Current Psychiatry

Clinical psychiatry, like other medical specialties, eagerly awaits treatment breakthroughs. Despite the availability of many pharmacotherapies, even common illnesses such as diabetes, hypertension, and bipolar disorder cannot be cured.

Until investigators unravel a disease’s pathophysiology, treatments tend to remain symptomatic. Molecular genetics research ultimately may revolutionize the treatment of serious body and mind disorders, but how long must we wait?

As naïve medical students in the 1970s, my friends and I believed cures certainly would be discovered before the new millennium for cancer, arthritis, Alzheimer’s dementia, schizophrenia, diabetes, major depression, and anxiety. Although progress has been made, the pace of developing effective new treatments has been much slower than we expected.

As a researcher, I understand why brave new treatments are elusive. Even so, I keep hoping to see “disruptive” discoveries that will bring solutions to our patients’ suffering. Psychiatry needs a surge in pharmacologic innovations to advance from decades-old, serendipitously discovered, partially effective drugs to highly specific and effective biologic interventions.

Where will these desired breakthroughs come from? The National Institute of Mental Health (NIMH) does not have the budget to develop new drugs for psychiatry. The pharmaceutical industry—on which psychiatry is almost entirely dependent for new medications—seems to have stalled. Drug companies are complex, for-profit enterprises that employ tens of thousands of researchers to discover, test, and develop new drugs under an increasingly stifling web of regulatory controls.

Although drug companies have made progress against disease, the public has a rather negative view of them. Americans seem to appreciate that drug discovery is arduous, time-consuming, and costly, but they hold pharmaceutical companies to a different standard than other corporations. Practically everyone applauds when a high-tech or apparel company makes huge profits, yet when a pharmaceutical company does so there is outrage. Like it or not, creating new medications requires massive investment, and—other than taxes—profits are the only way to provide the resources for psychopharmacology research and development (R&D).

Perhaps the lull in new psychopharmacologics reflects escalating pressures on drug companies:

• Patent life is limited.
• Product development takes years and significant financial risk (only 1 in 10,000 new molecular entities makes it to market).
• Liability costs are skyrocketing because of unrealistic public expectations for new medications: high efficacy and no side effects.

Drug companies compound their problems by overspending on marketing and lobbying, and they often merge with one another to create behemoths that stifle innovation. No wonder we see so many reformulations of existing products and “me-too” drugs instead of high-risk, high-cost novel approaches to disease management.

What practical solutions could rejuvenate drug discovery? The answers are not simple, but consider these ideas:

• Extend by several years the patents on breakthrough (novel mechanism, first-in-class) drugs, and during this extension earmark a good chunk of profits for R&D.
• Limit punitive damages from lawsuits related to breakthrough medications to remove this impediment to innovation.
• Create incentives for drug companies to collaborate with NIMH researchers to translate neurobiologic and molecular genetics discoveries into innovative, biologically specific agents for psychiatric brain diseases.

Forging private-public collaborations may be a winning formula for all, with seriously afflicted patients as the ultimate beneficiaries of new drugs for their unmet needs.

Clinical psychiatry, like other medical specialties, eagerly awaits treatment breakthroughs. Despite the availability of many pharmacotherapies, even common illnesses such as diabetes, hypertension, and bipolar disorder cannot be cured.

Until investigators unravel a disease’s pathophysiology, treatments tend to remain symptomatic. Molecular genetics research ultimately may revolutionize the treatment of serious body and mind disorders, but how long must we wait?

As naïve medical students in the 1970s, my friends and I believed cures certainly would be discovered before the new millennium for cancer, arthritis, Alzheimer’s dementia, schizophrenia, diabetes, major depression, and anxiety. Although progress has been made, the pace of developing effective new treatments has been much slower than we expected.

As a researcher, I understand why brave new treatments are elusive. Even so, I keep hoping to see “disruptive” discoveries that will bring solutions to our patients’ suffering. Psychiatry needs a surge in pharmacologic innovations to advance from decades-old, serendipitously discovered, partially effective drugs to highly specific and effective biologic interventions.

Where will these desired breakthroughs come from? The National Institute of Mental Health (NIMH) does not have the budget to develop new drugs for psychiatry. The pharmaceutical industry—on which psychiatry is almost entirely dependent for new medications—seems to have stalled. Drug companies are complex, for-profit enterprises that employ tens of thousands of researchers to discover, test, and develop new drugs under an increasingly stifling web of regulatory controls.

Although drug companies have made progress against disease, the public has a rather negative view of them. Americans seem to appreciate that drug discovery is arduous, time-consuming, and costly, but they hold pharmaceutical companies to a different standard than other corporations. Practically everyone applauds when a high-tech or apparel company makes huge profits, yet when a pharmaceutical company does so there is outrage. Like it or not, creating new medications requires massive investment, and—other than taxes—profits are the only way to provide the resources for psychopharmacology research and development (R&D).

Perhaps the lull in new psychopharmacologics reflects escalating pressures on drug companies:

• Patent life is limited.
• Product development takes years and significant financial risk (only 1 in 10,000 new molecular entities makes it to market).
• Liability costs are skyrocketing because of unrealistic public expectations for new medications: high efficacy and no side effects.

Drug companies compound their problems by overspending on marketing and lobbying, and they often merge with one another to create behemoths that stifle innovation. No wonder we see so many reformulations of existing products and “me-too” drugs instead of high-risk, high-cost novel approaches to disease management.

What practical solutions could rejuvenate drug discovery? The answers are not simple, but consider these ideas:

• Extend by several years the patents on breakthrough (novel mechanism, first-in-class) drugs, and during this extension earmark a good chunk of profits for R&D.
• Limit punitive damages from lawsuits related to breakthrough medications to remove this impediment to innovation.
• Create incentives for drug companies to collaborate with NIMH researchers to translate neurobiologic and molecular genetics discoveries into innovative, biologically specific agents for psychiatric brain diseases.

Forging private-public collaborations may be a winning formula for all, with seriously afflicted patients as the ultimate beneficiaries of new drugs for their unmet needs.

Clinical psychiatry, like other medical specialties, eagerly awaits treatment breakthroughs. Despite the availability of many pharmacotherapies, even common illnesses such as diabetes, hypertension, and bipolar disorder cannot be cured.

Until investigators unravel a disease’s pathophysiology, treatments tend to remain symptomatic. Molecular genetics research ultimately may revolutionize the treatment of serious body and mind disorders, but how long must we wait?

As naïve medical students in the 1970s, my friends and I believed cures certainly would be discovered before the new millennium for cancer, arthritis, Alzheimer’s dementia, schizophrenia, diabetes, major depression, and anxiety. Although progress has been made, the pace of developing effective new treatments has been much slower than we expected.

As a researcher, I understand why brave new treatments are elusive. Even so, I keep hoping to see “disruptive” discoveries that will bring solutions to our patients’ suffering. Psychiatry needs a surge in pharmacologic innovations to advance from decades-old, serendipitously discovered, partially effective drugs to highly specific and effective biologic interventions.

Where will these desired breakthroughs come from? The National Institute of Mental Health (NIMH) does not have the budget to develop new drugs for psychiatry. The pharmaceutical industry—on which psychiatry is almost entirely dependent for new medications—seems to have stalled. Drug companies are complex, for-profit enterprises that employ tens of thousands of researchers to discover, test, and develop new drugs under an increasingly stifling web of regulatory controls.

Although drug companies have made progress against disease, the public has a rather negative view of them. Americans seem to appreciate that drug discovery is arduous, time-consuming, and costly, but they hold pharmaceutical companies to a different standard than other corporations. Practically everyone applauds when a high-tech or apparel company makes huge profits, yet when a pharmaceutical company does so there is outrage. Like it or not, creating new medications requires massive investment, and—other than taxes—profits are the only way to provide the resources for psychopharmacology research and development (R&D).

Perhaps the lull in new psychopharmacologics reflects escalating pressures on drug companies:

• Patent life is limited.
• Product development takes years and significant financial risk (only 1 in 10,000 new molecular entities makes it to market).
• Liability costs are skyrocketing because of unrealistic public expectations for new medications: high efficacy and no side effects.

Drug companies compound their problems by overspending on marketing and lobbying, and they often merge with one another to create behemoths that stifle innovation. No wonder we see so many reformulations of existing products and “me-too” drugs instead of high-risk, high-cost novel approaches to disease management.

What practical solutions could rejuvenate drug discovery? The answers are not simple, but consider these ideas:

• Extend by several years the patents on breakthrough (novel mechanism, first-in-class) drugs, and during this extension earmark a good chunk of profits for R&D.
• Limit punitive damages from lawsuits related to breakthrough medications to remove this impediment to innovation.
• Create incentives for drug companies to collaborate with NIMH researchers to translate neurobiologic and molecular genetics discoveries into innovative, biologically specific agents for psychiatric brain diseases.

Forging private-public collaborations may be a winning formula for all, with seriously afflicted patients as the ultimate beneficiaries of new drugs for their unmet needs.

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

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

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

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

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

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

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

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

Weight gain occurs with most antidepressants but is frequently overlooked, perhaps because clinicians are focused instead on metabolic effects of antipsychotics and mood stabilizers. Patients taking antidepressants often complain of weight gain, however, and many of the drugs’ FDA-approved package inserts acknowledge this effect.

Two-thirds of patients with major depression present with weight loss, and gaining weight can be associated with successful treatment. Weight gain is of concern—and likely to be drug-induced—if it exceeds the disease-induced weight loss and continues after depressive symptoms improve.

Weight may change early or late during antidepressant treatment, and gaining in the first weeks usually predicts future gains.¹ Patients who are overweight when treatment begins are especially at risk if given weight-promoting agents. This article:

• compares antidepressant effects on patient weight
• discusses mechanisms by which antidepressants may cause weight gain
• outlines a plan to prevent excess weight gain when patients start antidepressant therapy
• recommends diet, exercise, cognitive-behavioral therapy (CBT), and medications for overweight patients on long-term antidepressant treatment.

Weight-gain potential by class

Unlike antipsychotics, antidepressants have not been associated in clinical trials with causing metabolic syndrome and diabetes. Even so, certain antidepressants can cause clinically significant and perhaps more insidious weight gain when compared with some second-generation antipsychotics (SGAs). For example, SGAs on average may cause 2.3 kg/month weight gain during the first 12 weeks of treatment, and mirtazapine caused 3 kg weight gain in a recent 6-week trial.^2,3

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) may pose a greater weight-gain risk than newer antidepressants, but selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been clinically noted to cause weight gain over time (Table 1).^4-16

SSRIs. Weight gain associated with long-term SSRI use seems clinically apparent, but the evidence is preliminary.

Paroxetine seems to be the SSRI most likely to cause weight gain. A 26- to 32-week comparison trial by Fava et al¹⁰ showed that weight gain risk with SSRI therapy varies with the drug used. In this trial, 284 patients with major depressive disorder were randomly assigned to double-blind treatment with paroxetine, sertraline, or fluoxetine:

• More of those taking paroxetine gained >7% in weight from baseline, and their weight gain was statistically significant.
• Sertraline-treated patients had modest, nonsignificant weight gain.
• Fluoxetine-treated patients had modest, nonsignificant weight loss.

Using paroxetine with an antipsychotic can be especially problematic. Fukowi and Murai¹⁷ described 2 cases in which adding paroxetine to risperidone caused severe weight gain (13.5 kg to >14 kg) in 4 to 5 months.

Citalopram may cause a 1- to 1.5-kg weight gain over 1 year,⁸ whereas fluvoxamine has been shown not to affect weight in obese patients.¹¹ Citalopram (like TCAs) can cause carbohydrate craving and early weight gain.¹⁸ Escitalopram caused a modest (0.5 kg) weight gain in elderly patients during an 8-week trial.¹³

Initial weight loss followed by overall weight gain after 1 year of SSRI treatment is a common clinical finding that was not noted in initial acute SSRI drug trials. In a comparison of fluoxetine’s acute and long-term effects,¹⁹ 839 patients experiencing a major depressive episode were first treated with open-label fluoxetine, 20 mg/d. After 12 weeks, 395 patients who met criteria for remission were randomly assigned to continue with placebo or fluoxetine, 20 mg/d, for 14, 38, or 50 weeks.

In the acute phase, a small but statistically significant weight loss (mean 0.35 kg, P

• 1.1 kg at 26 weeks (P
• 2.2 kg at 38 weeks (P
• 3.1 kg at 50 weeks (P

The authors concluded that the weight gain—similar with fluoxetine or placebo—was probably associated with recovery from depression rather than fluoxetine treatment, although this was not a controlled variable in the study.

Table 1

Long-term effects of antidepressants on body weight, by class*

Causes of weight gain

Serotonin. Appetite is controlled by cultural, psychological, neurochemical, and metabolic factors. Among neurochemical factors, serotonin helps regulate appetite and is the neurotransmitter most often manipulated in depression treatment.

Serotonin receptor agonists such as fenfluramine and dexfenfluramine have an acute anorexigenic effect. In rats, 5-HT2c receptor agonism decreases eating behavior, and mice lacking 5-HT2c receptors are obese.²⁰ This may explain why SGAs or antidepressants that block 5-HT2c pose the greatest risk of weight gain.

SSRI or SNRI treatment might increase serotonin in the synaptic cleft, allowing 5-HT2c receptor down-regulation that is slower than—but similar in effect to—the acute 5-HT2c blockade caused by the SGAs.²¹ Weight gain from SSRI use reflects on these medications’ multiple serotonergic mechanisms. Serotonin appears to regulate carbohydrate intake and can increase food intake.²²

Nefazodone and trazodone block 5HT2a receptors potently, and the norepinephrine (nefazodone only) and serotonin reuptake pumps (both agents) less potently. Differences in their mechanism (nefazodone increases norepinephrine) and lack of 5-HT2c blockade might be responsible for their reported weight neutrality.

Tricyclics block differing ratios of norepinephrine and serotonin reuptake pumps, resulting in postsynaptic serotonergic and adrenergic receptor desensitization and, later, down-regulation. TCAs with higher serotonin reuptake blockade may increase weight through this desensitization.

TCAs also affect appetite by blocking histaminergic (H1) pathways. Drugs with high affinity for blocking H1 receptors have been associated with carbohydrate craving¹⁸ and low satiety rates that allow increased calorie intake. TCAs have antimuscarinic, antihistaminic, and alpha adrenoceptor-blocking actions, all of which may contribute to weight gain.

In theory, beta-3 adrenergic receptors in adipose tissue may play a role in weight control by converting fat into heat and energy, especially in response to norepinephrine. TCAs or SNRIs that favor a noradrenergic profile may promote weight loss or neutrality. The relatively weight-neutral selegiline patch, which avoids first-pass metabolism and active adverse metabolites, also may use this mechanism.²³

Mirtazapine blocks presynaptic alpha-2 and postsynaptic 5HT2a, 5HT2c, and 5HT₃ serotonin receptors as well as H1 histamine receptors. Both 5HT2c and H1 blockade result in weight gain, the drug’s most apparent adverse effect. This mechanism is similar to that of the SGA olanzapine.

TNF-α. Obese persons have increased plasma levels of TNF-α and its soluble receptor (sTNF-R p75), which may induce insulin resistance. Activation of the TNF-α system, such as by amitriptyline or mirtazapine, may promote weight gain.²⁴

Preventing weight gain

Early intervention is key to preventing drug-related weight gain and treating obesity. Provide informed consent and psychoeducation when prescribing antidepressants. In patients at metabolic risk, consider using weight-neutral or weight-loss agents (Table 2),^4-16 and monitor for weight gain (Table 3). At-risk patients have:

• abdominal obesity (waist circumference >40 inches [102 cm] in men, >35 inches [88 cm] in women, or waist-to-hip ratio >0.9 in women and >1.0 in men)
• hyperlipidemia
• elevated body mass index (BMI [overweight=BMI 25 to 30 kg/m², obesity=BMI >30 kg/m²])
• hypertension
• diabetes mellitus or impaired glucose tolerance
• history of stroke or cardiovascular disease
• family history of obesity, hypertension, diabetes, or hyperlipidemia.

Use SGA guidelines? Consider following modified American Diabetes Association guidelines for metabolic monitoring of patients treated with SGAs.²⁵ We suggest that you follow SGA guidelines as a default when using mirtazapine—which is pharmacodynamically the most similar to SGAs—and TCAs. For patients taking other antidepressants, we recommend that you:

• measure blood pressure and weight, and calculate BMI often
• instruct patients to weigh themselves at home at least weekly in the morning and to report gains >5 lbs.

An overall 10-lb weight gain is clinically significant in most patients and calls for a management plan. Abdominal girth often increases as part of metabolic syndrome. If you choose to measure this variable and are uncomfortable reaching around patients while measuring, allow patients to apply the tape measure themselves.

Lab tests. Obtain fasting glucose and lipid levels at baseline for most patients and then quarterly in those with initial weight gain, medical comorbidities, or family history of hypertension, hypercholesterolemia, or diabetes. Many clinicians also screen for hypothyroidism and anemia, and these tests may be added. For patients without metabolic risk factors taking SSRIs and SNRIs, start quarterly draws if weight increases rapidly by >5 lbs or if BMI approaches ≥30 kg/m². Tracking fasting triglycerides can serve as a sentinel for metabolic syndrome, which sometimes occurs before substantial weight gain or hyperglycemia.

Table 2

Antidepressants’ relative long-term effects on body weight

Table 3

Using antidepressants in patients at metabolic risk for weight gain

Dietary measures

If weight gain has occurred, a safe initial goal for patients is to lose 0.5% to 1% initial body weight per week—or 5% to 10% of weight across several months. Diet and exercise produce maximal benefit but require commitment and motivation, which are often difficult or impossible for depressed patients. Encouraging the patient’s efforts is worthwhile; if intervention is postponed until remission is achieved, weight gain may be substantially higher and more difficult to treat.

Cutting fat and calories. The first step in losing weight is to restrict high-fat and high-calorie foods and eat smaller portions. If this fails, then switch the patient to a low- or very-low-calorie diet, which provides a quick initial weight loss. This can motivate the patient but should be tried only under a physician’s supervision.

Many patients benefit from structured commercial weight-loss programs, but the likelihood of regaining the weight is high if stopped. These programs typically recommend 1,200 kcal/day for women and 1,800 kcal/day for men, with 55% of calories from carbohydrates, about 25% to 35% from protein, and 10% to 25% from fat.

In a study of 100 patients, those on 2 liquid meal replacements per day plus snacks and 1 low-fat meal (approximately 1,200 to 1,500 kcal/day) lost considerable weight in the first 3 months but regained some weight later. Many maintained weight loss on 1 liquid meal replacement per day plus snacks and 2 low-fat meals.²⁶

Low- and very-low-calorie diets are indicated for patients with BMI >35 kg/m²:

• in whom conservative treatment (a portion-controlled, low-fat diet) has failed
• and who are willing to maintain at least 1 year of treatment and major lifestyle changes.

A low-calorie diet provides ≥1,000 kcal/day; very low-calorie diets may provide ≤800 kcal/day and rely mostly on liquid meal replacements. This semi-starvation can produce fatigue, weakness, lightheadedness, and changes in vital signs, including blood pressure, heart rate, and respiratory rate. For this reason, extreme diets require a team approach with the primary care clinician and a dietitian.

Among mentally healthy patients following very-low-calorie diets in clinical trials, 90% lose ≥10 kg and 50% lose ≥20 kg in the first 4 to 6 months.²⁷ Most weight loss occurs in the first 12 to 16 weeks, after which an ad libitum low-fat, high-fiber diet can be used.

Exercise has physiologic and psychological benefits, including inhibiting food intake and promoting a sense of self-control. Physical exercise increases insulin sensitivity and reduces the risk of secondary medical problems, such as heart disease. Walking ≥40 minutes daily produces maximal benefit, but walking even 30 minutes 3 times a week can help maintain weight.

CBT. Eating habits can be changed through identifying lifestyle behaviors to be modified, setting goals, modifying triggers of excessive eating, and reinforcing desired behavior with CBT. Gradual but consistent behavior change leads to healthier eating habits, exercise, and weight loss. Behavior modification alone can generate a weight loss of 0.5 kg to 0.7 kg per week.²⁸

A study of 6 schizophrenia patients (mean age 37) examined CBT effects on weight gain associated with clozapine (n=4) or olanzapine (n=2). Mean BMI decreased from 29.6 kg/m² to 25.1 kg/m² after 7 to 9 sessions of individual CBT, followed by 16 biweekly group sessions that focused on weight reduction and weight maintenance. A dietician provided detailed counseling.²⁸

Using medications for weight loss

Switching. To avoid polypharmacy, consider switching the patient to a weight-neutral or weight-losing antidepressant, such as bupropion. Keep in mind when switching medications, however, that the next agent with less weight-gain potential might not deliver comparable antidepressant efficacy.

Antiobesity drugs. Short of switching, an antiobesity drug (Table 4)^29-31 or off-label intervention (Table 5)^32-36 may be warranted. Antiobesity drugs should not be used as primary therapy for obesity. Their use may be warranted, however, for psychiatric patients who:

• are unable to fully participate in diet and exercise programs because of symptoms (such as cognitive impairment or severe negative symptoms)
• lack social support (such as reflected by financial problems, homelessness, or poor compliance with treatment recommendations).

Generally, we reserve antiobesity drugs for patients with BMI >30 kg/m² (or >27 kg/m² in patients with diabetes, hyperlipidemia, or cardiovascular disease). Before adding these agents to a psychotropic regimen, however, review the relative risks and benefits with the patient and his or her primary care physician.

The goal of pharmacotherapy is for the patient to lose 5% to 10% of baseline weight in 3 to 6 months. Failure to achieve this goal is an indication to stop the medication. A plateau in weight loss after 6 to 9 months is expected and is not cause for discontinuation. If successful, drug treatment may be continued indefinitely, and both physician and patient must understand the intention to treat long-term. Most patients regain weight upon discontinuation.

Table 4

Medications indicated for treating obesity

Table 5

Medications used ‘off label’ for treating obesity

Related resources

• Centers for Disease Control and Prevention. Overweight and obesity: contributing factors. www.cdc.gov/nccdphp/dnpa/obesity/contributing_factors.htm.
• Mathur R. What causes obesity? www.medicinenet.com/obesity_weight_loss/page2.htm.

Drug brand names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Metformin • Glucophage
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Nefazodone • Serzone
• Nizatidine • Axid
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Paroxetine • Paxil
• Phenelzine • Nardil
• Selegiline (transdermal) • EMSAM
• Sertraline • Zoloft
• Sibutramine • Meridian
• Topiramate • Topamax
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

Dr. Schwartz has received grants from or served as a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Jazz Pharmaceuticals, Pfizer Inc., and Wyeth.

Other authors report no financial relationship with any companies whose products are mentioned in this article or with manufacturers of competing products.

Weight gain occurs with most antidepressants but is frequently overlooked, perhaps because clinicians are focused instead on metabolic effects of antipsychotics and mood stabilizers. Patients taking antidepressants often complain of weight gain, however, and many of the drugs’ FDA-approved package inserts acknowledge this effect.

Two-thirds of patients with major depression present with weight loss, and gaining weight can be associated with successful treatment. Weight gain is of concern—and likely to be drug-induced—if it exceeds the disease-induced weight loss and continues after depressive symptoms improve.

Weight may change early or late during antidepressant treatment, and gaining in the first weeks usually predicts future gains.¹ Patients who are overweight when treatment begins are especially at risk if given weight-promoting agents. This article:

• compares antidepressant effects on patient weight
• discusses mechanisms by which antidepressants may cause weight gain
• outlines a plan to prevent excess weight gain when patients start antidepressant therapy
• recommends diet, exercise, cognitive-behavioral therapy (CBT), and medications for overweight patients on long-term antidepressant treatment.

Weight-gain potential by class

Unlike antipsychotics, antidepressants have not been associated in clinical trials with causing metabolic syndrome and diabetes. Even so, certain antidepressants can cause clinically significant and perhaps more insidious weight gain when compared with some second-generation antipsychotics (SGAs). For example, SGAs on average may cause 2.3 kg/month weight gain during the first 12 weeks of treatment, and mirtazapine caused 3 kg weight gain in a recent 6-week trial.^2,3

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) may pose a greater weight-gain risk than newer antidepressants, but selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been clinically noted to cause weight gain over time (Table 1).^4-16

SSRIs. Weight gain associated with long-term SSRI use seems clinically apparent, but the evidence is preliminary.

Paroxetine seems to be the SSRI most likely to cause weight gain. A 26- to 32-week comparison trial by Fava et al¹⁰ showed that weight gain risk with SSRI therapy varies with the drug used. In this trial, 284 patients with major depressive disorder were randomly assigned to double-blind treatment with paroxetine, sertraline, or fluoxetine:

• More of those taking paroxetine gained >7% in weight from baseline, and their weight gain was statistically significant.
• Sertraline-treated patients had modest, nonsignificant weight gain.
• Fluoxetine-treated patients had modest, nonsignificant weight loss.

Using paroxetine with an antipsychotic can be especially problematic. Fukowi and Murai¹⁷ described 2 cases in which adding paroxetine to risperidone caused severe weight gain (13.5 kg to >14 kg) in 4 to 5 months.

Citalopram may cause a 1- to 1.5-kg weight gain over 1 year,⁸ whereas fluvoxamine has been shown not to affect weight in obese patients.¹¹ Citalopram (like TCAs) can cause carbohydrate craving and early weight gain.¹⁸ Escitalopram caused a modest (0.5 kg) weight gain in elderly patients during an 8-week trial.¹³

Initial weight loss followed by overall weight gain after 1 year of SSRI treatment is a common clinical finding that was not noted in initial acute SSRI drug trials. In a comparison of fluoxetine’s acute and long-term effects,¹⁹ 839 patients experiencing a major depressive episode were first treated with open-label fluoxetine, 20 mg/d. After 12 weeks, 395 patients who met criteria for remission were randomly assigned to continue with placebo or fluoxetine, 20 mg/d, for 14, 38, or 50 weeks.

In the acute phase, a small but statistically significant weight loss (mean 0.35 kg, P

• 1.1 kg at 26 weeks (P
• 2.2 kg at 38 weeks (P
• 3.1 kg at 50 weeks (P

The authors concluded that the weight gain—similar with fluoxetine or placebo—was probably associated with recovery from depression rather than fluoxetine treatment, although this was not a controlled variable in the study.

Table 1

Long-term effects of antidepressants on body weight, by class*

Causes of weight gain

Serotonin. Appetite is controlled by cultural, psychological, neurochemical, and metabolic factors. Among neurochemical factors, serotonin helps regulate appetite and is the neurotransmitter most often manipulated in depression treatment.

Serotonin receptor agonists such as fenfluramine and dexfenfluramine have an acute anorexigenic effect. In rats, 5-HT2c receptor agonism decreases eating behavior, and mice lacking 5-HT2c receptors are obese.²⁰ This may explain why SGAs or antidepressants that block 5-HT2c pose the greatest risk of weight gain.

SSRI or SNRI treatment might increase serotonin in the synaptic cleft, allowing 5-HT2c receptor down-regulation that is slower than—but similar in effect to—the acute 5-HT2c blockade caused by the SGAs.²¹ Weight gain from SSRI use reflects on these medications’ multiple serotonergic mechanisms. Serotonin appears to regulate carbohydrate intake and can increase food intake.²²

Nefazodone and trazodone block 5HT2a receptors potently, and the norepinephrine (nefazodone only) and serotonin reuptake pumps (both agents) less potently. Differences in their mechanism (nefazodone increases norepinephrine) and lack of 5-HT2c blockade might be responsible for their reported weight neutrality.

Tricyclics block differing ratios of norepinephrine and serotonin reuptake pumps, resulting in postsynaptic serotonergic and adrenergic receptor desensitization and, later, down-regulation. TCAs with higher serotonin reuptake blockade may increase weight through this desensitization.

TCAs also affect appetite by blocking histaminergic (H1) pathways. Drugs with high affinity for blocking H1 receptors have been associated with carbohydrate craving¹⁸ and low satiety rates that allow increased calorie intake. TCAs have antimuscarinic, antihistaminic, and alpha adrenoceptor-blocking actions, all of which may contribute to weight gain.

In theory, beta-3 adrenergic receptors in adipose tissue may play a role in weight control by converting fat into heat and energy, especially in response to norepinephrine. TCAs or SNRIs that favor a noradrenergic profile may promote weight loss or neutrality. The relatively weight-neutral selegiline patch, which avoids first-pass metabolism and active adverse metabolites, also may use this mechanism.²³

Mirtazapine blocks presynaptic alpha-2 and postsynaptic 5HT2a, 5HT2c, and 5HT₃ serotonin receptors as well as H1 histamine receptors. Both 5HT2c and H1 blockade result in weight gain, the drug’s most apparent adverse effect. This mechanism is similar to that of the SGA olanzapine.

TNF-α. Obese persons have increased plasma levels of TNF-α and its soluble receptor (sTNF-R p75), which may induce insulin resistance. Activation of the TNF-α system, such as by amitriptyline or mirtazapine, may promote weight gain.²⁴

Preventing weight gain

Early intervention is key to preventing drug-related weight gain and treating obesity. Provide informed consent and psychoeducation when prescribing antidepressants. In patients at metabolic risk, consider using weight-neutral or weight-loss agents (Table 2),^4-16 and monitor for weight gain (Table 3). At-risk patients have:

• abdominal obesity (waist circumference >40 inches [102 cm] in men, >35 inches [88 cm] in women, or waist-to-hip ratio >0.9 in women and >1.0 in men)
• hyperlipidemia
• elevated body mass index (BMI [overweight=BMI 25 to 30 kg/m², obesity=BMI >30 kg/m²])
• hypertension
• diabetes mellitus or impaired glucose tolerance
• history of stroke or cardiovascular disease
• family history of obesity, hypertension, diabetes, or hyperlipidemia.

Use SGA guidelines? Consider following modified American Diabetes Association guidelines for metabolic monitoring of patients treated with SGAs.²⁵ We suggest that you follow SGA guidelines as a default when using mirtazapine—which is pharmacodynamically the most similar to SGAs—and TCAs. For patients taking other antidepressants, we recommend that you:

• measure blood pressure and weight, and calculate BMI often
• instruct patients to weigh themselves at home at least weekly in the morning and to report gains >5 lbs.

An overall 10-lb weight gain is clinically significant in most patients and calls for a management plan. Abdominal girth often increases as part of metabolic syndrome. If you choose to measure this variable and are uncomfortable reaching around patients while measuring, allow patients to apply the tape measure themselves.

Lab tests. Obtain fasting glucose and lipid levels at baseline for most patients and then quarterly in those with initial weight gain, medical comorbidities, or family history of hypertension, hypercholesterolemia, or diabetes. Many clinicians also screen for hypothyroidism and anemia, and these tests may be added. For patients without metabolic risk factors taking SSRIs and SNRIs, start quarterly draws if weight increases rapidly by >5 lbs or if BMI approaches ≥30 kg/m². Tracking fasting triglycerides can serve as a sentinel for metabolic syndrome, which sometimes occurs before substantial weight gain or hyperglycemia.

Table 2

Antidepressants’ relative long-term effects on body weight

Table 3

Using antidepressants in patients at metabolic risk for weight gain

Dietary measures

If weight gain has occurred, a safe initial goal for patients is to lose 0.5% to 1% initial body weight per week—or 5% to 10% of weight across several months. Diet and exercise produce maximal benefit but require commitment and motivation, which are often difficult or impossible for depressed patients. Encouraging the patient’s efforts is worthwhile; if intervention is postponed until remission is achieved, weight gain may be substantially higher and more difficult to treat.

Cutting fat and calories. The first step in losing weight is to restrict high-fat and high-calorie foods and eat smaller portions. If this fails, then switch the patient to a low- or very-low-calorie diet, which provides a quick initial weight loss. This can motivate the patient but should be tried only under a physician’s supervision.

Many patients benefit from structured commercial weight-loss programs, but the likelihood of regaining the weight is high if stopped. These programs typically recommend 1,200 kcal/day for women and 1,800 kcal/day for men, with 55% of calories from carbohydrates, about 25% to 35% from protein, and 10% to 25% from fat.

In a study of 100 patients, those on 2 liquid meal replacements per day plus snacks and 1 low-fat meal (approximately 1,200 to 1,500 kcal/day) lost considerable weight in the first 3 months but regained some weight later. Many maintained weight loss on 1 liquid meal replacement per day plus snacks and 2 low-fat meals.²⁶

Low- and very-low-calorie diets are indicated for patients with BMI >35 kg/m²:

• in whom conservative treatment (a portion-controlled, low-fat diet) has failed
• and who are willing to maintain at least 1 year of treatment and major lifestyle changes.

A low-calorie diet provides ≥1,000 kcal/day; very low-calorie diets may provide ≤800 kcal/day and rely mostly on liquid meal replacements. This semi-starvation can produce fatigue, weakness, lightheadedness, and changes in vital signs, including blood pressure, heart rate, and respiratory rate. For this reason, extreme diets require a team approach with the primary care clinician and a dietitian.

Among mentally healthy patients following very-low-calorie diets in clinical trials, 90% lose ≥10 kg and 50% lose ≥20 kg in the first 4 to 6 months.²⁷ Most weight loss occurs in the first 12 to 16 weeks, after which an ad libitum low-fat, high-fiber diet can be used.

Exercise has physiologic and psychological benefits, including inhibiting food intake and promoting a sense of self-control. Physical exercise increases insulin sensitivity and reduces the risk of secondary medical problems, such as heart disease. Walking ≥40 minutes daily produces maximal benefit, but walking even 30 minutes 3 times a week can help maintain weight.

CBT. Eating habits can be changed through identifying lifestyle behaviors to be modified, setting goals, modifying triggers of excessive eating, and reinforcing desired behavior with CBT. Gradual but consistent behavior change leads to healthier eating habits, exercise, and weight loss. Behavior modification alone can generate a weight loss of 0.5 kg to 0.7 kg per week.²⁸

A study of 6 schizophrenia patients (mean age 37) examined CBT effects on weight gain associated with clozapine (n=4) or olanzapine (n=2). Mean BMI decreased from 29.6 kg/m² to 25.1 kg/m² after 7 to 9 sessions of individual CBT, followed by 16 biweekly group sessions that focused on weight reduction and weight maintenance. A dietician provided detailed counseling.²⁸

Using medications for weight loss

Switching. To avoid polypharmacy, consider switching the patient to a weight-neutral or weight-losing antidepressant, such as bupropion. Keep in mind when switching medications, however, that the next agent with less weight-gain potential might not deliver comparable antidepressant efficacy.

Antiobesity drugs. Short of switching, an antiobesity drug (Table 4)^29-31 or off-label intervention (Table 5)^32-36 may be warranted. Antiobesity drugs should not be used as primary therapy for obesity. Their use may be warranted, however, for psychiatric patients who:

• are unable to fully participate in diet and exercise programs because of symptoms (such as cognitive impairment or severe negative symptoms)
• lack social support (such as reflected by financial problems, homelessness, or poor compliance with treatment recommendations).

Generally, we reserve antiobesity drugs for patients with BMI >30 kg/m² (or >27 kg/m² in patients with diabetes, hyperlipidemia, or cardiovascular disease). Before adding these agents to a psychotropic regimen, however, review the relative risks and benefits with the patient and his or her primary care physician.

The goal of pharmacotherapy is for the patient to lose 5% to 10% of baseline weight in 3 to 6 months. Failure to achieve this goal is an indication to stop the medication. A plateau in weight loss after 6 to 9 months is expected and is not cause for discontinuation. If successful, drug treatment may be continued indefinitely, and both physician and patient must understand the intention to treat long-term. Most patients regain weight upon discontinuation.

Table 4

Medications indicated for treating obesity

Table 5

Medications used ‘off label’ for treating obesity

Related resources

• Centers for Disease Control and Prevention. Overweight and obesity: contributing factors. www.cdc.gov/nccdphp/dnpa/obesity/contributing_factors.htm.
• Mathur R. What causes obesity? www.medicinenet.com/obesity_weight_loss/page2.htm.

Drug brand names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Metformin • Glucophage
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Nefazodone • Serzone
• Nizatidine • Axid
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Paroxetine • Paxil
• Phenelzine • Nardil
• Selegiline (transdermal) • EMSAM
• Sertraline • Zoloft
• Sibutramine • Meridian
• Topiramate • Topamax
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

Dr. Schwartz has received grants from or served as a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Jazz Pharmaceuticals, Pfizer Inc., and Wyeth.

Other authors report no financial relationship with any companies whose products are mentioned in this article or with manufacturers of competing products.

Weight gain occurs with most antidepressants but is frequently overlooked, perhaps because clinicians are focused instead on metabolic effects of antipsychotics and mood stabilizers. Patients taking antidepressants often complain of weight gain, however, and many of the drugs’ FDA-approved package inserts acknowledge this effect.

Two-thirds of patients with major depression present with weight loss, and gaining weight can be associated with successful treatment. Weight gain is of concern—and likely to be drug-induced—if it exceeds the disease-induced weight loss and continues after depressive symptoms improve.

Weight may change early or late during antidepressant treatment, and gaining in the first weeks usually predicts future gains.¹ Patients who are overweight when treatment begins are especially at risk if given weight-promoting agents. This article:

• compares antidepressant effects on patient weight
• discusses mechanisms by which antidepressants may cause weight gain
• outlines a plan to prevent excess weight gain when patients start antidepressant therapy
• recommends diet, exercise, cognitive-behavioral therapy (CBT), and medications for overweight patients on long-term antidepressant treatment.

Weight-gain potential by class

Unlike antipsychotics, antidepressants have not been associated in clinical trials with causing metabolic syndrome and diabetes. Even so, certain antidepressants can cause clinically significant and perhaps more insidious weight gain when compared with some second-generation antipsychotics (SGAs). For example, SGAs on average may cause 2.3 kg/month weight gain during the first 12 weeks of treatment, and mirtazapine caused 3 kg weight gain in a recent 6-week trial.^2,3

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) may pose a greater weight-gain risk than newer antidepressants, but selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been clinically noted to cause weight gain over time (Table 1).^4-16

SSRIs. Weight gain associated with long-term SSRI use seems clinically apparent, but the evidence is preliminary.

Paroxetine seems to be the SSRI most likely to cause weight gain. A 26- to 32-week comparison trial by Fava et al¹⁰ showed that weight gain risk with SSRI therapy varies with the drug used. In this trial, 284 patients with major depressive disorder were randomly assigned to double-blind treatment with paroxetine, sertraline, or fluoxetine:

• More of those taking paroxetine gained >7% in weight from baseline, and their weight gain was statistically significant.
• Sertraline-treated patients had modest, nonsignificant weight gain.
• Fluoxetine-treated patients had modest, nonsignificant weight loss.

Using paroxetine with an antipsychotic can be especially problematic. Fukowi and Murai¹⁷ described 2 cases in which adding paroxetine to risperidone caused severe weight gain (13.5 kg to >14 kg) in 4 to 5 months.

Citalopram may cause a 1- to 1.5-kg weight gain over 1 year,⁸ whereas fluvoxamine has been shown not to affect weight in obese patients.¹¹ Citalopram (like TCAs) can cause carbohydrate craving and early weight gain.¹⁸ Escitalopram caused a modest (0.5 kg) weight gain in elderly patients during an 8-week trial.¹³

Initial weight loss followed by overall weight gain after 1 year of SSRI treatment is a common clinical finding that was not noted in initial acute SSRI drug trials. In a comparison of fluoxetine’s acute and long-term effects,¹⁹ 839 patients experiencing a major depressive episode were first treated with open-label fluoxetine, 20 mg/d. After 12 weeks, 395 patients who met criteria for remission were randomly assigned to continue with placebo or fluoxetine, 20 mg/d, for 14, 38, or 50 weeks.

In the acute phase, a small but statistically significant weight loss (mean 0.35 kg, P

• 1.1 kg at 26 weeks (P
• 2.2 kg at 38 weeks (P
• 3.1 kg at 50 weeks (P

The authors concluded that the weight gain—similar with fluoxetine or placebo—was probably associated with recovery from depression rather than fluoxetine treatment, although this was not a controlled variable in the study.

Table 1

Long-term effects of antidepressants on body weight, by class*

Causes of weight gain

Serotonin. Appetite is controlled by cultural, psychological, neurochemical, and metabolic factors. Among neurochemical factors, serotonin helps regulate appetite and is the neurotransmitter most often manipulated in depression treatment.

Serotonin receptor agonists such as fenfluramine and dexfenfluramine have an acute anorexigenic effect. In rats, 5-HT2c receptor agonism decreases eating behavior, and mice lacking 5-HT2c receptors are obese.²⁰ This may explain why SGAs or antidepressants that block 5-HT2c pose the greatest risk of weight gain.

SSRI or SNRI treatment might increase serotonin in the synaptic cleft, allowing 5-HT2c receptor down-regulation that is slower than—but similar in effect to—the acute 5-HT2c blockade caused by the SGAs.²¹ Weight gain from SSRI use reflects on these medications’ multiple serotonergic mechanisms. Serotonin appears to regulate carbohydrate intake and can increase food intake.²²

Nefazodone and trazodone block 5HT2a receptors potently, and the norepinephrine (nefazodone only) and serotonin reuptake pumps (both agents) less potently. Differences in their mechanism (nefazodone increases norepinephrine) and lack of 5-HT2c blockade might be responsible for their reported weight neutrality.

Tricyclics block differing ratios of norepinephrine and serotonin reuptake pumps, resulting in postsynaptic serotonergic and adrenergic receptor desensitization and, later, down-regulation. TCAs with higher serotonin reuptake blockade may increase weight through this desensitization.

TCAs also affect appetite by blocking histaminergic (H1) pathways. Drugs with high affinity for blocking H1 receptors have been associated with carbohydrate craving¹⁸ and low satiety rates that allow increased calorie intake. TCAs have antimuscarinic, antihistaminic, and alpha adrenoceptor-blocking actions, all of which may contribute to weight gain.

In theory, beta-3 adrenergic receptors in adipose tissue may play a role in weight control by converting fat into heat and energy, especially in response to norepinephrine. TCAs or SNRIs that favor a noradrenergic profile may promote weight loss or neutrality. The relatively weight-neutral selegiline patch, which avoids first-pass metabolism and active adverse metabolites, also may use this mechanism.²³

Mirtazapine blocks presynaptic alpha-2 and postsynaptic 5HT2a, 5HT2c, and 5HT₃ serotonin receptors as well as H1 histamine receptors. Both 5HT2c and H1 blockade result in weight gain, the drug’s most apparent adverse effect. This mechanism is similar to that of the SGA olanzapine.

TNF-α. Obese persons have increased plasma levels of TNF-α and its soluble receptor (sTNF-R p75), which may induce insulin resistance. Activation of the TNF-α system, such as by amitriptyline or mirtazapine, may promote weight gain.²⁴

Preventing weight gain

Early intervention is key to preventing drug-related weight gain and treating obesity. Provide informed consent and psychoeducation when prescribing antidepressants. In patients at metabolic risk, consider using weight-neutral or weight-loss agents (Table 2),^4-16 and monitor for weight gain (Table 3). At-risk patients have:

• abdominal obesity (waist circumference >40 inches [102 cm] in men, >35 inches [88 cm] in women, or waist-to-hip ratio >0.9 in women and >1.0 in men)
• hyperlipidemia
• elevated body mass index (BMI [overweight=BMI 25 to 30 kg/m², obesity=BMI >30 kg/m²])
• hypertension
• diabetes mellitus or impaired glucose tolerance
• history of stroke or cardiovascular disease
• family history of obesity, hypertension, diabetes, or hyperlipidemia.

Use SGA guidelines? Consider following modified American Diabetes Association guidelines for metabolic monitoring of patients treated with SGAs.²⁵ We suggest that you follow SGA guidelines as a default when using mirtazapine—which is pharmacodynamically the most similar to SGAs—and TCAs. For patients taking other antidepressants, we recommend that you:

• measure blood pressure and weight, and calculate BMI often
• instruct patients to weigh themselves at home at least weekly in the morning and to report gains >5 lbs.

An overall 10-lb weight gain is clinically significant in most patients and calls for a management plan. Abdominal girth often increases as part of metabolic syndrome. If you choose to measure this variable and are uncomfortable reaching around patients while measuring, allow patients to apply the tape measure themselves.

Lab tests. Obtain fasting glucose and lipid levels at baseline for most patients and then quarterly in those with initial weight gain, medical comorbidities, or family history of hypertension, hypercholesterolemia, or diabetes. Many clinicians also screen for hypothyroidism and anemia, and these tests may be added. For patients without metabolic risk factors taking SSRIs and SNRIs, start quarterly draws if weight increases rapidly by >5 lbs or if BMI approaches ≥30 kg/m². Tracking fasting triglycerides can serve as a sentinel for metabolic syndrome, which sometimes occurs before substantial weight gain or hyperglycemia.

Table 2

Antidepressants’ relative long-term effects on body weight

Table 3

Using antidepressants in patients at metabolic risk for weight gain

Dietary measures

If weight gain has occurred, a safe initial goal for patients is to lose 0.5% to 1% initial body weight per week—or 5% to 10% of weight across several months. Diet and exercise produce maximal benefit but require commitment and motivation, which are often difficult or impossible for depressed patients. Encouraging the patient’s efforts is worthwhile; if intervention is postponed until remission is achieved, weight gain may be substantially higher and more difficult to treat.

Cutting fat and calories. The first step in losing weight is to restrict high-fat and high-calorie foods and eat smaller portions. If this fails, then switch the patient to a low- or very-low-calorie diet, which provides a quick initial weight loss. This can motivate the patient but should be tried only under a physician’s supervision.

Many patients benefit from structured commercial weight-loss programs, but the likelihood of regaining the weight is high if stopped. These programs typically recommend 1,200 kcal/day for women and 1,800 kcal/day for men, with 55% of calories from carbohydrates, about 25% to 35% from protein, and 10% to 25% from fat.

In a study of 100 patients, those on 2 liquid meal replacements per day plus snacks and 1 low-fat meal (approximately 1,200 to 1,500 kcal/day) lost considerable weight in the first 3 months but regained some weight later. Many maintained weight loss on 1 liquid meal replacement per day plus snacks and 2 low-fat meals.²⁶

Low- and very-low-calorie diets are indicated for patients with BMI >35 kg/m²:

• in whom conservative treatment (a portion-controlled, low-fat diet) has failed
• and who are willing to maintain at least 1 year of treatment and major lifestyle changes.

A low-calorie diet provides ≥1,000 kcal/day; very low-calorie diets may provide ≤800 kcal/day and rely mostly on liquid meal replacements. This semi-starvation can produce fatigue, weakness, lightheadedness, and changes in vital signs, including blood pressure, heart rate, and respiratory rate. For this reason, extreme diets require a team approach with the primary care clinician and a dietitian.

Among mentally healthy patients following very-low-calorie diets in clinical trials, 90% lose ≥10 kg and 50% lose ≥20 kg in the first 4 to 6 months.²⁷ Most weight loss occurs in the first 12 to 16 weeks, after which an ad libitum low-fat, high-fiber diet can be used.

Exercise has physiologic and psychological benefits, including inhibiting food intake and promoting a sense of self-control. Physical exercise increases insulin sensitivity and reduces the risk of secondary medical problems, such as heart disease. Walking ≥40 minutes daily produces maximal benefit, but walking even 30 minutes 3 times a week can help maintain weight.

CBT. Eating habits can be changed through identifying lifestyle behaviors to be modified, setting goals, modifying triggers of excessive eating, and reinforcing desired behavior with CBT. Gradual but consistent behavior change leads to healthier eating habits, exercise, and weight loss. Behavior modification alone can generate a weight loss of 0.5 kg to 0.7 kg per week.²⁸

A study of 6 schizophrenia patients (mean age 37) examined CBT effects on weight gain associated with clozapine (n=4) or olanzapine (n=2). Mean BMI decreased from 29.6 kg/m² to 25.1 kg/m² after 7 to 9 sessions of individual CBT, followed by 16 biweekly group sessions that focused on weight reduction and weight maintenance. A dietician provided detailed counseling.²⁸

Using medications for weight loss

Switching. To avoid polypharmacy, consider switching the patient to a weight-neutral or weight-losing antidepressant, such as bupropion. Keep in mind when switching medications, however, that the next agent with less weight-gain potential might not deliver comparable antidepressant efficacy.

Antiobesity drugs. Short of switching, an antiobesity drug (Table 4)^29-31 or off-label intervention (Table 5)^32-36 may be warranted. Antiobesity drugs should not be used as primary therapy for obesity. Their use may be warranted, however, for psychiatric patients who:

• are unable to fully participate in diet and exercise programs because of symptoms (such as cognitive impairment or severe negative symptoms)
• lack social support (such as reflected by financial problems, homelessness, or poor compliance with treatment recommendations).

Generally, we reserve antiobesity drugs for patients with BMI >30 kg/m² (or >27 kg/m² in patients with diabetes, hyperlipidemia, or cardiovascular disease). Before adding these agents to a psychotropic regimen, however, review the relative risks and benefits with the patient and his or her primary care physician.

The goal of pharmacotherapy is for the patient to lose 5% to 10% of baseline weight in 3 to 6 months. Failure to achieve this goal is an indication to stop the medication. A plateau in weight loss after 6 to 9 months is expected and is not cause for discontinuation. If successful, drug treatment may be continued indefinitely, and both physician and patient must understand the intention to treat long-term. Most patients regain weight upon discontinuation.

Table 4

Medications indicated for treating obesity

Table 5

Medications used ‘off label’ for treating obesity

Related resources

• Centers for Disease Control and Prevention. Overweight and obesity: contributing factors. www.cdc.gov/nccdphp/dnpa/obesity/contributing_factors.htm.
• Mathur R. What causes obesity? www.medicinenet.com/obesity_weight_loss/page2.htm.

Drug brand names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Metformin • Glucophage
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Nefazodone • Serzone
• Nizatidine • Axid
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Paroxetine • Paxil
• Phenelzine • Nardil
• Selegiline (transdermal) • EMSAM
• Sertraline • Zoloft
• Sibutramine • Meridian
• Topiramate • Topamax
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

Dr. Schwartz has received grants from or served as a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Jazz Pharmaceuticals, Pfizer Inc., and Wyeth.

Other authors report no financial relationship with any companies whose products are mentioned in this article or with manufacturers of competing products.

A patient, a colleague, or perhaps you have been stalked. The chances of a woman being stalked are an estimated 1 in 14; for men, it is 1 in 50.¹ Fearful stalking victims may restrict their lives, change jobs, and curtail social activities to protect themselves from unwanted attention, physical assault, or even murder. They may develop anxiety, depression, or posttraumatic stress disorder (PTSD).^2,3

Historical, clinical, and behavioral factors increase a stalker’s risk for committing violence (Table 1).^2-7 As a psychiatrist, you may be asked to consult with local law enforcement and stalking victims to assess and manage victims’ risk. To best protect them, be aware of:

• 5 types of stalkers and their typical response to management strategies
  
• legal and safety issues to consider before taking actions that might endanger stalking victims
  
• strategies to help victims protect themselves
  
• interventions for victims and stalkers.
  

Table 1

Factors that increase the risk of violence

Stalker types

Mullen et al⁸ developed a clinically oriented, validated stalker classification system to identify an individual stalker’s type, risks, and probable responses to management interventions (Table 2).

Rejected stalkers—the most common and dangerous type—pursue the victim, often a former intimate partner, after a relationship ends. They often acknowledge a complex and volatile mix of desire for reconciliation and revenge. These stalkers likely have a history of criminal assault.

Rejected stalkers appear to respond best to a combination of coordinated legal sanctions and mental health intervention. Because they are most likely to be violent, rejected stalkers need intensive probation or parole supervision.⁵

Intimacy-seeking stalkers want an intimate relationship with a victim they believe is their “true love” and tend to imbue their victims with special desirability, excellence, and other qualities consistent with their belief of romanticized love. Most have erotomanic delusions, and the rest have morbid infatuations with the victim. Intimacy-seeking stalkers typically are unperturbed by legal sanctions, viewing them as the price to pay for “true love.” They often require court-mandated psychiatric treatment.

Incompetent stalkers know the victim is disinterested but forge ahead in hopes that their behavior will lead to a relationship. Their stalking can be viewed as crude or “incompetent” attempts to court the victim. Incompetent stalkers often are intellectually limited; they feel entitled to a partner but because of underdeveloped social skills are unable to build upon lesser forms of social interaction. Unlike intimacy-seekers, incompetent stalkers do not endow the victim with unique qualities.

In addition to needing legal sanctions and possible mental health treatment, incompetent stalkers often require social skills training. Otherwise, they are likely to continue their pattern of stalking with other victims.

Resentful stalkers who suffer from mental illness generally require court-ordered psychiatric treatment but are difficult to engage in therapy. Legal sanctions may inflame this type of stalker.

Predatory stalkers prepare for a sexual assault. They stalk to discover the victim’s vulnerabilities and seldom give warnings, so the victim is often unaware of the danger.

Predatory stalkers frequently suffer from paraphilias and have prior convictions for sexual offenses. They must be secured in a correctional or forensic setting to address their paraphilias and propensity for violence.

Table 2

Identifying types of stalkers

Managing victims’ risk

Effectively managing a victim’s stalking risk is a dynamic process. It is critical to use professional judgment in a flexible manner and to work as a team with professionals from other agencies (Box).^9-12

Protective orders. Obtaining a protective order may or may not be helpful. Most domestic violence research indicates that such orders protect abused women.¹³ This is important because stalking by a former intimate partner often occurs in relationships characterized by domestic violence.¹⁴ In addition to potentially preventing stalking behavior, a protective order may provide legal evidence of the course of stalking, as well as document a “fearful victim,” which is required by law to obtain a criminal conviction.

No conclusive studies have investigated the effectiveness of protective orders specifically related to stalkers, so consider the stalker’s reaction to previous orders.¹⁵ Counsel a victim who obtains a protective order against a former intimate partner to avoid developing a false sense of security. Rejected stalkers who have considerable emotional investment in the relationship may not be deterred by the threat of criminal sanctions. Furthermore, stalkers who are psychotic may misperceive and disregard criminal injunctions. In rare cases, a protective order may escalate stalking and violence.¹⁵

Dramatic moments. Advise a victim to remain vigilant during “dramatic moments” when violence risk may be especially heightened.¹⁵ These include:

• arrests
  
• issuance of protective orders
  
• court hearings
  
• custody hearings
  
• anniversary dates
  
• family-oriented holidays.
  

• arranging to be out of town on that date
  
• notifying law enforcement and victim advocates.
  

Treating victims’ symptoms

As a result of the risks they face, stalking victims often suffer significant “social damage.” To cope with being stalked, many victims must make substantial life changes, such as relocating or finding new employment. They may need to restrict outings, adapt security measures, and take time off from work.¹⁶ This social damage and anxiety may predispose them to substance abuse.¹⁷

Stalking victims also experience emotional distress.^3,18 They commonly report symptoms of anxiety disorders, in particular PTSD, and one-quarter experience depression and suicidal ruminations.¹⁹ Victims who perceive their stalking as severe report elevated levels of helplessness, anxiety, PTSD, and depression.²⁰

Few studies focus on the duration of victims’ symptoms or their successful treatment.²¹ Mullen⁸ has recommended a comprehensive approach that includes education, supportive counseling, psychotherapy, and pharmacotherapy. In particular, cognitive-oriented therapy can target common issues such as anxiety leading to feelings of loss of control and associated avoidance. Pharmacotherapy for anxiety or depressive symptoms follows recommended treatment guidelines.

Because the stalking and associated stress may have an adverse impact on the victim’s personal relationships, partner and family therapy may be necessary. Support organizations for stalking victims, such as Survivors of Stalking, can provide education, safety information, and emotional support.

Improving victims’ safety

Coach a victim to take responsibility for his or her safety by becoming familiar with local stalking laws, resources, and law enforcement policies.^13,22 Emphasize that a victim must be assertive to ensure that safety measures are in place (Table 3).^3,8,10,15,18

As soon as unwanted pursuit is apparent, the victim should unequivocally tell the stalker that no relationship is wanted.⁸ This message must be firm, reasonable, and as clear as possible. The victim should not attempt to deliver the message gently or let the stalker “down easy.” Otherwise, the stalker may believe the victim is ambivalent about the decision and will continue or redouble his or her efforts.

After delivering this message, the victim should not engage in any further discussion or initiate contact with the stalker. The victim must avoid all contact to minimize the effects of “intermittent positive reinforcement.”¹⁵

The victim should document and preserve evidence by recording the dates and times of each unwanted contact, including vandalism, in an “incident log” or journal. Encourage him or her to photograph and note the date of any property damage. This documentation will help establish a clear course of illegal conduct and can prove invaluable to police and prosecution efforts.

The victim should preserve any evidence—including gifts, mementos, and other materials—by placing it in a plastic bag labeled with the date, time, and place it was received. Encourage the victim to:

• resist the urge to discard evidence that may evoke feelings of fear, shame, or disgust
  
• avoid handling evidence, and store it in a secure location.
  

• establish a post office box to prevent someone from stealing mail containing personal information
  
• shred personal mail instead of placing it in the trash.
  

Security experts often advise victims not to adhere to their usual, predictable routines by, for example, taking different daily travel routes or being prepared to go out of town at short notice.² Victims should also make contingency plans in case their social supports are unavailable in an emergency. Victim advocacy agents can give information about services and locations of local “safe houses” or domestic violence shelters.

Table 3

Victim safety strategies

Treating stalkers

Failing to treat a mentally ill stalker may result in continued risk to the victim. For example, an intimacy-seeking stalker with erotomanic delusions who is confined without treatment likely will be released with no significant reduction in risk. No reliable outcome data exist on treatment for stalkers, however, so you must rely on empirically derived clinical data.

If you work with stalkers, you must be familiar with your state’s duty-to-protect statutes and relevant case law related to stalking so you can discuss legal obligations with the stalker before beginning treatment.

Most stalkers will be difficult to engage in treatment because they have been compelled by a court order to seek therapy. Initially you are likely to encounter the stalker’s striking lack of insight into the nature and consequences of this behavior. The stalker may seek validation for his or her actions while demonstrating little interest in ending the obsessional behavior. Expect well-entrenched defenses of denial, rationalization, and minimization.

A comprehensive description of treatment for stalkers is beyond the scope of this article. However, clinicians with experience treating stalkers recommend the following interventions:⁴

• thorough psychiatric assessment and diagnosis
  
• treatment of Axis I or II pathology
  
• cognitive-behavioral therapy to focus on the stalker’s misperceptions
  
• motivational interviewing techniques to help the stalker appreciate the need for intervention
  
• victim empathy development
  
• social skills enhancement
  
• periodic risk assessments.
  

• Stalking Resource Center, National Center for Victims of Crime. www.ncvc.org/src.
  
• Pinals DA, ed. Stalking: a psychiatric perspective. New York: Oxford University Press; 2007.
  
• The Antistalking Web Site resources. www.antistalking.com/resource.htm.
  
• U.S. Department of Justice anti-stalking resources. www.usdoj.gov/ovw/stalking.htm.
  

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

A patient, a colleague, or perhaps you have been stalked. The chances of a woman being stalked are an estimated 1 in 14; for men, it is 1 in 50.¹ Fearful stalking victims may restrict their lives, change jobs, and curtail social activities to protect themselves from unwanted attention, physical assault, or even murder. They may develop anxiety, depression, or posttraumatic stress disorder (PTSD).^2,3

Historical, clinical, and behavioral factors increase a stalker’s risk for committing violence (Table 1).^2-7 As a psychiatrist, you may be asked to consult with local law enforcement and stalking victims to assess and manage victims’ risk. To best protect them, be aware of:

• 5 types of stalkers and their typical response to management strategies
  
• legal and safety issues to consider before taking actions that might endanger stalking victims
  
• strategies to help victims protect themselves
  
• interventions for victims and stalkers.
  

Table 1

Factors that increase the risk of violence

Stalker types

Mullen et al⁸ developed a clinically oriented, validated stalker classification system to identify an individual stalker’s type, risks, and probable responses to management interventions (Table 2).

Rejected stalkers—the most common and dangerous type—pursue the victim, often a former intimate partner, after a relationship ends. They often acknowledge a complex and volatile mix of desire for reconciliation and revenge. These stalkers likely have a history of criminal assault.

Rejected stalkers appear to respond best to a combination of coordinated legal sanctions and mental health intervention. Because they are most likely to be violent, rejected stalkers need intensive probation or parole supervision.⁵

Intimacy-seeking stalkers want an intimate relationship with a victim they believe is their “true love” and tend to imbue their victims with special desirability, excellence, and other qualities consistent with their belief of romanticized love. Most have erotomanic delusions, and the rest have morbid infatuations with the victim. Intimacy-seeking stalkers typically are unperturbed by legal sanctions, viewing them as the price to pay for “true love.” They often require court-mandated psychiatric treatment.

Incompetent stalkers know the victim is disinterested but forge ahead in hopes that their behavior will lead to a relationship. Their stalking can be viewed as crude or “incompetent” attempts to court the victim. Incompetent stalkers often are intellectually limited; they feel entitled to a partner but because of underdeveloped social skills are unable to build upon lesser forms of social interaction. Unlike intimacy-seekers, incompetent stalkers do not endow the victim with unique qualities.

In addition to needing legal sanctions and possible mental health treatment, incompetent stalkers often require social skills training. Otherwise, they are likely to continue their pattern of stalking with other victims.

Resentful stalkers who suffer from mental illness generally require court-ordered psychiatric treatment but are difficult to engage in therapy. Legal sanctions may inflame this type of stalker.

Predatory stalkers prepare for a sexual assault. They stalk to discover the victim’s vulnerabilities and seldom give warnings, so the victim is often unaware of the danger.

Predatory stalkers frequently suffer from paraphilias and have prior convictions for sexual offenses. They must be secured in a correctional or forensic setting to address their paraphilias and propensity for violence.

Table 2

Identifying types of stalkers

Managing victims’ risk

Effectively managing a victim’s stalking risk is a dynamic process. It is critical to use professional judgment in a flexible manner and to work as a team with professionals from other agencies (Box).^9-12

Protective orders. Obtaining a protective order may or may not be helpful. Most domestic violence research indicates that such orders protect abused women.¹³ This is important because stalking by a former intimate partner often occurs in relationships characterized by domestic violence.¹⁴ In addition to potentially preventing stalking behavior, a protective order may provide legal evidence of the course of stalking, as well as document a “fearful victim,” which is required by law to obtain a criminal conviction.

No conclusive studies have investigated the effectiveness of protective orders specifically related to stalkers, so consider the stalker’s reaction to previous orders.¹⁵ Counsel a victim who obtains a protective order against a former intimate partner to avoid developing a false sense of security. Rejected stalkers who have considerable emotional investment in the relationship may not be deterred by the threat of criminal sanctions. Furthermore, stalkers who are psychotic may misperceive and disregard criminal injunctions. In rare cases, a protective order may escalate stalking and violence.¹⁵

Dramatic moments. Advise a victim to remain vigilant during “dramatic moments” when violence risk may be especially heightened.¹⁵ These include:

• arrests
  
• issuance of protective orders
  
• court hearings
  
• custody hearings
  
• anniversary dates
  
• family-oriented holidays.
  

• arranging to be out of town on that date
  
• notifying law enforcement and victim advocates.
  

Treating victims’ symptoms

As a result of the risks they face, stalking victims often suffer significant “social damage.” To cope with being stalked, many victims must make substantial life changes, such as relocating or finding new employment. They may need to restrict outings, adapt security measures, and take time off from work.¹⁶ This social damage and anxiety may predispose them to substance abuse.¹⁷

Stalking victims also experience emotional distress.^3,18 They commonly report symptoms of anxiety disorders, in particular PTSD, and one-quarter experience depression and suicidal ruminations.¹⁹ Victims who perceive their stalking as severe report elevated levels of helplessness, anxiety, PTSD, and depression.²⁰

Few studies focus on the duration of victims’ symptoms or their successful treatment.²¹ Mullen⁸ has recommended a comprehensive approach that includes education, supportive counseling, psychotherapy, and pharmacotherapy. In particular, cognitive-oriented therapy can target common issues such as anxiety leading to feelings of loss of control and associated avoidance. Pharmacotherapy for anxiety or depressive symptoms follows recommended treatment guidelines.

Because the stalking and associated stress may have an adverse impact on the victim’s personal relationships, partner and family therapy may be necessary. Support organizations for stalking victims, such as Survivors of Stalking, can provide education, safety information, and emotional support.

Improving victims’ safety

Coach a victim to take responsibility for his or her safety by becoming familiar with local stalking laws, resources, and law enforcement policies.^13,22 Emphasize that a victim must be assertive to ensure that safety measures are in place (Table 3).^3,8,10,15,18

As soon as unwanted pursuit is apparent, the victim should unequivocally tell the stalker that no relationship is wanted.⁸ This message must be firm, reasonable, and as clear as possible. The victim should not attempt to deliver the message gently or let the stalker “down easy.” Otherwise, the stalker may believe the victim is ambivalent about the decision and will continue or redouble his or her efforts.

After delivering this message, the victim should not engage in any further discussion or initiate contact with the stalker. The victim must avoid all contact to minimize the effects of “intermittent positive reinforcement.”¹⁵

The victim should document and preserve evidence by recording the dates and times of each unwanted contact, including vandalism, in an “incident log” or journal. Encourage him or her to photograph and note the date of any property damage. This documentation will help establish a clear course of illegal conduct and can prove invaluable to police and prosecution efforts.

The victim should preserve any evidence—including gifts, mementos, and other materials—by placing it in a plastic bag labeled with the date, time, and place it was received. Encourage the victim to:

• resist the urge to discard evidence that may evoke feelings of fear, shame, or disgust
  
• avoid handling evidence, and store it in a secure location.
  

• establish a post office box to prevent someone from stealing mail containing personal information
  
• shred personal mail instead of placing it in the trash.
  

Security experts often advise victims not to adhere to their usual, predictable routines by, for example, taking different daily travel routes or being prepared to go out of town at short notice.² Victims should also make contingency plans in case their social supports are unavailable in an emergency. Victim advocacy agents can give information about services and locations of local “safe houses” or domestic violence shelters.

Table 3

Victim safety strategies

Treating stalkers

Failing to treat a mentally ill stalker may result in continued risk to the victim. For example, an intimacy-seeking stalker with erotomanic delusions who is confined without treatment likely will be released with no significant reduction in risk. No reliable outcome data exist on treatment for stalkers, however, so you must rely on empirically derived clinical data.

If you work with stalkers, you must be familiar with your state’s duty-to-protect statutes and relevant case law related to stalking so you can discuss legal obligations with the stalker before beginning treatment.

Most stalkers will be difficult to engage in treatment because they have been compelled by a court order to seek therapy. Initially you are likely to encounter the stalker’s striking lack of insight into the nature and consequences of this behavior. The stalker may seek validation for his or her actions while demonstrating little interest in ending the obsessional behavior. Expect well-entrenched defenses of denial, rationalization, and minimization.

A comprehensive description of treatment for stalkers is beyond the scope of this article. However, clinicians with experience treating stalkers recommend the following interventions:⁴

• thorough psychiatric assessment and diagnosis
  
• treatment of Axis I or II pathology
  
• cognitive-behavioral therapy to focus on the stalker’s misperceptions
  
• motivational interviewing techniques to help the stalker appreciate the need for intervention
  
• victim empathy development
  
• social skills enhancement
  
• periodic risk assessments.
  

• Stalking Resource Center, National Center for Victims of Crime. www.ncvc.org/src.
  
• Pinals DA, ed. Stalking: a psychiatric perspective. New York: Oxford University Press; 2007.
  
• The Antistalking Web Site resources. www.antistalking.com/resource.htm.
  
• U.S. Department of Justice anti-stalking resources. www.usdoj.gov/ovw/stalking.htm.
  

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

A patient, a colleague, or perhaps you have been stalked. The chances of a woman being stalked are an estimated 1 in 14; for men, it is 1 in 50.¹ Fearful stalking victims may restrict their lives, change jobs, and curtail social activities to protect themselves from unwanted attention, physical assault, or even murder. They may develop anxiety, depression, or posttraumatic stress disorder (PTSD).^2,3

Historical, clinical, and behavioral factors increase a stalker’s risk for committing violence (Table 1).^2-7 As a psychiatrist, you may be asked to consult with local law enforcement and stalking victims to assess and manage victims’ risk. To best protect them, be aware of:

• 5 types of stalkers and their typical response to management strategies
  
• legal and safety issues to consider before taking actions that might endanger stalking victims
  
• strategies to help victims protect themselves
  
• interventions for victims and stalkers.
  

Table 1

Factors that increase the risk of violence

Stalker types

Mullen et al⁸ developed a clinically oriented, validated stalker classification system to identify an individual stalker’s type, risks, and probable responses to management interventions (Table 2).

Rejected stalkers—the most common and dangerous type—pursue the victim, often a former intimate partner, after a relationship ends. They often acknowledge a complex and volatile mix of desire for reconciliation and revenge. These stalkers likely have a history of criminal assault.

Rejected stalkers appear to respond best to a combination of coordinated legal sanctions and mental health intervention. Because they are most likely to be violent, rejected stalkers need intensive probation or parole supervision.⁵

Intimacy-seeking stalkers want an intimate relationship with a victim they believe is their “true love” and tend to imbue their victims with special desirability, excellence, and other qualities consistent with their belief of romanticized love. Most have erotomanic delusions, and the rest have morbid infatuations with the victim. Intimacy-seeking stalkers typically are unperturbed by legal sanctions, viewing them as the price to pay for “true love.” They often require court-mandated psychiatric treatment.

Incompetent stalkers know the victim is disinterested but forge ahead in hopes that their behavior will lead to a relationship. Their stalking can be viewed as crude or “incompetent” attempts to court the victim. Incompetent stalkers often are intellectually limited; they feel entitled to a partner but because of underdeveloped social skills are unable to build upon lesser forms of social interaction. Unlike intimacy-seekers, incompetent stalkers do not endow the victim with unique qualities.

In addition to needing legal sanctions and possible mental health treatment, incompetent stalkers often require social skills training. Otherwise, they are likely to continue their pattern of stalking with other victims.

Resentful stalkers who suffer from mental illness generally require court-ordered psychiatric treatment but are difficult to engage in therapy. Legal sanctions may inflame this type of stalker.

Predatory stalkers prepare for a sexual assault. They stalk to discover the victim’s vulnerabilities and seldom give warnings, so the victim is often unaware of the danger.

Predatory stalkers frequently suffer from paraphilias and have prior convictions for sexual offenses. They must be secured in a correctional or forensic setting to address their paraphilias and propensity for violence.

Table 2

Identifying types of stalkers

Managing victims’ risk

Effectively managing a victim’s stalking risk is a dynamic process. It is critical to use professional judgment in a flexible manner and to work as a team with professionals from other agencies (Box).^9-12

Protective orders. Obtaining a protective order may or may not be helpful. Most domestic violence research indicates that such orders protect abused women.¹³ This is important because stalking by a former intimate partner often occurs in relationships characterized by domestic violence.¹⁴ In addition to potentially preventing stalking behavior, a protective order may provide legal evidence of the course of stalking, as well as document a “fearful victim,” which is required by law to obtain a criminal conviction.

No conclusive studies have investigated the effectiveness of protective orders specifically related to stalkers, so consider the stalker’s reaction to previous orders.¹⁵ Counsel a victim who obtains a protective order against a former intimate partner to avoid developing a false sense of security. Rejected stalkers who have considerable emotional investment in the relationship may not be deterred by the threat of criminal sanctions. Furthermore, stalkers who are psychotic may misperceive and disregard criminal injunctions. In rare cases, a protective order may escalate stalking and violence.¹⁵

Dramatic moments. Advise a victim to remain vigilant during “dramatic moments” when violence risk may be especially heightened.¹⁵ These include:

• arrests
  
• issuance of protective orders
  
• court hearings
  
• custody hearings
  
• anniversary dates
  
• family-oriented holidays.
  

• arranging to be out of town on that date
  
• notifying law enforcement and victim advocates.
  

Treating victims’ symptoms

As a result of the risks they face, stalking victims often suffer significant “social damage.” To cope with being stalked, many victims must make substantial life changes, such as relocating or finding new employment. They may need to restrict outings, adapt security measures, and take time off from work.¹⁶ This social damage and anxiety may predispose them to substance abuse.¹⁷

Stalking victims also experience emotional distress.^3,18 They commonly report symptoms of anxiety disorders, in particular PTSD, and one-quarter experience depression and suicidal ruminations.¹⁹ Victims who perceive their stalking as severe report elevated levels of helplessness, anxiety, PTSD, and depression.²⁰

Few studies focus on the duration of victims’ symptoms or their successful treatment.²¹ Mullen⁸ has recommended a comprehensive approach that includes education, supportive counseling, psychotherapy, and pharmacotherapy. In particular, cognitive-oriented therapy can target common issues such as anxiety leading to feelings of loss of control and associated avoidance. Pharmacotherapy for anxiety or depressive symptoms follows recommended treatment guidelines.

Because the stalking and associated stress may have an adverse impact on the victim’s personal relationships, partner and family therapy may be necessary. Support organizations for stalking victims, such as Survivors of Stalking, can provide education, safety information, and emotional support.

Improving victims’ safety

Coach a victim to take responsibility for his or her safety by becoming familiar with local stalking laws, resources, and law enforcement policies.^13,22 Emphasize that a victim must be assertive to ensure that safety measures are in place (Table 3).^3,8,10,15,18

As soon as unwanted pursuit is apparent, the victim should unequivocally tell the stalker that no relationship is wanted.⁸ This message must be firm, reasonable, and as clear as possible. The victim should not attempt to deliver the message gently or let the stalker “down easy.” Otherwise, the stalker may believe the victim is ambivalent about the decision and will continue or redouble his or her efforts.

After delivering this message, the victim should not engage in any further discussion or initiate contact with the stalker. The victim must avoid all contact to minimize the effects of “intermittent positive reinforcement.”¹⁵

The victim should document and preserve evidence by recording the dates and times of each unwanted contact, including vandalism, in an “incident log” or journal. Encourage him or her to photograph and note the date of any property damage. This documentation will help establish a clear course of illegal conduct and can prove invaluable to police and prosecution efforts.

The victim should preserve any evidence—including gifts, mementos, and other materials—by placing it in a plastic bag labeled with the date, time, and place it was received. Encourage the victim to:

• resist the urge to discard evidence that may evoke feelings of fear, shame, or disgust
  
• avoid handling evidence, and store it in a secure location.
  

• establish a post office box to prevent someone from stealing mail containing personal information
  
• shred personal mail instead of placing it in the trash.
  

Security experts often advise victims not to adhere to their usual, predictable routines by, for example, taking different daily travel routes or being prepared to go out of town at short notice.² Victims should also make contingency plans in case their social supports are unavailable in an emergency. Victim advocacy agents can give information about services and locations of local “safe houses” or domestic violence shelters.

Table 3

Victim safety strategies

Treating stalkers

Failing to treat a mentally ill stalker may result in continued risk to the victim. For example, an intimacy-seeking stalker with erotomanic delusions who is confined without treatment likely will be released with no significant reduction in risk. No reliable outcome data exist on treatment for stalkers, however, so you must rely on empirically derived clinical data.

If you work with stalkers, you must be familiar with your state’s duty-to-protect statutes and relevant case law related to stalking so you can discuss legal obligations with the stalker before beginning treatment.

Most stalkers will be difficult to engage in treatment because they have been compelled by a court order to seek therapy. Initially you are likely to encounter the stalker’s striking lack of insight into the nature and consequences of this behavior. The stalker may seek validation for his or her actions while demonstrating little interest in ending the obsessional behavior. Expect well-entrenched defenses of denial, rationalization, and minimization.

A comprehensive description of treatment for stalkers is beyond the scope of this article. However, clinicians with experience treating stalkers recommend the following interventions:⁴

• thorough psychiatric assessment and diagnosis
  
• treatment of Axis I or II pathology
  
• cognitive-behavioral therapy to focus on the stalker’s misperceptions
  
• motivational interviewing techniques to help the stalker appreciate the need for intervention
  
• victim empathy development
  
• social skills enhancement
  
• periodic risk assessments.
  

• Stalking Resource Center, National Center for Victims of Crime. www.ncvc.org/src.
  
• Pinals DA, ed. Stalking: a psychiatric perspective. New York: Oxford University Press; 2007.
  
• The Antistalking Web Site resources. www.antistalking.com/resource.htm.
  
• U.S. Department of Justice anti-stalking resources. www.usdoj.gov/ovw/stalking.htm.
  

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