.
172. Yosselson-Superstine S, Lipman AG, Sanders SH. Adjunctive antianxiety agents in the management of chronic pain. Isr J Med Sci. 1985;21(2):113-117.
173. Buffett-Jerrott SE, Stewart SH. Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des. 2002;8(1):45-58.
174. Hendler N, Cimini C, Ma T, Long D. A comparison of cognitive impairment due to benzodiazepines and to narcotics. Am J Psychiatry. 1980;137(7):828-830.
175. Cicccone DS, Just N, Bandilla EB, Reimer E, Ilbeigi MS, Wu W. Psychological correlates of opioid use in patients with chronic nonmalignant pain: a preliminary test of the downhill spiral hypothesis. J Pain Symptom Manage. 2000;20(3):180-192.
176. Caplehorn JR, Drummer OH. Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Aust N Z J Public Health. 2002;26(4):358-362.
177. Ernst E, Bartu A, Popescu A, Ileutt KF, Hansson R, Plumley N. Methadone-related deaths in Western Australia 1993-99. Aust N Z J Public Health. 2002;26(4):364-370.
178. Merskey H. Pharmacological approaches other than opioid in chronic non-cancer pain management. Acta Anaesthesiol Scand. 1997;41(1 Pt 2):187-190.
179. Patt RB, Proper G, Reddy S. The neuroleptics as adjuvant analgesics. J Pain Symptom Manage. 1994;9(7):446-453.
180. Cendan CM, Pujalte JM, Portillo-Salido E, Baeyens JM. Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice. Psychopharmacology. 2005;182(4):485-493.
181. Fishbain DA, Cutler RB, Lewis J, Cole B, Rosomoff RS, Rosomoff HL. Do the second-generation “atypical neuroleptics” have analgesic properties? A structured evidence-based review. Pain Med. 2004;5(4):359-365.
182. Pridmore S, Samilowitz H, Oberoi G. Will the atypical antipsychotics be analgesics? Australas Psychiatry. 2003;11:59-61.
183. Schreiber S, Backer MM, Weizman R, Pick CG. Augmentation of opioid induced antinociception by the atypical antipsychotic drug risperidone in mice. Neurosci Lett. 1997;228(1):25-28.
184. Schreiber S, Getslev V, Backer MM, Weizman R, Pick CG. The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency. Pharmacol Biochem Behav. 1999;64(1):75-80.
185.    Weizman T, Pick CG, Backer MM, Rigai T, Bloch M, Schreiber S. The antinociceptive effect of amisulpride in mice is mediated through opioid mechanisms. Eur J Pharmacol. 2003;478(2-3):155-159.
186. Janicak P, Dowd S, Strong M, Minhas-Pannu S. The role of risperidone in the management of mood disorders. Psychiatr Ann. 2002;32:733-738.
187. Aigner M, Ossege M, Sycha T. Neuroleptics for acute and chronic pain (Protocol). Cochrane Database Syst Rev. 2004;(3):CD004844.
188. Malt EA, Olafsson S, Aakvaag A, Lund A, Ursin H. Altered dopaimine D2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls. J Affect Disord. 2003;75(1):77-82.
189. Hidalgo J, Rico-Villademoros F, Calandre EP. An open-label study of quetiapine in the treatment of fibromyalgia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):71-77.
190. Rico-Villademoros F, Hidalgo J, Dominguez I, Garcia-Leiva JM, Calandre EP. Atypical antipsychotics in the treatment of fibromyalgia: a case series with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(1):161-164.
191. Calandre EP, Hidalgo J, Rico-Villademoros F. Use of ziprasidone in patients with fibromyalgia: a case series. Rheumatol Int. 2007;27:473-476.


Dr. Breitbart is chief of psychiatry service in the Department of Psychiatry and Behavioral Sciences and attending psychiatrist at the Pain and Palliative Care Service in the Department of Neurology, at the Memorial Sloan-Kettering Cancer Center in New York City; and professor of psychiatry at Weill Medical College of Cornell University in New York City. Dr. Gibson is research coordinator in the Department of Psychiatry and Behavioral Sciences at the Memorial Sloan-Kettering Cancer Center.

Disclosures: Dr. Breitbart is a consultant to and receives honoraria from Cephalon. Dr. Gibson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: William Breitbart, MD, Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, 641 Lexington Ave, 7th Floor, New York, NY 10022; Tel: 646-888-0020; Fax: 212-888-2356; E-mail: Breitbaw@mskcc.org.




Effective management of cancer pain in patients requires a multidisciplinary approach, enlisting expertise from a wide variety of clinical specialties including the utilization of psychiatric interventions for pain and associated psychological distress. This article reviews the multidimensional nature of cancer pain and the interrelationships between cancer pain and psychiatric/psychological factors. The prevalence of psychiatric disorders in cancer pain patients and their management are reviewed. The use of both pharmacologic and nonpharmacologic psychiatric interventions for cancer pain are reviewed.


Introduction: Prevalence of Pain in Cancer

Pain is a common problem for cancer patients, with approximately 70% of patients experiencing severe pain at some time in the course of their illness.1 It has been suggested that nearly 75% of patients with advanced cancer have pain2 and that 50% of terminally ill patients are in moderate-to-severe pain.3 It is also estimated that 25% of cancer patients die in severe pain.4 There is considerable variability in the prevalence of pain amongst different types of cancer, with as many as 85% of patients experiencing significant pain during the course of their illness.5 Yet, despite its prevalence, studies have shown that pain is frequently underdiagnosed and inadequately treated.4,6 It is important to remember that pain is frequently only one of several symptoms present in cancer patients. In a survey of symptoms, patients were found to suffer from an average of three troubling physical symptoms in addition to pain.7 With disease progression, the number of distressing physical symptoms (eg, fatigue, insomnia, dyspnea) also increases and patients with advanced disease report a median of 11 symptoms.8 Consequently, a global evaluation of the symptom burden allows for a more complete understanding of the impact of pain for the cancer patient.9


Multidimensional Concept of Cancer Pain

Pain, especially in cancer patients, is not a purely nociceptive or physical experience but rather involves complex aspects of human functioning including personality, affect, cognition, behavior, and social relations.10 A more enlightened description of the pain resulting from cancer and terminal illness coined by Cecily Saunders11 is “total pain,” a label that attempts to describe the all-encompassing nature of this type of pain. It is important to note that the use of analgesic drugs alone does not always lead to pain relief.12 A recent study13 demonstrated that psychological factors play a modest but important role in pain intensity. The interaction of cognitive, emotional, socio-environmental, and nociceptive aspects of cancer pain shown in the Figure illustrates the multidimensional nature of pain in cancer and suggests a model for multimodal intervention.14 The challenge of untangling and addressing both the physical and psychological issues involved in pain is essential to developing rational and effective management strategies. Psychosocial therapies directed primarily at psychological variables have profound impact on nociception, while somatic therapies directed at nociception have beneficial effects on the psychological aspects of cancer pain. Ideally, such somatic and psychosocial therapies are used simultaneously in the multidisciplinary approach to pain management in cancer patients.15



Psychological Factors in Pain Experience

Pain has profound effects on psychological distress in cancer patients, and psychological factors such as anxiety, depression, and the meaning of pain can intensify cancer pain experience. Daut and Cleeland16 showed that cancer patients who attribute a new pain to an unrelated benign cause report less interference with their activity and pleasure than cancer patients who believe their pain represents progression of disease. Spiegel and Bloom17 found that women with metastatic breast cancer experience more intense pain if they believe their pain represents spread of their cancer, and if they are depressed. Beliefs about the meaning of pain and the presence of a mood disturbance are better predictors of level of pain than is the site of metastasis.

In an attempt to define the potential relationships between cancer pain and psychosocial variables, Padilla and colleagues18 found that there were pain-related quality-of-life variables in three domains, including physical well being; psychological well being consisting of affective factors, cognitive factors, spiritual factors, communication, coping, and meaning of pain or cancer; and interpersonal well being focusing on social support or role functioning. Patients who feel that their pain is related to their cancer report pain of greater intensity coupled with greater affective distress.19 All too frequently, however, psychological variables are proposed to explain continued pain or lack of response to therapy when in fact medical factors have not been adequately appreciated. Often, the psychiatrist is the last physician to consult on a cancer patient with pain. In that role one must be vigilant that an accurate pain diagnosis is made and be able to assess the adequacy of the medical analgesic management provided. Psychological distress in terminally ill patients with pain must initially be assumed to be the consequence of uncontrolled pain. Personality factors may be quite distorted by the presence of pain, and relief of pain often results in the disappearance of a perceived psychiatric disorder.6,20


Psychiatric Disorders and Pain in Cancer

There is an increased frequency of psychiatric disorders found in cancer patients with pain. In the Psychosocial Collaborative Oncology Group Study21 on the prevalence of psychiatric disorders in cancer patients, 39% of patients who received a psychiatric diagnosis (Table 1) reported significant pain, while only 19% of patients without a psychiatric diagnosis had significant pain. The psychiatric disorders seen in cancer patients with pain include primarily adjustment disorder with depressed or anxious mood (69%) and major depressive disorder (MDD; 15%). This finding of increased frequency of psychiatric disturbance in cancer pain patients has been reported by several authors.22,23



Cancer patients with advanced disease are a particularly vulnerable group. The incidence of pain, depression, and delirium increases with greater debilitation and advanced stages of illness.24 Approximately 25% of all cancer patients experience severe depressive symptoms, with the prevalence increasing to 77% in those with advanced illness. The prevalence of organic mental disorders (delirium) among cancer patients requiring psychiatric consultation has been found to range from 25% to 40% and to be as high as 85% during the terminal stages of illness.25 Narcotic analgesics such as meperidine, levorphanol, and morphine sulphate can cause confusional states, particularly in the elderly and terminally ill.26 Thus, psychiatric disorders are important to identify and treat in patients with cancer pain because they can potentially interfere with the accurate assessment of pain and complicate the management of pain if untreated.


Cancer Pain and Suicide

While depression is a general risk factor for suicide, uncontrolled pain is a major cancer-specific risk factor for suicide and suicidal ideation in cancer patients.27-29 Cancer is perceived by the public as an extremely painful disease compared with other medical conditions. In Wisconsin, a study revealed that 69% of the public agreed that cancer pain could cause a person to consider suicide.30 The majority of suicides observed among patients with cancer had severe pain, which was often inadequately controlled or poorly tolerated.31 Although relatively few cancer patients commit suicide, they are at increased risk.30,32 Patients with advanced illness are at highest risk and are the most likely to have the complications of pain, depression, delirium, and deficit symptoms. Psychiatric disorders are frequently present in hospitalized cancer patients who attempt suicide. A review of the psychiatric consultation data at Memorial Sloan-Kettering Cancer Center showed that 33% of cancer patients who were seen for evaluation of suicide risk received a diagnosis of MDD; approximately 20% met criteria for delirium, and >50% were diagnosed with an adjustment disorder.27

Thoughts of suicide probably occur quite frequently, particularly in the setting of advanced illness,33 and seem to act as a steam valve for feelings often expressed by patients as “If it gets too bad, I always have a way out.” It has been the experience of the authors of this article working with terminally ill pain patients that once a trusting and safe relationship develops, patients almost universally reveal that they have had occasionally persistent thoughts of suicide as a means of escaping the threat of being overwhelmed by pain. However, recent published reports suggest that suicidal ideation is relatively infrequent in cancer patients and is limited to those who are significantly depressed. Silberfarb and colleagues34 found that only three of 146 breast cancer patients had suicidal thoughts, whereas none of the 100 cancer patients interviewed in a Finnish study expressed suicidal thoughts.9 A study conducted at Saint Boniface Hospice in Winnipeg, Canada, demonstrated that only 10 of 44 terminally ill cancer patients were suicidal or desired an early death, and all 10 were suffering from clinical depression.35 At Memorial Sloan-Kettering Cancer Center (MSKCC), suicide-risk evaluation accounted for 8.6% of psychiatric consultations, usually requested by staff in response to patients verbalizing suicidal wishes.27 In the 71 cancer patients who had suicidal ideation with serious intent, significant pain was a factor in only 30% of cases. In striking contrast, virtually all 71 suicidal cancer patients had a psychiatric disorder (mood disturbance or organic mental disorder) at the time of evaluation.27

The authors of this article examined the role of cancer pain in desire for hastened death. Severity of clinical depression and hopelessness were significantly associated with suicidal ideation. In multivariate analyses, depression and hopelessness provided independent and unique contributions to the prediction of the desire for hastened death, while social support and physical functioning added significant but smaller contributions.36 In looking at 185 cancer pain patients involved in ongoing research protocols of the MSKCC Pain and Psychiatry Services,37 suicidal ideation occurred in 17% of the study population with the majority reporting suicidal ideation without intent to act. Interestingly, in this population of cancer patients who all had significant pain, suicidal ideation was not directly related to pain intensity but was strongly related to degree of depression and mood disturbance. Pain was related to suicidal ideation indirectly in that patients’ perception of poor pain relief was associated with suicidal ideation. Perceptions of pain relief may have more to do with aspects of hopelessness than pain itself. Pain plays an important role in vulnerability to suicide; however, associated psychological distress and mood disturbance seem to be essential cofactors in raising the risk of suicide in cancer patients. Pain has adverse effects on patients’ quality of life and sense of control and impairs the family’s ability to provide support. Factors other than pain such as mood disturbance, delirium, loss of control, and hopelessness contribute to cancer suicide risk.31 Therefore, pain is both a unique and synergistic contributor to suicide risk in cancer patients. Frequency of suicidal ideation in one study was associated with poor well being, depression, anxiety, and shortness of breath, but not with other somatic symptoms such as pain, nausea, and loss of appetite.38


Assessment Issues in the Treatment of Cancer Pain

Inadequate management of cancer pain is often due to inability to properly assess pain in all its dimensions.1,4,15 All too frequently, psychological variables are proposed to explain continued pain or lack of response to therapy, when in fact medical factors have not been adequately appreciated. Other causes of inadequate pain management include lack of knowledge of current pharmacy or psychotherapeutic approaches; focus on prolonging life rather than alleviating suffering; lack of communication between doctor and patient; limited expectations of patients to achieve pain relief; limited capacity of patients impaired by organic mental disorders to communicate; unavailability of narcotics; doctors’ fear of causing respiratory depression; and, most importantly, doctors’ fear of amplifying addiction and substance abuse. In advanced cancer, several factors have been noted to predict the undermanagement of cancer pain, including a discrepancy between physician and patient in judging the severity of pain, the presence of pain that physicians did not attribute to cancer, better performance status for patients ≥70 years of age, and female gender.39

The risk of inducing respiratory depression is too often overestimated and can limit appropriate use of narcotic analgesics for pain and symptom control. Bruera and colleagues40 demonstrated that, in a population of terminally ill cancer patients with respiratory failure and dyspnea, administration of subcutaneous morphine actually improved dyspnea without causing a significant deterioration in respiratory function. The adequacy of cancer pain management can be influenced by the lack of concordance between patient ratings or complaints of their pain and those made by caregivers. Persistent cancer pain is often ascribed to a psychological cause when it does not respond to treatment attempts. The clinical experience of the authors of this article finds that patients who report their pain as “severe” are quite likely to be viewed as having a psychological contribution to their complaints. Staff members’ ability to empathize with a patient’s pain complaint may be limited by the intensity of the pain complaint. Grossman and colleagues41 found that while there is a high degree of concordance between patient and caregiver ratings of patient pain intensity at the low and moderate levels, this concordance breaks down at high levels. Thus, a clinician’s ability to assess a patient’s level of pain becomes unreliable once a patient’s report of pain intensity rises >7 on a visual analog rating scale of 0 to 10. Physicians must be educated in the limitations of their ability to objectively assess the severity of a subjective pain experience. Additionally, patient education is often a useful intervention in such cases. Patients are more likely to be believed and adequately treated if they are taught to request pain relief in a non-hysterical, business-like fashion.


Psychiatric Management of Pain in Cancer

Optimal treatment of pain associated with cancer is multimodal and includes pharmacologic, psychotherapeutic, cognitive-behavioral, anesthetic, neuro-stimulatory, and rehabilitative approaches. Psychiatric participation in cancer pain management involves the use of psychotherapeutic, cognitive-behavioral, and psychopharmacologic interventions, usually in combination.


Psychotherapy and Cancer Pain

The goals of psychotherapy with cancer patients experiencing pain are to provide support, knowledge, and skills (Table 2). Utilizing short-term supportive psychotherapy focused on the crisis created by the medical illness, the therapist provides emotional support, continuity, and information, and assists in adaptation. The therapist has a role in emphasizing past strengths, supporting previously successful coping strategies, and teaching new coping skills such as relaxation, cognitive coping, use of analgesics, self-observation, documentation, assertiveness, and communication. Communication skills are of paramount importance for both patient and family, particularly around pain and analgesic issues. The patient and family are the unit of concern and need a more general, long-term, supportive relationship within the healthcare system in addition to specific psychological approaches dealing with pain and dying, which a psychiatrist, psychologist, social worker, chaplain, or nurse can provide.



Utilizing psychotherapy to diminish symptoms of anxiety and depression, factors that can intensify pain, empirically has beneficial effects on cancer pain experience. Spiegel and Bloom42 demonstrated, in a controlled randomized prospective study, the effect of both supportive group therapy for metastatic breast cancer patients in general and, in particular, the effect of hypnotic pain control exercises. Their support group focused not on interpersonal processes or self exploration, but rather on a series of themes related to the practical and existential problems of living with cancer. Patients were divided into two treatment groups and a control group. The treatment patients experienced significantly less pain than the control patients. Those in the group that combined a self-hypnosis exercise group showed a slight increase, and the control group showed a large increase in pain.

Group interventions for individuals with cancer pain (even in advanced stages of disease) are a powerful means of sharing experiences and identifying successful coping strategies. The limitations of using group interventions for patients with advanced disease are primarily pragmatic. The patient must be physically comfortable enough to participate and have the cognitive capacity to be aware of group discussion. It is often helpful for family members to attend support groups during the terminal phases of the patient’s illness. Interventions aimed at spouses and family members of cancer pain patients can also be beneficial (See section on Novel Psychosocial Interventions below).43 Passik and colleagues43 have worked with spouses of brain tumor patients in a psychoeducational group that has included spouses at all phases of the patient’s diagnosis and treatment. They have demonstrated how bereavement issues are often a focus of such interventions from the time of diagnosis. The leaders have been impressed by the increased quality of patient care that can be given at home by the spouse (including pain management and all forms of nursing care) when the spouses engage in such support.

Psychotherapeutic interventions that have multiple foci may be most useful. Based upon a prospective study of cancer pain, cognitive-behavioral and psychoeducational techniques based upon increasing support, self-efficacy, and providing education may prove helpful in assisting patients in dealing with increased pain.44 Results of an evaluation of patients with cancer pain indicate that psychological and social variables are significant predictors of pain. More specifically, distress specific to the illness, self-efficacy, and coping styles were predictors of increased pain.


Cognitive-Behavioral Techniques

Cognitive-behavioral techniques can be useful as adjuncts to the management of pain in cancer patients (Table 3). These techniques fall into two major categories of cognitive techniques and behavioral techniques. Both techniques include a range of techniques including passive relaxation with mental imagery, cognitive distraction or focusing, progressive muscle relaxation, biofeedback, hypnosis, and music therapy.20,45-47 The goal of treatment is to guide the patient toward a sense of control over pain. Some techniques are primarily cognitive in nature, focusing on perceptual and thought processes, and others are directed at modifying patterns of behavior that help cancer patients cope with pain. Behavioral techniques for pain control seek to modify physiologic pain reactions, respondent pain behaviors, and operant pain behaviors (Table 4).





Relaxation Techniques

Several techniques can be used to achieve a mental and physical state of relaxation. Muscular tension, autonomic arousal, and mental distress exacerbate pain.46,47 Some specific relaxation techniques include passive relaxation focusing attention on sensations of warmth and decreased tension in various parts of the body, progressive muscle relaxation involving active tensing and relaxing of muscles, and meditation.



Hypnosis can be a useful adjunct in the management of cancer pain.42,48-53 Hypnotherapy, usually involving the teaching of self-hypnotic techniques, can be used effectively in the management of pain associated with invasive procedures.54 In a controlled trial comparing self hypnosis with cognitive-behavioral therapy in relieving mucositis following a bone marrow transplant, patients utilizing self-hypnosis reported a significant reduction in pain compared to patients who used cognitive-behavioral techniques.44 The hypnotic trance is essentially a state of heightened and focused concentration, and thus it can be used to manipulate the perception of pain.



Fotopoulos and colleagues55 noted significant pain relief in a group of cancer patients who were taught electromyographic (EMG) and electroencephalographic biofeedback-assisted relaxation. Only two of 17 were able to maintain analgesia after the treatment ended. A lack of generalization of effect can be a problem with biofeedback techniques. Although physical condition may make a prolonged training period impossible, especially for the terminally ill, most cancer patients can often utilize EMG and temperature biofeedback techniques for learning relaxation-assisted pain control.56


Novel Psychosocial Interventions

It should be noted that non-traditional psychosocial interventions for cancer pain hold great promise. For example, Keefe57 tested the efficacy of a partner-guided cancer pain management protocol. The partner-guided pain management training protocol was a three-session intervention conducted in patients’ homes that integrated educational information about cancer pain with systematic training of patients and partners in cognitive and behavioral pain coping skills. Data analyses revealed that the partner-guided pain management protocol produced significant increases in partners’ ratings of their self-efficacy for helping the patient control pain and self-efficacy for controlling other symptoms.


Psychotropic Adjuvant Analgesics for Pain in the Patient With Advanced Illness

The patient with advanced disease and pain has much to gain from the appropriate and maximal utilization of psychotropic drugs. Psychotropic drugs, particularly the tricyclic antidepressants (TCAs), are useful as adjuvant analgesics in the pharmacologic management of cancer pain and neuropathic pain. Table 5 lists the various psychotropic medications with analgesic properties, their routes of administration, and their approximate daily doses. These medications are not only effective in managing symptoms of anxiety, depression, insomnia, or delirium that commonly complicate the course of advanced disease in patients with cancer who are in pain, but also potentiate the analgesic effects of the opioid drugs and have innate analgesic properties of their own.58 A common use of adjuvant analgesics is to manage neuropathic pain. In this population, non-opioid adjuvant drugs that are neuroactive or neuromodulatory may be needed to complement opioid therapy. The primary adjuvant analgesics are anticonvulsant and antidepressants but a variety of other drugs are used.59





The current literature supports the use of antidepressants as adjuvant analgesic agents in the management of a wide variety of chronic pain syndromes, including cancer pain.60-67 While clinically useful as adjuvant analgesics in managing some pain syndromes (eg, human immunodeficiency virus neuropathies), there are no published controlled clinical trials of antidepressants as analgesics.68,69 Amitriptyline is the TCA most studied and proven effective as an analgesic in numerous clinical trials, addressing a wide variety of chronic pains.70-74 Other TCAs that have been shown to have efficacy as analgesics include imipramine,75-77 desipramine,78,79 nortriptyline,80 clomipramine,81,82 doxepin,83 and sertraline.84 In a placebo-controlled double-blind study of imipramine in chronic cancer pain, Walsh85 demonstrated that imipramine had analgesic effects independent of its mood effects, and was a potent co-analgesic when used along with morphine. Sertraline has been showed to reduce hot flashes in early stage breast cancer patients taking tamoxifen; however, compared to a placebo the reduction was not significant.86 In general, the TCAs are utilized in cancer pain as adjuvant analgesics, potentiating the effects of opioid analgesics, and are rarely used as the primary analgesic.65,85,87 Ventafridda and colleagues65 reviewed a multicenter clinical experience with antidepressants trazodone and amitriptyline in the treatment of chronic cancer pain that included a deafferentation of neuropathic component. Almost all of these patients were already receiving weak or strong opioids and experienced improved pain control. A subsequent randomized double-blind study showed both amitriptyline and trazodone to have similar therapeutic analgesic efficacy.65 Magni and colleagues66 reviewed the use of antidepressants in Italian cancer centres and found that a wide range of antidepressants were used for a variety of cancer pain syndromes, with amitriptyline being the most commonly prescribed for a variety of cancer pains. In nearly all cases, antidepressants were used in association with opioids. There is some evidence that there may be a subgroup of patients who respond differentially to TCAs and therefore if amitriptyline fails to alleviate pain another tricyclic should be tried.87 The TCAs are effective as adjuvants in cancer pain through a few mechanisms that include antidepressant activity,60 potentiation or enhancement of opioid analgesia,88-90 and direct analgesic effects.91

The heterocyclic and non-cyclic antidepressants such as trazodone, mianserin, maprotiline, and the newer serotonin-specific reuptake inhibitors fluoxetine and paroxetine may also be useful as adjuvant analgesics for cancer patients with pain; however, clinical trials of their efficacy as analgesics have been equivocal.92-96 Several case reports suggest that fluoxetine may be a useful adjuvant analgesic in the management of headache,97 fibrositis,98 and diabetic neuropathy.99 In a recent clinical trial, fluoxetine was shown to be no better than placebo as an analgesic in painful diabetic neuropathy.100 Paroxetine is the first serotonin-specific reuptake inhibitor shown to be a highly effective analgesic in the treatment of neuropathic pain,101 and may be a useful addition to the armamentarium of adjuvant analgesics for cancer pain. Although it has not been tested on cancer pain, selective serotonin reuptake inhibitors (SSRIs) such as citalopram have also been shown to help with neuropathic pain.102 Escitalopram, a newer SSRI, has advantages over other SSRIs; it has the highest selectivity in its class, no active metabolite, and does not significantly affect the cytochrome P450 isoenzyme.103 While escitalopram has not been tested on cancer pain, it has been shown to reduce both depression and anxiety.104 SSRIs may offer greater benefit to these patients as evidenced by greater improvements in quality-of-life measures.105

Newer antidepressants such as sertraline, venlafaxine, and nefazodone may also eventually prove to be clinically useful as adjuvant analgesics. For example, nefazodone has been demonstrated to potentiate opioid analgesics in an animal model106 and venlafaxine has been shown by Tasmuth and colleagues107 to decrease the maximum pain intensity following treatment of breast cancer. Recent randomized controlled trials suggest that fluoxetine and desipramine were effective and well tolerated in improving depression and the quality of life in women with advanced cancer. Duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, has been shown to treat depression and reduce painful physical symptoms108; however, it is untested in cancer patients.

It is clear that many antidepressants have analgesic properties. There is no definite indication that any one drug is more effective than the others, although the most experience has been accrued with amitriptyline, which remains the first drug of choice. In terms of appropriate dosage, there is evidence that the therapeutic analgesic effects of amitriptyline are correlated with serum levels just as the antidepressant effects are, and analgesic treatment failure is due to low serum levels.70,71,109 A high-dose regimen of up to 150 mg amitriptyline is suggested.73,110 As to the time course of onset of analgesia or with antidepressants, there appears to be a biphasic process that occurs with immediate or early analgesic effects that occur within hours or days82,88,91 and later, longer analgesic effects that peak over a 4–6 week period.70-72

Treatment should be initiated with a small dose of amitriptyline, for example, that is administered 10–25 mg at bedtime (especially in debilitated patients) and increased slowly by 10–25 mg every 2–4 days toward 150 mg; a frequent assessment of pain and side effects should be conducted until a beneficial effect is achieved. Maximal effect as an adjuvant analgesic may require continuation of athedrug for 2–6 weeks. Serum levels of antidepressants, when available, may also help in management to assure that therapeutic serum levels of drugs are being achieved. Both pain and depression in cancer patients often respond to lower doses (25–100 mg) of an antidepressant than are usually required in the physically healthy (100–300 mg), most likely because of impaired metabolism of these drugs. The choice of drug often depends on the side-effect profile, existing medical problems, nature of depressive symptoms if present, and past response to specific antidepressants. Sedating drugs such as amitriptyline are helpful when insomnia complicates the presence of pain and depression on a cancer patient. Anticholinergic properties of some of these drugs should also be kept in mind. Occasionally, in patients who have limited analgesic response to a TCA, potentiation of analgesia can be accomplished with the addition of lithium augmentation.111 TCAs have been shown to be effective as analgesics for mucositis when compared to opioids; for patients for whom opioids are contraindicated, TCAs may be used.112

In a small sample, mirtazapine has been shown to improve—though not statistically significant—pain, nausea, appetite, insomnia, and anxiety. Gains were small, but one must consider that patients left untreated are likely to show decline, not improvement, in these symptoms.113 Freynhagen and colleagues114 showed that in a large sample of 594 patients, from baseline to endpoint (a 6-week period), mirtazapine significantly improves pain, sleep disturbances, irritability, and exhaustion.

Monoamine oxidase inhibitors (MAOIs) are also less useful in the cancer setting because of dietary restriction and potentially dangerous interactions between MAOIs and narcotics such as meperidine. Amongst the MAOIs available, phenelzine has been shown to have adjuvant analgesic properties in patients with atypical facial pain and migraine.115,116



The psychostimulants dextroamphetamine and methylphenidate are useful antidepressants prescribed selectively for medically ill cancer patients with depression.117,118 Psychostimulants are also useful in diminishing excessive sedation secondary to narcotic analgesics, and are potent adjuvant analgesics. It has been demonstrated that a regimen of methylphenidate 10 mg with breakfast and 5 mg with lunch significantly decreased sedation and potentiated the analgesic effect of narcotics in patients with cancer pain.119-121 Dextroamphetamine has also been reported to have additive analgesic effects when used with morphine in postoperative pain.122 In a relatively low dose, psychostimulants stimulate appetite, promote a sense of well-being, and improve feelings of weakness and fatigue in cancer patients. Treatment with dextroamphetamine or methylphenidate usually begins with a dose of 2.5 mg at 8am and 12pm. The dosage is slowly increased over several days until a desired effect is achieved or side effects (eg, overstimulation, anxiety, insomnia, paranoia, confusion) intervene. Typically, a dose >30 mg/day is not necessary, although occasionally patients require up to 60 mg/day. Tolerance will develop and adjustment of dose may be necessary. A useful strategy in treating cancer pain associated with depression is to start a psychostimulant (starting dose of methylphenidate 2.5 mg at 8am and 12pm) and then to add a TCA after several days to help prolong and potentiate the short effect of the stimulant.

Modafinil is an interesting psychostimulant in that it has properties of stimulants but lacks the same potential of misuse and dependance as other stimulants.123 A study by DeBattista and colleagues124 tested modafinil on subjects with MDD and partial response to antidepressants. The study found that adjunctive treatment with modafinil significantly improved fatigue and depressive symptoms. Furthermore, modafinil was found to increase cognitive functioning. Fatigue is a common symptom of cancer and cancer treatment, and modafinil has repeatedly been shown to combat fatigue in non-cancer populations.125,126



Methotrimeprazine is a phenothiazine that is equianalgesic to morphine, has none of the opioid effects on gut motility, and probably produces analgesia through a-adrenergic blockade.127 In patients who are opioid tolerant, it provides an alternative approach in providing analgesia by a non-opioid mechanism. It is a dopamine blocker and so has antiemetic as well an anxiolytic effects. Methotrimeprazine can produce sedation and hypotension and should be given cautiously by slow intravenous infusion. Haloperidol is the drug of choice in the management of delirium or psychoses in cancer patients, and has clinical usefulness as a co-analgesic for cancer pain.128 Pimozide, a butyrophenone, has been shown to be effective as an analgesic in the management of trigeminal neuralgia, at doses of 4–12 mg/day.129

Although studies on the use of atypical antipsychotics in the treatment of delirium are lacking, Boettger and Breitbart130 reviewed the literature and found that olanzapine, risperidone, quetiapine, and ziprasidone successfully treat delirium. Olanzapine has been used to treat unmanaged pain in the context of anxiety and mild cognitive impairment. Patients received olanzapine 2.5–7.5 mg/day. Daily pain scores decreased; anxiety and cognitive impairment resolved.131 Boettger and Breitbart130 suggest that olanzapine and risperidone are the likely to be the most effective atypical antipsychotics for treating delirium. However, it is important to note that olanzapine has more sedating qualities than risperidone.



Hydroxyzine is a mild anxiolytic with sedating and analgesic properties that are useful in the anxious cancer patient with pain.132,133 This antihistamine has antiemetic activity as well. One hundred milligrams of parenteral hydroxizine has analgesic activity approaching morphine 8 mg, and has additive analgesic effects when combined with morphine. Benzodiazepines have not been thought to have direct analgesic properties, although they are potent anxiolytics and anticonvulsants.134 Some authors have suggested that their anticonvulsant properties make certain benzodiazepines useful in the management of neuropathic pain. Fernandez and colleagues135 showed that alprazolam, a unique benzodiazepine with mild antidepressant properties, was a helpful adjuvant analgesic in cancer patients with phantom limb pain or deafferentation (neuropathic) pain. Clonazepam may also be useful in the management of lancinating neuropathic pains in the cancer setting and has been reported to be an effective analgesic for patients with trigeminal neuralgia, headache, and posttraumatic neuralgia.136,137



The inadequate management of cancer pain is often caused by the inability to properly assess pain in all its dimensions. All too frequently, physicians presume that either psychological or medical variables are the exclusive causes of serious pain in cancer patients, thus overlooking the multidimensional nature of cancer pain. Other causes of inadequate pain management in cancer populations include a lack of knowledge of current psychopharmacologic or psychotherapeutic adjunctive treatments for cancer pain and lack of knowledge regarding comorbid psychiatric disorders that can exacerbate or interfere with the proper assessment and treatment of cancer pain. This article has addressed such issues. Effective management of cancer pain in patients requires a multidisciplinary approach. Psychiatrists form an important part of such treatment teams and can greatly assist in controlling and reducing the suffering cancer patients often undergo. PP



1. Foley KM. The treatment of cancer pain. N Eng J Med. 1985;313(2):84-95.
2. Fitzgibbon DR. Cancer pain: management. In: Loeser JD, Butler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:659-703.
3. Weiss SC, Emanuel LL, Fairclough DL, Emanuel EJ. Understanding the experience of pain in terminally ill patients. Lancet. 2001;357(9265):1311-1315.
4. Twycross RG, Lack SA. Symptom Control in Far Advanced Cancer: Pain Relief. 1983, London, England: Pitman Brooks; 1983.
5. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ, Albe-Fessard DG, eds. Advances in Pain Research and Therapy. New York, NY: Raven Press; 1975:59-75.
6. Marks RM, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med. 1973;78(2):173-181.
7. Grond S, Zech D, Diefenbach C, Bischoff A. Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage. 1994;9(6):372-382.
8. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1000 patients. Support Care Cancer. 2000;8(3):175-179.
9. Achte KA, Vauhkonen ML. Cancer and the psyche [Swedish]. Nord Psykiatr Tidsskr. 1971;25(3):199-212.
10. Stiefel F. Psychosocial aspects of cancer pain. Support Care Cancer. 1993;1(3):130-134.
11. Saunders CM. The Management of Terminal Illness. London, England: Hospital Medicine Publications; 1967.
12. Hanks GW. Opioid-responsive and opioid-non-responsive pain in cancer. Br Med Bull. 1991;47(3):7187-7131.
13. Syrjala KL, Chapko ME. Evidence for a biopsychosocial model of cancer treatment-related pain. Pain. 1995;61(1):69-79.
14. Breitbart W. Psychiatric aspects of cancer pain. In: Bonica JJ, Albe-Fessard DG, eds. Advances in Pain Research and Therapy. New York, NY: Raven Press; 1975:73-87.
15. Breitbart W. Psychiatric management of cancer pain. Cancer. 1989;63(11 suppl):2336-2342.
16. Daut RL, Cleeland CS. The prevalence and severity of pain in cancer. Cancer. 1982;50(9):1913-1918.
17. Spiegel D, Bloom JR. Pain in metastatic breast cancer. Cancer. 1983;52(2):341-345.
18. Padilla G, Ferrell B, Grant M, Rhiner M. Defining the content domain of quality of life for cancer patients with pain. Cancer Nurs. 1990;13(2):108-115.
19. Smith WB, Gracely RH, Safer MA. The meaning of pain: cancer patients’ rating and recall of pain intensity and affect. Pain. 1998;78(2):123-129.
20. Cleeland CS, Tearnan BH. Behavioral control of cancer pain. In: Holzman D, Turk DC, eds. Pain Mangement. New York, NY: Pergamon Press; 1986:93-212.
21. Derogatis LR, Morrow GR, Fetting J. The prevalence of psychiatric disorders among cancer patients. JAMA. 1983;249(6):751-757.
22. Ahles TA, Blanchard EB, Ruckdeschel JC. The multidimensional nature of cancer related pain. Pain. 1983;17(3):277-288.
23. Woodforde JM, Fielding JR. Pain and cancer. J Psychosomatic Res. 1970;14(4):365-370.
24. Bukberg J, Penman D, Holland J. Depression in hospitalized cancer patients. Psychosom Med. 1984;46(3):199-212.
25. Massie JM, Holland JC, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry. 1983;140:1048-1050.
26. Bruera E, Macmillan K, Hanson J, MacDonald RN. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain. 1989;39(1):13-16.
27. Breitbart W. Suicide in cancer patients. Oncology (Williston Park). 1987;1(2):49-55.
28. Breitbart W. Cancer pain and suicide. In: Advances in Pain Research and Therapy. Benedetti C, Chapman CR, Giron G, eds. New York, NY: Raven Press; 1990:399-412.
29. Rosefield B, Krivos, Breitbart W, Chochinov HM. Suicide, assisted suicide and euthanasia in the terminally ill. In: Chochinov HM, Breitbart W, eds. Handbook of Psychiatry in Palliative Medicine. New York, NY: Oxford University Press; 2000:51-62.
30. Levin DN, Cleeland CS, Dar R. Public attitudes toward cancer pain. Cancer. 1985;56(9):2337-2339.
31. Bolund C. Suicide and cancer: II. Medical and care factors in suicides by cancer patients in Sweden, 1973-1976. J Psychosoc Oncol. 1985;3:17-30.
32. Farberow NL, Schneidman ES, Leonard CV. Suicide Among General Medical and Surgical Hospital Patients With Malignant Neoplasms. Washington, DC: US Veterans Administration; 1963.
33. Massie M, Gagnon P, Holland J. Depression and suicide in patients with cancer. J Pain Symptom Manage. 1994;9(5):325-331.
34. Silberfarb PM, Maurer LH, Crouthamel CS. Psychological aspects of neoplastic disease: I. Functional status of breast cancer patients during different treatment regimens. Am J Psychiatry. 1980;137(4):450-455.
35. Brown JH, Henteleff P, Barakat S, Rowe JR. Is it normal for terminally ill patients to desire death? Am J Psychiatry. 1986;143(2):208-211.
36. Breitbart W, Rosenfeld B, Pessin H, et al. Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA. 2000;284(22):2907-2911.
37. Saltzburg D. The relationship of pain and depression to suicidal ideation in cancer patients. Poster presented at: The 25th Annual Meeting of the American Society of Clinical Oncology; May 21-23, 1989. San Francisco, CA.
38. Suarez-Almazor ME, Newman C, Hanson J, Bruera E. Attitudes of terminally ill cancer patients about euthanasia and assisted suicide: predominance of psychosocial determinants and beliefs over symptom distress and subsequent survival. J Clin Oncol. 2002;20(8):2134-2141.
39. Cleeland C, Gonin R, Hatfield A, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med. 1994;330(9):592-596.
40. Bruera E, MacMillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnea of terminal cancer patients. J Pain Symptom Manage. 1990;5(6):341-344.
41. Grossman SA, Sheidler VR, Swedeen K, Mucenski J, Piantadosi S. Correlations of patient and caregiver ratings of cancer pain. J Pain Symptom Manage. 1991;6(2):53-57.
42. Spiegel D, Bloom JR. Group therapy and hypnosis reduce metastatic breast carcinoma pain. Psychosom Med. 1983;45(4):333-339.
43. Passik S, Horowitz S, Malkin M, Gargan R. A psychoeducational support program for spouses of brain tumor patients. Poster presented at: The 150th Annual Meeting of the American Psychiatric Association. Symposium on New Trends in the Psychological Support of the Cancer Patient. New Orleans, LA; May 11-16, 1991.
44. Syrjala K, Cummings C, Donaldson G. Hypnosis or cognitive behavioral training for the reduction of pai and nausea during cancer treatment: a controlled trial. Pain. 1992;48(2):137-146.
45. Fishman B, Loscalzo M. Cognitive-behavioral interventions in the management of cancer pain: principles and applications. Med Clin North Am. 1987;71(2):271-287.
46. Cleeland CS. Nonpharmacologic management of cancer pain. J Pain Symptom Manage. 1987;2(2):S23-S28.
47. Loscalzo M, Jacobsen PB. Practical behavioral approaches to the effective management of pain and distress. J Psychosoc Oncol. 1990;8(2-3):139-169.
48. Spiegel D. The use of hypnosis in controlling cancer pain. CA Cancer J Clin. 1985;35(4):221-231.
49. Levitan AA. The use of hypnosis with cancer patients. Psychiatr Med. 1992;10(1):119-131.
50. Tan SY, Leucht CA. Cognitive-behavioral therapy for clinical pain control: a 15-year update and its relationship to hypnosis. Int J Clin Exp Hypn. 1997;45(4):396-416.
51. Douglas DB. Hypnosis: useful, neglected, available. Am J Hosp Palliat Care. 1999;16(5):665-670.
52. Rajasekaran M, Edmonds PM, Higginson IL. Systematic review of hypnotherapy for treating symptoms in terminally ill adult cancer patients. Palliative Medicine. 2005;19(5):418-426.
53. Montgomery GH, DuHamel KN, Redd WH. A meta-analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypn. 2000;48(2):138-153.
54. Montgomery GH, Weltz CR, Seltz M, Bovbjerg DH. Brief presurgery hypnosis reduces distress and pain in excisional breast biopsy patients. Int J Clin Exp Hypn. 2002;50(1):17-32.
55. Fotopoulos SS, Graham C, Cook MR. Psychophysiologic control of cancer pain. In: Bonica JJ, Ventafridda V, eds. Advances in Pain Research and Therapy. New York, NY: Raven Press; 1979:231-244.
56. Kazak AE, Penati B, Brophy P, Himelstein B. Pharmacologic and psychologic interventions for procedural pain. Pediatrics. 1998;102(1 Pt 1):59-66.
57. Keefe FJ. Partner-Guided Cancer Pain Management at the End of Life: A Preliminary Study. Journal of Pain and Symptom Management. 2005;29:263-272.
58. Breitbart W. Psychotropic adjuvant analgesics for cancer pain. Psychooncology. 1998;7:333-345.
59. Farrar JT, Portenoy RK. Neuropathic cancer pain: the role of adjuvant analgesics. Oncology. 2001;15(11):1435-1442,1445,1450-1453.
60. France RD. The future for antidepressants: treatment of pain. Psychopathology. 1987;20(suppl 1):99-113.
61. Getto CJ, Sorkness CA, Howell T. ssues in drug management. Part I. Antidepressants and chronic nonmalignant pain: a review. J Pain Symptom Control. 1987;2(1):9-18.
62. Walsh TD. Antidepressants and chronic pain. Clinical Neuropharmacology. 1983;6:271-295.
63. Walsh TD. Adjuvant analgesic therapy in cancer pain. In: Foley KM, Bonica JJ, Ventafridda V, Callaway M, eds. Proceedings of the Second International Congress on Cancer Pain (Advances in Pain Research and Therapy). New York, NY: Raven Press; 1990.
64. Butler S. Present status of tricyclic antidepressants in chronic pain therapy. In: Bonica JJ, Albe-Fessard DG, eds. Advances in Pain Research and Therapy. New York, NY: Raven Press; 1986;173-196.
65. Ventafridda V, Bonezzi C, Caraceni A, et al. Antidepressants for cancer pain and other painful syndromes with deafferentation component: comparison of amitriptyline and trazodone. Ital J Neurol Sci. 1987;8(6):579-587.
66. Magni G, Arsie D, De Leo D. Antidepressants in the treatment of cancer pain. A survey in Italy. Pain. 1987;29(3):347-353.
67. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992;49(2):205-219.
68. Breitbart W. Pain management in the patient with AIDS. Hematology/Oncology Annals. 1994;2:391-399.
69. Lefkowitz M, Breitbart W. Chronic pain and AIDS. Innovation in Pain Medicine. 1992;36:(2-3):18.
70. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic-neuropathy pain in patients with normal and depressed mood. Neurology, 1987;37(4):589-596.
71. Max MB, Schafer SC, Culnane M, et al. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1982;38(9):427-432.
72. Pilowsky I, Hallett EC, Bassett DL, Thomas PG, Penhall RK. A controlled study of amitriptyline in the treatment of chronic pain. Pain. 1982;14(2):169-179.
73. Sharav Y, Singer E, Schmidt E, Dionne RA, Dubner R. The analgesic effect of amitriptyline on chronic facial pain. Pain. 1987;31(2):199-209.
74. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in post herpetic neuralgia. Neurology. 1982;32(6):671-673.
75. Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984;251(13):1727-1730.
76. Young RJ, Clarke BF. Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs. Diabet Med. 1985;2(5):363-366.
77. Sindrup SH, Ejlertsen B, Froland A, Sindrup EH, Brosen K, Gram LF. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Pharmacol. 1989;37(2):151-153.
78. Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45(1):3-9.
79. Gordon N, Heller P, Gear R, Levine J. Temporal factors in the enhancement of morphine analgesic by desipramine. Pain. 1993;53(3):273-276.
80. Gomez-Perez FJ, Rull JA, Dies H. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain. 1985;23(4):395-400.
81. Langohr HD, Stohr M, Petruch F. An open and double-blind crosover study on the efficacy of clomipramine (anafranil) in patients with painful mono- and polyneuropathies. Eur Neurol. 1982;21(5):309-315.
82. Tiegno M, Pagnoni B, Calmi A, Rigoli M, Braga PC, Panerai AE. Chlorimipramine compared to pentazocine as a unique treatment in post-operative pain. Int J Clin Pharmacol Res. 1987;7:141-143.
83. Hameroff SR, Cork RC, Scherer K, et al. Doxepin effects on chronic pain, depression and plasma opioids. J Clin Psychiatry. 1982;43(8 Pt 2):22-27.
84. Lee RA, West RM, Wilson JD. The response to sertraline in men with chronic pelvic pain syndrome. Sex Transm Infect. 2005;81(2):147-149.
85. Walsh TD. Controlled study of imipramine and morphine in chronic pain due to advanced cancer. Poster presented at: The 22nd Annual Meeting of the American Society of Clinical Oncology. May 4-6, 1986; Los Angeles, CA.
86. Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J. 2006. 12(2):114-122.
87. Watson CP, Chipman M, Reed K, Evans RJ, Birket N. Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized double-blind crossover trial. Pain. 1992;48(1):29-36.
88. Botney M, Fields HL. Amitriptyline potentiates morphine analgesia by direct action on the central nervous system. Ann Neurol. 1983;13(2):160-164.
89. Malseed RT, Goldstein FJ. Enhancement of morphine analgesia by tricyclic antidepressnts. Neuropharmacology. 1979;18(10):827-829.
90. Ventafridda V, Bianchi M, Ripamonti C Studies on the effects of antidepressant drugs on the antinociceptive action of morphine and on plasma morphine in rat and man. Pain. 1990;43(2):155-162.
91. Spiegel K, Kalb R, Pasternak GW. Analgesic activity of tricyclic antidepressants. Ann Neurol. 1983;13(4):462-465.
92. Davidoff G, Guarracini M, Roth E, Sliwa J, Yarkony G. Trazodone hydrochloride in the treatment of dysesthetic pain in traumatic myelopathy: a randomized, double-blind, placebo-controlled study. Pain. 1987;29(2):151-161.
93. Costa D, Mogos I, Toma T. Efficacy and safety of mianserin in the treatment of depression of woman with cancer. Acta Psychiatr Scand Suppl. 1985;320:85-92.
94. Eberhard G, von Knorring L, Nilsson HL, et al. A double-blind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes. Neuropsychobiology. 1988;19(1):25-34.
95. Feighner JP. A comparative trial of fluoxetine and amitriptyline in patients with major depressive disorder. J Clin Psychiatry. 1985;46(9):369-372.
96. Hynes MD, Lochner MA, Bemis KG, Hymson DL. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its descriminative stimulus properties or affinity for opioid receptors. Life Sci. 1985;36(24):2317-2323.
97. Diamond S, Freitag FG. The use of fluoxetine in the treatment of headache. Clin J Pain. 1989;5(2):200-201.
98. Geller SA. Treatment of fibrositis with fluoxetine hydrochloride (Prozac). Am J Med. 1989;87(5):594-595.
99. Theesen KA, Marsh WR. Relief of diabetic neuropathy with fluoxetine. DICP. 1989;23(7-8):572-574.
100. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
101. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42(2):135-144.
102. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992;52(5):547-552.
103. Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J Psychiatry Neurosci. 2006;31(2):122-131. Erratum in: J Psychiatry Neurosci. 2006;31(4):228.
104. Thase ME. Managing depressive and anxiety disorders with escitalopram. Expert Opin Pharmacother, 2006;7(4):429-440.
105. Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology. 1998;7(4):291-300.
106. Pick CG, Paul D, Eison MS, Pasternak GW. Potentiation of opioid analgesia by the antidepressant nefazodone. Eur J Pharmacol. 1992;211(3):375-381.
107. Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain. 2002;6(1):17-24.
108. Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol. 2004;24(4):389-399.
109. McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect of amitriptyline in chronic pain. Anesthesia. 1993;48:281-285.
110. Watson CP, Evans RJ. A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia. Pain. 1985;23(4):387-394.
111. Tyler MA. Treatment of the painful shoulder syndrome with amitriptyline and lithium carbonate. Can Med Assoc J. 1974;111(2):137-140.
112. Ehrnrooth E, Grau C, Zachariae R, Andersen J. Randomized trial of opioids versus tricyclic antidepressants for radiation-induced mucositis pain in head and neck cancer. Acta Oncol. 2001;40(6):745-750.
113. Theobald DE, Kirsh KL, Holtsclaw E, Donaghy K, Passik SD. An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage. 2002;23(5):442-447.
114. Freynhagen R, Muth-Selbach U, Lipfert P, et al. The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin. 2006;22(2):257-264.
115. Lascelles RG. Atypical facial pain and depression. Br J Psychiatry. 1966;122(488):651.
116. Anthony M, Lance JW. Monoamine oxidase inhibition in the treatment of migraine. Arch Neurol. 1969;21(3):263-268.
117. Fernandez F, Adams F, Holmes VF, Levy JK, Neidhart M. Methylphenidate for depressive disorders in cancer patients. Psychosomatics. 1987;28(9):455-461.
118. Kaufmann MW, Murray GB, Cassem NH. Use of psychostimulants in medically ill depressive patients. Psychosomatics. 1982;23(8):817-819.
119. Bruera E, Chadwick S, Brenneis C, Hanson J, MacDonald RN. Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep. 1987;71(1):67-70.
120. Bruera E, Brenneis C, Paterson AH, MacDonald RN. Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage. 1989;4(1):3-6.
121. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates: a preliminary report. Pain. 1992;50(1):75-77.
122. Forrest WH Jr, Brown BW Jr, Brown CR, et al. Dextroamphetamine with morphine for the treatment of post-operative pain. N Engl J Med. 1977;296(13):712-715.
123. Morrow GR, Shelke AR, Roscoe JA, Hickok JT, Mustian K. Management of cancer-related fatigue. Cancer Invest. 2005;23(3):229-239.
124. DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.
125. Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW, Douglas NJ. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med. 2001;163(4):918-923.
126. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72(2):179-183.
127. Beaver WT, Wallenstein SL, Houde RW, Rogers A. A comparison of the analgesic effect of methotrimeprazine and morphine in patients with cancer. Clin Pharmacol Ther. 1966;7(4):436-446.
128. Maltbie AA, Cavenar JO Jr, Sullivan JL, Hammett EB, Zung WW. Analgesia and haloperidol: a hypothesis. J Clin Psychiatry. 1979;40(7):323-326.
129. Lechin F, van der Dijs B, Lechin ME, et al. Pimozide therapy for trigeminal neuralgia. Arch Neurol. 1989;46(9):960-963.
130. Boettger S, Breitbart W. Atypical antipsychotics in the management of delirium: a review of the empirical literature. Palliat Support Care. 2005;3(3):227-237.
131. Khojainova N, Santiago-Palma J, Kornick C, Breitbart W, Gonzales GR. Olanzapine in the management of cancer pain. J Pain Symptom Manage. 2002;23(4):346-350.
132. Beaver WT, Feise V. Comparison of the analgesic effects of morphine, hydroxyzine and their combination in patients with post-operative pain. In: Bonica JJ, Albe-Fessard DG, eds. Advances in Pain Research and Therapy. New York, NY: Raven Press; 1975:533-557.
133. Rumore MM, Schlichting DA. Clinical efficacy of antihistamines as analgesics. Pain. 1986;25(1):7-22.
134. Coda B, Mackie A, Hill H. Influence of alprazolam on opioid analgesia and side effects during steady-stage morphine infusions. Pain. 1992;50(3):309-316.
135. Fernandez F, Adams F, Holmes VF. Analgesic effect of alprazolam in patients with chronic, organic pain of malignant origin. J Clin Psychopharmacol. 1987;7(3):167-169.
136. Caccia MR. Clonazepam in facial neuralgia and cluster headache: clinical and electrophysiological study. Eur Neurol. 1975;13(6):560-563.
137. Swerdlow M, Cundill JG. Anticonvulsant drugs used in the treatment of lancinating pains. A comparison. Anaesthesia. 1981;36(12):1129-1132.


Dr. Lebovits is associate professor in the Departments of Anesthesiology and Psychiatry at New York University Medical Center in New York City and director of psychological services in the Division of Neurology and Integrative Pain Medicine at ProHealth Care Associates, LLP, in Lake Success, New York.

Disclosures: Dr. Lebovits reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Allen Lebovits, PhD, Director, Psychological Services, Division of Neurology and Integrative Pain Medicine, ProHEALTH Care Associates, LLP, 3 Delaware Dr, Lake Success, NY 11042; Tel: 516-622-6096; Fax: 516-622-6082; E-mail: alebovits@prohealthcare.com.




Focus Points

• The cognitive-behavioral approach is the most commonly utilized psychological approach in treating patients with chronic pain.
• Cognitive-behavioral approaches include hypnosis, relaxation (eg, guided imagery, progressive muscular relaxation, meditation, music therapy), biofeedback, coping skills training, cognitive restructuring, supportive and group therapy, and stress-management techniques.
• The integration of psychological interventions with conventional medical methods in the treatment of chronic pain is essential.



The cognitive-behavioral approach is the most commonly utilized psychological approach in treating patients with chronic pain. Cognitive-behavioral approaches include hypnosis, relaxation (including guided imagery, progressive muscular relaxation, meditation, and music therapy), biofeedback, coping skills training, cognitive restructuring, supportive and group therapy, and stress-management techniques. The primary component of the cognitive-behavioral approach is relaxation therapy, which is a systematic method of gaining awareness of physiologic processes and attaining both a cognitive and physiologic sense of tranquility. A National Institutes of Health Technology panel, conducting an extensive scientific review of the literature, concluded that the evidence is “strong” (its highest rating) for the effectiveness of relaxation in reducing chronic pain. Specific relaxation strategies that have been shown to reduce levels of pain include guided imagery, progressive muscle relaxation, and meditation. Despite the generally accepted efficacy of these methods with pain patients, their relative ease of implementation, and their very low side-effect profile, barriers still exist with the integration of psychological therapies into standard medical care.



The psychological intervention with patients with chronic pain is an integral part of a multidisciplinary approach to pain management. The overall goal of pain management is to return the patient to a more optimal level of functioning. Improved functionality rather than cure of pain is often the focus of pain management. Many pain patients have difficulty accepting that the primary treatment goal is improved functionality rather than pain relief.

The most commonly utilized psychological approach in treating patients with chronic pain is the cognitive-behavioral approach. The goal of cognitive-behavioral treatments is to enable the patient to reframe the belief that pain is uncontrollable to a belief that pain can be under his or her control.1,2 It is based upon the theory that thoughts, emotions, and behavior can influence the pain experience. Although the pain is not “cured,” the patient may be better able to cope with it. A National Institutes of Health (NIH) technology assessment conference on the efficacy of mind-body approaches for the treatment of chronic pain and insomnia found “strong” to “moderate” evidence to support the use of relaxation techniques, hypnosis, cognitive-behavioral therapy (CBT), and biofeedback in reducing chronic pain.3 Meta-analyses with cancer patients have similarly concluded that cognitive-behavioral methods for cancer pain are more effective than no treatment or attention-placebo and do have additive effects over that found with hypnosis or imagery alone.4,5 Patients benefit from these nonpharmacologic approaches when delivered by trained professionals rather than a patient’s untrained use.6

A recent evidence-based review7 of patients suffering with chronic low back pain found that psychological interventions resulted in positive effects on pain intensity, pain-related interference, health-related quality of life, and depression. Cognitive-behavioral and self-regulatory treatments (hypnosis, biofeedback, and relaxation) were the most effective treatments.

The initial step is educating the patient about the mind-body relationship. The effectiveness of this step depends on the patient’s defensiveness, level of knowledge about the mechanism of pain, and attitudes about the mind-body relationship. Cognitive-behavioral approaches include hypnosis, relaxation (eg, guided imagery, progressive muscular relaxation, meditation, music therapy), biofeedback, coping skills training, cognitive restructuring, supportive and group therapy, and stress-management techniques.



Hypnosis is a particularly effective therapeutic technique with pain patients. It has been used and studied largely in cancer pain related to procedures, surgery, and chemotherapy. Up to 90% of patients can benefit from the use of hypnosis.8,9

Hypnosis not only induces relaxation and a passive disregard of intrusive thoughts, but can also introduce specific goals through suggestions. These suggestions enable patients to experience analgesia or reinterpretation of their pain. Posthypnotic suggestions allow the patient continued use of the new behavior and assistance in recreating the relaxed state when needed following termination of hypnosis. Suggestion appears to be the most important element in reducing pain.10 It is unclear what the exact mechanism is to explain the efficacy of hypnosis,8 with theories ranging from reductions in peak somatosensory event-related potentials11 to decreased cortical arousal with increased occipital regional bloodflow in areas involved with mental absorption and attention.10,12 Length of treatment with hypnosis does not add to its effectiveness8,13 and individuals vary widely in their hypnotic susceptibility for reasons that are largely unknown.

In a study by Spiegel and Bloom,14 women with metastatic breast carcinoma pain undergoing weekly group therapy with self hypnosis had significantly lower pain ratings over 1 year than a control group. In another study, patients undergoing hypnosis reported a significant reduction in oral mucositis pain associated with bone marrow transplantation.15 An NIH consensus conference on symptom management in cancer noted that hypnosis is particularly helpful with procedural pain and mouth sores.16 A review of outcome studies utilizing hypnosis with chronic pain patients concluded that hypnosis is “consistently superior” to no treatment but only equally as effective as other treatments.17 There is conflicting evidence about the use of the term “hypnosis” with patients, with a meta-analysis showing that it increases efficacy beyond relaxation and imagery,9 but another study indicating the reverse.18



The primary component of the cognitive-behavioral approach is relaxation therapy, which is a systematic method of gaining awareness of physiologic processes and attaining both a cognitive and physiologic sense of tranquility.19 Relaxation training is currently one of the most widely used cognitive psychological techniques in the management of chronic pain. Relaxation training acts on pain by lowering anxiety,20 altering sympathetic activity,21 and reducing generalized arousal and muscle tension,22 as well as by its cognitive effects of distraction.3,22 Studies report the effectiveness of relaxation in reducing pain,23 with one study reporting pain reduction in 38% of advanced cancer patients in a hospice.24 A comprehensive review of the literature on relaxation training and pain supports the effectiveness of this approach with patients with pain.25 An NIH Technology panel, conducting an extensive scientific review of the literature, concluded that the evidence is “strong” (its highest rating) for the effectiveness of relaxation in reducing chronic pain.3

Although relaxation/imagery has been noted to significantly affect pain in a palliative care setting,26 research reviews have found that relaxation training is more effective than no treatment with chronic pain but only equally as effective as other self-regulation techniques.17 Often, the initial step of relaxation training is learning controlled diaphragmatic breathing which diverts the patient’s attention and can induce the relaxation effect by itself.

Live relaxation as well as audiotaped relaxation produced significant positive changes in pain sensation, intensity, and severity, in cancer pain patients.27 The live method was most effective. A meta-analysis of 15 studies evaluating the effects of relaxation on treatment side effects noted a statistically significant reduction in pain.13 Specific relaxation strategies that have been shown to reduce levels of pain include guided imagery, progressive muscle relaxation, and meditation (Table 1).15,28-30



Guided Imagery

Relaxation methods may be most effective with pain when used with imagery.15 Imagery-based relaxation may reduce pain through more of a structured focus than non-imagery based relaxation methods. A review of the literature on behavioral interventions for cancer treatment side effects concludes that methods involving relaxation and imagery hold the greatest promise for benefit to cancer patients.31

Guided imagery has patients focus on a multisensory imaginary scene. Focusing on the different sensory modalities of the scene can make the image more engaging. Typically, the image is elicited from the patient, and the patient is guided through the image, substituting sensations such as warmth or numbness for pain. Patients need to set aside time to practice in a comfortable position without any interruptions. Imagery can work as an effective distraction technique. An alternative use of imagery is to have the patient focus on the pain rather than distract away from it. In this technique, the patient might visualize the pain as a color, for example, red, and makes it less bright until it turns light pink corresponding to lower pain intensity.


Progressive Muscular Relaxation

In progressive muscular relaxation, patients are taught to alternately tense and relax major muscle groups throughout the body. Only non-painful muscle groups and body locations are used. Patients learn to recognize and differentiate feelings of tension from relaxation and then apply these skills in situations that are painful. Sixteen muscle groups can be initially tensed and relaxed. The number of muscle groups is reduced as the patient becomes more proficient. The patient is instructed to focus on the pleasantness of the relaxation phase. Progressive muscle relaxation is recommended if a muscle tension is thought to be a major contributing factor to the patient’s pain29 as well as with the patient who has a difficult time visualizing images.



Meditation is defined as “the intentional self-regulation of attention from moment to moment.”30 Concentration meditation, involving the focused attention on a point or object such as a mantra, differs from mindfulness meditation, which emphasizes detached observation from one moment to the next of a changing field of objects. The primary advantage of mindfulness meditation is the ability to adapt a detached view of the pain sensation, which can lead to an “uncoupling” of the affective from sensory interpretation of pain. As a result, patients have lower levels of reactivity to pain. A study of 51 refractory chronic pain patients going through a mindfulness meditation program showed that 65% experienced a reduction of >33% in their pain ratings.30


Music Therapy

Music therapy has been defined as the use of specifically prescribed music under the supervision of a music therapist to aid in the physiologic, psychological, and emotional integration of an individual.32

Music therapy can have a beneficial effect on mood and pain when given a choice of music33 as a method of relaxation and distraction.34 Diversional and associative qualities of music may distract a patient’s attention from the adverse nature of a stimulus. Music may also have a powerful impact on reducing the emotional components of pain such as fear and anxiety, thus mediating the very perception of pain. Individual music preferences is an important factor to consider.35

A recent review of the literature on the effectiveness of music in alleviating pain in the palliative care setting is positive.36 Music therapy can be an effective independent intervention for providing pain relief in cancer patients.33 Although music therapy can be an effective intervention in the relief of pain,37,38 the literature in this area is scant, anecdotal, and lacking studies with good research design.26

Music may stimulate the release of endogenous opiates in the central nervous system, which can modulate the perception of the sensory and affective components of pain.36 Other potential mediating mechanisms that have been postulated include an increased sense of control, reduction in anxiety, regulation of muscle tension, and distraction.39,40 Music therapy may enable patients to control their pain by distracting their attention away from the pain and by changing their emotional experiences.32,41 Music may also distract by inhibiting pain through selective attention that is mediated by the thalamus, which alerts the prefrontal cortex to the sound rather than to the painful stimulus.42



Biofeedback can be a particularly effective modality for teaching chronic pain patients relaxation as well as self-regulation of physiologic processes. Patients learn to modify specific physiologic processes based on auditory and/or visual feedback. It is based on the educational paradigm that learning occurs with feedback which then enables a desired response. Ongoing physiologic processes (such as muscle tension or surface electromyogram, temperature, heart rate, sweat gland activity, or basal skin response, and breath rate) can be monitored, and visual (through graphs, images, or games) and auditory feedback (through tones or music) are provided. The latest application of biofeedback is neurofeedback, which teaches patients to regulate electroencephalograph activity or brain waves.

Body sensors attached to a computer enable the patient to achieve relaxation, which can increase pain tolerance, decrease emotional distress, and even relax specific muscle spasms. Physiologic self control leads to a sense of control, better coping skills, and hopefulness. Pain syndromes with which biofeedback is most effective include headaches, transmandibular joint dysfunction, myofascial pain syndrome, fibromyalgia, and pain exacerbated by stress or anxiety (Table 2).



Coping Skills Training

Patients can learn to adopt more effective active coping styles rather than the passive ineffective coping styles such as catastrophizing, avoidance, and denial. Coping-skills training can be effective methods in reducing pain, particularly those who do not respond to hypnosis or imagery alone (Table 3).


Family members can be very helpful to the therapist in supporting patients’ “wellness” behaviors rather than reinforcing “pain” behaviors. Decreased reliance on medications and utilization of the healthcare system as well as reduced level of subjective pain sensation are important but secondary treatment goals. The simultaneous engagement of physical therapy as part of the patient’s recovery is essential as it mitigates the negative influence of deconditioning that many patients experience. Activity and physical therapy are often the focus of the psychological therapy and need to be continually inquired about and reinforced.

Activity pacing, which involves the scheduling of rest periods so that patients do not overdo an activity and sabotage their progress, can be very beneficial for many pain patients. Overexertion, which often results in increased pain and prolonged rest, often has negative sequelae such as increased muscle tension and increased utilization of medications. Teaching patients to schedule their daily activities into periods of moderate activity followed by limited rest can increase their self confidence.43 Overly inactive patients are taught to initiate activities in a very limited fashion and gradually increase activities followed by rest. Patients are also taught to schedule pleasant and enjoyable activities during the day. Additionally, the use of pain diaries to help identify stressful situations or times of day that exacerbate pain can help patients regulate their behaviors and/or emotions to facilitate more adaptive pain coping skills.


Cognitive Restructuring

Cognitive restructuring, or reframing, is often used very effectively as part of an overall cognitive-behavioral treatment approach for patients suffering from chronic pain. It is based on the theory that cognitions determine behavior, affect, and physiology (eg, increased muscle tension). Patients learn to identify, challenge, and eventually change self-defeating thoughts (eg, “I am worthless”). With this technique, pain patients are taught to identify maladaptive negative thoughts, which are often overgeneralizing, or catastrophizing statements about oneself or one’s illness (eg, ‘“pain means I need more surgery,” “no one can help me”) that pervade their thinking, and to replace them with more constructive and adaptive positive thoughts (eg,“I can still do many important things”). Patients are taught to use their adaptive thoughts when confronted with pain or situations that lead to pain. Unless patients practice, they may relapse in face of stressful and/or difficult situations, which can lead to increased depression and helplessness. Family and/or significant other support can be very influential in ensuring the promotion of the generalization and maintenance of the newly acquired cognitive skills.


Supportive and Group Therapy

Group therapy has become a popular form of psychological intervention for the chronic pain patient.44 A recent meta-analysis of randomized controlled trials of CBT for chronic pain found that most treatments were delivered in groups.45 The advantages of group therapy are that pain patients learn they are not alone in their suffering, the group can be an effective support system, and patients can learn from other patients’ pain coping skills. Patients will often accept challenges from other patients to improve functionality more readily than from an individual therapist whom the patient may feel does not understand or appreciate his or her pain. The major goals of group therapy often are to promote behavior change, educate patients, and provide social support.44 Social support can be influential in reducing psychological disability.


Stress Management

Many patients with chronic pain feel high levels of stress as the result of repeated medical interventions that have failed to provide relief. Often, stress-management interventions can be very helpful. Many patients readily acknowledge that stressors, such as return to work issues and conflicts with family and friends, can exacerbate pain. Reducing perceived stress can be very helpful in reducing levels of pain. The initial step in stress-management programs is to identify one’s stressors in daily life. This is frequently followed by cognitive-behavioral methods such as relaxation training and cognitive restructuring. Other important stress-management interventions that can be particularly helpful to chronic pain patients include using time management techniques, sharing feelings and problems, using humor, and participating in physical exercise. 

Time management consists of creating daily task lists arranged by priority, complete with time estimates. Done properly, time management is effective for pain patients who are overwhelmed by their illness, their pain, and trying to reintegrate back into their work and social lives. Time management is an important intervention, particularly for “workaholics” or very disorganized patients. Time management consists of instructing patients to make daily lists of tasks to be done, prioritizing them with regard to their importance, estimating the amount of time each task takes, and possibly delegating the ones that others can do. If done properly, time-management methods can relieve a significant amount of stress for pain patients who often feel overwhelmed trying to cope with their illness and pain as well as to reintegrate back into their work and social lives (Table 4).


Sharing feelings and problems with others such as significant others, patients, or professionals can be an effective method of relieving stress. Patients often have great difficulty coping with their functional limitations, decisions about treatment, and the ensuing medical and psychological sequelae. Internalizing emotions or keeping them pent up is generally considered to be unhealthy and has been correlated with a variety of medical conditions including chronic pain. Patients with strong support systems have been shown to cope more effectively with stress.
The use of humor can be an effective stress reducer. Laughing at one’s problems and taking a humorous perspective on difficult situations can facilitate stress reduction. Similarly, making time for fun by involving oneself in recreational activities can be a good distraction and break up the chronicity of stress.

If medically feasible, physical exercise on a regular basis, usually recommended to be done three times a week for 20–30 minutes, can be a particularly effective stress reducer. Patients who have been physically inactive need to be cautioned to avoid injury by starting out slowly. Chronic pain patients should never initiate a physical exercise program without the guidance of a physiatrist or physical therapist. Swimming is considered to be one of the best cardiovascular exercises, particularly good for chronic pain patients as there is limited stress placed on the joints.


Cognitive-Behavioral Interventions With Children And Adolescents

Research on the use of cognitive-behavioral interventions with children and adolescents in pain is less extensive than with adults. Much of the relevant literature has focused on procedure-related pain, where distraction techniques are recommended for procedures in cancer pain,29 particularly with children.46,47 It is increasingly recognized that cognitive-behavioral interventions suitable for adults may not be appropriate in the pediatric setting. There may be specific cognitive-behavioral interventions for children and adolescents that are particularly efficacious. Since children often have active imaginations they are receptive to imagery and relaxation methods. Although cognitive-behavioral methods have been consistently demonstrated to be effective in relieving headaches in children, the evidence for other types of chronic pain has not been as conclusively demonstrated.48 There are only anecdotal descriptions and case studies reporting on the usefulness of CBT in cancer pain patients.48


Barriers to Integration of Cognitive-Behavioral Therapies

The integration of psychological interventions such as CBT with conventional medical methods in the treatment of chronic pain is essential. This is highlighted by reports of increased mortality, including reduced cancer survival, as a result of unresolved pain.49,50 Additionally, the success of medical interventions such as surgery and spinal cord implantation in reducing pain has been shown to be largely dependent on psychosocial factors.51 The interdisciplinary evaluation and treatment of these patients, requiring collaboration among healthcare professionals, is essential, widely practiced today, and considered to be the standard of care.52,53 Multidisciplinary approaches that include a psychological component such as CBT reduce pain interference and work-related disability (Table 5).7



Despite the generally accepted efficacy of these methods with pain patients, their relative ease of implementation, and their very low side-effect profile, barriers still exist with the integration of psychological therapies such as CBT into standard medical care.3 First, there still remains an overemphasis on the biomedical model, both in clinical care and in medical education. Second, there is a lack of standardization of psychological techniques such as CBT. Third, there is a lack of patient compliance in practicing these methods. Fourth, there is a physician reluctance to prescribe for psychological methods due to lack of awareness of the benefits of these techniques and concern regarding patient perception that referral reflects mental illness. Fifth, inconsistent and poor reimbursement by third party payers hinder the delivery of services. Sixth, there are ill-defined credentialing criteria for providers of such services which create an unreliability in the delivery of these methods. Last, psychosocial interventions are time intensive and often necessitate many visits, which can impede physician and patient acceptance. These barriers to the integration and implementation of psychological therapies such as CBT in the management of pain can hopefully be overcome with physician and patient education as well as additional research.3



With chronic pain, the emphasis is often on the medical intervention, considering the psychological intervention only when medical management has failed. This, however, may not be in the patient’s best interest considering clinical experience shows that psychological techniques such as hypnosis are less effective in later stages when pain may be more severe54 or when the patient may be suffering from drug-induced adverse effects55 such as compromised cognitive function from high doses of opioids. This would argue for an earlier consideration of psychological techniques when pain levels are less severe or the patient is less medicated. This approach might also be beneficial for treatment side effects and might reduce medication requirements as well.

Chronic pain requires a multidisciplinary approach based on the conjoint utilization of interconnected specialties. The integration of cognitive-behavioral methods as an integral part of a psychiatric pain practice can only lead to more effective treatment of this very difficult-to-treat population. The utilization of these techniques has been demonstrated to improve the treatment outcome for the multitude of issues that these patients have. PP



1. Bradley LA. Cognitive-behavioral therapy for chronic pain. In: Gatchel RJ, Turk DC, eds. Psychological Approaches to Pain Management. New York, NY: Guilford Press; 1996:131-147.
2. Bradley LA, McKendree-Smith NL, Cianfrini LR. Cognitive-behavioral therapy interventions for pain associated with chronic illness: evidence for their effectiveness. Semin Pain Med. 2003;1(2):44-54.
3. NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches Into the Treatment of Chronic Pain and Insomnia. Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. JAMA. 1996;276(4):313-318.
4. Sellick SM, Zaza C. Critical review of 5 nonpharmacologic strategies for managing cancer pain. Cancer Prev Contr. 1998;2(1):7-14.
5. Thomas EM, Weiss SM. Nonpharmacological interventions with chronic cancer pain in adults. Cancer Contr. 2000;7(2):157-164.
6. Kwekkeboom KL. Pain management strategies used by patients with breast and gynecologic cancer with postoperative pain. Cancer Nurs. 2001;24(5):378-386.
7. Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-Analysis of psychological interventions for chronic low back pain. Health Psychol. 2007;26(1):1-9.
8. Montgomery GH, Weltz CR, Seltz M, Bovbjerg DH. Brief presurgery hypnosis reduces distress and pain in excisional breast biopsy patients. Intern J Clin Experim Hypnosis. 2002;50(1):17-32.
9. Kirsch I, Montgomery G, Sapirstein G. Hypnosis as an adjunct to cognitive-behavioral psychotherapy: a meta-analysis. J Consult Clin Psychol. 1995;63(2):214-220.
10. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulated but not somatosensory cortex. Science. 1997;277(5328):968-971.
11. De Pascalis V, Magurano MR, Bellusci A, Chen AC. Somatosensory event-related potential and autonomic activity to varying pain reduction cognitive strategies in hypnosis. Clin Neurophysiol. 2001;112(8):1475-1485.
12. Rainville P, Hofbauer RK, Bushnell MC, Duncan GH, Price DD. Hypnosis modulates activity in brain structures involved in the regulation of consciousness. J Cogn Neurosci. 2002;14(6):887-901.
13. Luebbert K, Dahme B, Hasenbring M. The effectiveness of relaxation training in reducing treatment-related symptoms and improving emotional adjustment in acute non-surgical cancer treatment: A meta-analytical review. Psycho-Oncol. 2001;10(6):490-502.
14. Spiegel D, Bloom J. Group therapy and hypnosis reduce metastatic breast carcinoma pain. Psychosom Med. 1983;45(4):333-339.
15. Syrjala KL, Cummings C, Donaldson G. Hypnosis or cognitive-behavioral training for the reduction of pain and nausea during cancer treatment: A controlled clinical trial. Pain. 1992;48(2):137-146.
16. Symptom management in cancer: pain, depression, and fatigue. NIH Consens Statement Online. 2002;19(4):1-29.
17. Kessler R, Patterson DR, Dane J. Hypnosis and relaxation with pain patients: evidence for effectiveness. Sem Pain Med. 2003;1(2):67-78.
18. Hendler CS, Redd WH. Fear of hypnosis: the role of labeling in patients’ acceptance of behavioral interventions. Behav Ther. 1986;17:2-13.
19. Arena JG, Blanchard EB. Biofeedback and relaxation therapy for chronic pain disorders. In: Gatchel RG, Turk DC, eds. Psychological Approaches to Pain Management. New York, NY: Guilford Press; 1996:179-230.
20. Borkovec TD, Sides JK. Critical procedural variables related to the psychological effects of progressive relaxation:a review. Behav Res. 1979;17:119-125.
21. Good M, Stanton-Hicks M, Grass JA, et al. Relief of postoperative pain with jaw relaxation, music, and their combination. Pain. 1999;81(1-2):163-172.
22. Good M. A comparison of the effects of jaw relaxation and music on postoperative pain. Nurs Res. 1995;44(1):52-57.
23. Syrjala KL, Chapko ME. Evidence for a biopsychosocial model of cancer treatment-related pain. Pain. 1995;61(1):69-79.
24. Fleming U. Relaxation therapy for far-advanced cancer. Practitioner. 1985;229(1403):471-475.
25. Turner JA, Chapman CR. Psychological interventions for chronic pain: a critical review. I. Relaxation training and biofeedback. Pain. 1982;12(1):1-21.
26. Pan CX, Morrison RS, Ness J, Fugh-Berman A, Leipzig RM. Complementary and alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life: a systematic review. J Pain Sympt Manag. 2000;20(5):374-387.
27. Sloman R. Relaxation and the relief of cancer pain. Nurs Clin North Am. 1995;30(4):697-709.
28. Graffam S, Johnson A. A comparison of two relaxation strategies for the relief of pain and its distress. J Pain Sympt Manag. 1987;2(4):229-231. 
29. American Pain Society: Guideline for the Management of Cancer Pain in Adults and Children. Glenview, IL: American Pain Society; 2005.
30. Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatr. 1982;4(1):33-47.
31. Redd WH, Montgomery GH, DuHamel KN. Behavioral interventions for cancer treatment side effects. J Natl Cancer Inst. 2001;93(11):810-823.
32. Munro S, Mount B. Music therapy in palliative care. Can Med Assoc J. 1978;119(9):1029-1034.
33. Beck SL. The therapeutic use of music for cancer-related pain. Oncol Nurs Forum. 1991;18(8):1327-1337.
34. Good M, Stanton-Hicks M, Grass JA, et al. Relaxation and music to reduce postsurgical pain. J Adv Nurs. 2001;33(2):208-215.
35. Good M, Picot BL, Salem SG, Chin CC, Picot SF, Lane D. Cultural differences in music chosen for pain relief. J Holistic Nurs. 2000;18(3):245-260.
36. O’Callaghan CC. Pain, music creativity and music therapy in palliative care. Am J Hosp Palliat Care. 1996;13(2):43-49.
37. Foley KM. The treatment of pain in the patient with cancer. CA Cancer J Clin. 1986;36(4):194-215.
38. Kerkvliet GJ. Music therapy may help control cancer pain. J Natl Cancer Inst. 1990;82(5):350-352.
39. Magill-Levreault L. Music therapy in pain and symptom management. J Palliat Care. 1993;9(4):42-48.
40. Hirsch S, Meckes D. Treatment of the whole person: Incorporating emergent perspectives in collaborative medicine, empowerment, and music therapy. J Psychosoc Oncol. 2000;18:65-77.
41. Brown CJ, Chen AC, Dworkin SF. Music in the control of human pain. Music Ther. 1989;8:47-60.
42. Hardy SG. Analgesia elicited by prefrontal stimulation. Brain Res. 1985;339(2):281-284.
43. Hirano PC, Laurent DD, Lorig K. Arthritis patient education studies, 1987-1991: a review of the literature. Patient Educ Couns. 1994;24(1):9-54.
44. Keefe FJ, Beaupre PM, Gil KM. Group therapy for patients with chronic pain. In: Gatchel RJ, Turk DC, eds. Psychological Approaches to Pain Management. New York, NY: Guilford Press; 1996:259-282.
45. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain. 1999;80(1-2):1-13.
46. Broome ME, Lillis PP, McGahee TW, Bates T. The use of distraction and imagery with children during painful procedures. Oncol Nurs Forum. 1992;19(3):499-502.
47. Broome ME, Rehwaldt M, Fogg L. Relationships between cognitive-behavioral techniques, temperament, observed distress, and pain reports in children and adolescents during lumbar puncture. J Ped Nurs. 1998;13(1):48-54.
48. McGrath PA, Holohan AL. Psychological interventions with children and adolescents: evidence for their effectiveness in treating chronic pain. Sem Pain Med. 2003;1(2):99-109.
49. McBeth J, Silman AJ, Macfarlane GJ. Association of widespread body pain with an increased risk of cancer and reduced cancer survival. Arthr Rheumat. 2003;48(6):1686-1692.
50. Liebeskind JC. Pain can kill. Pain. 1991;44(1):3-4.
51. Nelson DV, Kennington M, Novy DM. Psychological selection criteria for implantable spinal cord stimulators. Pain Forum. 1996;5:93-103.
52. Lebovits AH. Chronic pain: the multidisciplinary approach. Int Anesthesiol Clin. 1991;29(1):1-7.
53. Okifuji A. Interdisciplinary pain management with pain patients: evidence for its effectiveness. Sem Pain Med. 2003;1(2):110-119.
54. Hilgard ER, Hilgard JR. Hypnosis in the Relief of Pain. Los Altos, CA: William Kaufmann Inc; 1983.
55. Roth RS, deRosayro AM. Cancer pain. In: Block AR, Kremer EF, Fernendez E, eds. Handbook of Pain Syndromes-Biopsychosocial Perspectives. Mahwah, NJ: Lawrence Erlbaum Associates. 1999:499-527.