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William Coryell, MD

Primary Psychiatry. 2002;9(12):47-50

Dr. Coryell is professor in the Department of Psychiatry at the University of Iowa College of Medicine in Iowa City.

Disclosure: This work was supported by an unrestricted educational grant from GlaxoSmithKline.



How does the clinician best manage side effects associated with mood stabilizers used for bipolar affective disorder? Informed management of side effects can improve a drug’s tolerability and therefore increase the likelihood that patients will continue to take the drug most effective for their illness. Placebo-controlled studies have supported the prophylactic use of lithium, carbamazepine, valproate, and lamotrigine for bipolar disorder. This review summarizes the case reports and controlled studies pertinent to the management of side effects for each of these agents.



While the importance of pharmacotherapy in the management of bipolar affective disorder has been established, all of the useful agents have also been associated with side effects. Side effects may be endured, they may lead to treatment noncompliance, or they may result in the replacement of a drug that is effective in controlling illness symptoms with an alternative that is possibly less so. Any of these possibilities will diminish the patient’s quality of life.

In comparison with efforts to demonstrate the efficacy of mood stabilizers in the acute and prophylactic treatment of bipolar affective disorder, the literature concerning the management of side effects is small, largely anecdotal, and rarely reviewed. The following undertakes such a review, with suggestions relevant to each of the mood stabilizers for which placebo-controlled trials have shown efficacy. The side effects discussed are the ones more commonly described and particular emphasis is given to those for which corrective measures other than drug discontinuation have been proposed.


Despite recent shifts in prescribing patterns, the efficacy of lithium in bipolar affective disorder is more thoroughly established than the efficacy of any other medication. Because its use was widespread before the advent of most of the other drugs now being prescribed for bipolar affective disorder, lithium’s side effects have been more fully characterized and a number of strategies for managing them
have emerged.


Nausea may be the first side effect encountered when lithium is introduced, particularly when doses are rapidly increased. Because nausea tends to reflect the rapidity with which plasma levels are increasing,1 loading procedures will increase its likelihood and this may adversely bias the patient’s attitude toward lithium therapy. An obvious solution would therefore be a temporary decrease in dose, followed by a more gradual approach to the targeted plasma level range. Also, nausea often improves when lithium is consistently taken with meals. A slow-release preparation may reduce nausea, but may also increase difficulties with diarrhea.2


A fine tremor, increased by voluntary movement, is often another early development in lithium therapy. It is often tolerated but may be quite distressing for the patient. If the tremor is seen to peak in intensity within several hours of each dose, a sustained-release preparation may be helpful. Also potentially helpful is a reduction in caffeine intake and the elimination of other drugs, such as tricyclic antidepressants, that may produce or worsen tremor. Because maintenance lithium levels at the lower end of the conventional therapeutic range produce less tremor,3,4 doses should be titrated against symptom control to determine whether lower doses provide relief.

When a distressing tremor persists despite dosing changes, modest doses of a β-blocker are indicated. According to a number of reports, propranolol 30–80 mg/day is often effective.5-7 β1 blockers, such as atenolol and metoprolol, have been used for patients at risk for bronchospasm.7,8

Polyuria and Polydipsia

Polydipsia is typically nonprogressive9 but may substantially interfere with sleep, and may lead to significant weight gain if the patient is relieving thirst with sugared drinks. As with tremor, symptoms are more likely at higher doses, and the problem often subsides when careful titration is used to determine the patient’s lowest effective dose.

According to several authors, polyuria is less likely with single daily dosing than with multiple-dose schedules.10-13 At least one study demonstrated that a shift from multiple dosing to single dosing reduced urinary volume,14 but another applied random assignment to alternate dosing schedules and found no difference in urine volume.15

If changes in dose and timing are unhelpful, the addition of a diuretic may produce a paradoxical reduction in urine volume. Hydrochlorothiazide 50 mg/day has been recommended, but amiloride,16 in doses titrated to 10 mg BID, is less likely to produce hypokalemia.

Weight Gain

Weight gain attributed to lithium can be an important issue for long-term compliance and may lead a clinician to consider alternative mood stabilizers. The results of randomized, prophylactic studies are pertinent. In the only comparison of lithium, valproate, and placebo, patients taking valproate, but not those taking lithium, experienced significantly more weight gain than those taking placebo.17 A randomized comparison of lithium and carbamazepine, on the other hand, indicated that carbamazepine resulted in significantly less weight gain.18 Existing evidence does not support a switch from lithium to valproate to limit weight gain.

As an alternative to switching mood stabilizers, clinicians should consider whether coadministered drugs may be contributing to the problem and whether these are necessary. Atypical antipsychotics are often used adjunctively to hasten symptom control in acute mania and then continued out of concern that monotherapy with lithium may be insufficient for prophylaxis. A gradual discontinuation is warranted to determine whether this is so.

Patients should also be asked whether they are drinking high-calorie beverages to relieve thirst or to counteract the metallic taste often experienced with lithium. A regular exercise program should be encouraged as this may enhance the control of both weight and depressive symptoms.19

Cognitive Impairment

Goodwin and Jamison20 found that  the most frequently cited reason for lithium noncompliance was “memory problems.” Clinicians often attribute complaints of mental sluggishness to residual depressive symptoms. However, placebo-controlled studies  have shown that at conventional therapeutic levels, lithium produces similar complaints in normal individuals21 and that deficits are measurable objectively as a slowing in cognitive performance.22

Lithium treatment is well-known to cause hypothyroidism. This is most commonly reflected in elevated thyroid-stimulating hormone (TSH) levels, but approximately 4% of patients on chronic lithium treatment develop abnormally low T3 and T4 levels.23 It is also well-known that depressive symptoms and complaints of sluggishness are typical concomitants of clinical hypothyroidism. Most clinicians who use lithium screen for hypothyroidism routinely and provide thyroid replacement when thyroxin levels are below normal limits.

However, subclinical hypothyroidism may also be a factor in both persistent depression24-26 and cognitive impairment.27,28 A trial of thyroid replacement is therefore warranted when either of these coexist with elevated TSH levels. T4 is commonly given but converging evidence now suggests that T3 provides more benefit in this role. Patients given T3 to augment antidepressant treatment in one study had significantly better outcomes than did those randomized to T4.29 In another study, those patients undergoing thyroid replacement with T4, who were randomized to receive part of their replacement as T3, reported significantly better mood and energy than did those who continued to receive T4 alone.30


As with lithium, many of the side effects associated with valproate are dose-dependent and can be reduced through attention to plasma levels. Bowden and colleagues31 identified 45 mcg/mL as the minimum therapeutic level. Changes in manic symptoms did not correlate with plasma levels above this threshold, but side effects increased markedly when levels exceeded 125 mcg/mL. This increase reflects dose-dependent protein binding and therefore, conditions that affect protein binding conditions may shift the threshold downward. Thus, older patients, especially those with liver disease, and those taking other drugs that compete for protein binding, may experiencea nonlinear increase in side effects beginning at a lower plasma level.


Anticonvulsants that increase γ-aminobutyric acid, as valproate does, tend to cause more sedation than do anticonvulsants, such as lamotrigine, which operate through the modulation of glutamatergic neurotransmission.32 While sedation offers an advantage in the acute control of manic symptoms, it becomes problematic during prophylaxis. Because this complaint does not seem to correlate with plasma levels within the therapeutic range, dose decreasing is often not helpful. If sedation is a problem during maintenance, the clinician should consider whether concomitant drugs, such as antipsychotics or benzodiazepines, can be eliminated at this stage.

Gastrointestinal Symptoms and Weight Gain

The most frequent side effects encountered by patients taking valproate are gastrointestinal in nature.33 Such complaints are less likely with divalproex than with valproic acid.33 If nausea persists with divalproex, a histamine2 blocker may prove helpful.34

Weight gain is at least as likely with valproate as with lithium.17 If weight gain is a prominent concern for a particular patient, the alternative mood stabilizers carbamazepine18,35 and lamotrigine36 should be considered. The continuation of any antipsychotics being given concomitantly should be reconsidered. As noted previously,a regular exercise program can have a number of benefits beyond weight control.


Valproate inhibits urea synthesis and the resulting elevations in serum ammonia levels can have clinical consequences varying from mild fatigue to coma.37 The neurology literature contains many references to this effect, though the psychiatric literature does not. This effect does not appear to be dose dependent and its manifestations—fatigue, cognitive slowing, and sedation—may be misinterpreted as depressive symptoms or even viewed as a positive response.38 Moreover, the tendency of valproate to increase ammonia levels is probably common rather than idiosyncratic.

Hjelm and colleagues39 showed that ammonia levels increased by an average of 101% among five healthy subjects given valproate at doses tapered to 1,500 mg/day over 1 week. Thus, an increase in lethargy after the establishment of valproate therapy warrants a check of ammonia levels. Some have suggested the administration of carnitine 1 g BID as a remedy.40 This may work by altering the effect of valproate on urea synthesis.


Carbamazepine was the first anticonvulsant to be widely used in bipolar affective disorder. There have been no direct comparisons of efficacy between carbamazepine and valproate, and little is known regarding which patients can be expected to respond to one rather than the other. This makes the differing side-effect profiles a relatively important factor as clinicians choose among the anticonvulsants.

Blood Dyscrasias

Carbamazepine has a well-known tendency to lower white cell counts. In perhaps the largest survey of this effect,41 carbamazepine was five times more likely to produce leukopenia than was valproate, though it was not more likely to produce severe leukopenia, defined as a white blood cell (WBC) count <3,000 mm3. The onset of leukopenia is most likely during the first 30 days of treatment and is unlikely after 60 days. The WBC threshold42 below which discontinuation is recommended has varied from 3,000 to 4,000 mm3. Notably, 11 of the cases with moderate leukopenia described by Tohen and colleagues41 continued on carbamazepine without adverse consequences. Lithium is known to stimulate leukocyte production and may serve to correct the leukopenia induced by carbamazepine.43 This combination would be particularly appropriate in cases of incomplete clinical response to carbamazepine monotherapy.


Hyponatremia is a relatively common side effect of carbamazepine and may be symptomatic.44 The patient’s medical regimen should be reviewed when low sodium values are noted. Discontinuation of carbamazepine may be averted by adjusting or eliminating coadministrated diuretics.


Lamotrigine offers advantages over valproate and carbamazepine in terms of such side effects as fatigue, somnolence, and weight gain.32 Weight, on average, has been shown to remain stable or to decrease during lamotrigine treatment.45 Although lamotrigine has only recently come into use as a mood stabilizer, it has been widely used as an antiepileptic and more than 583,000 patient-years of experience have accumulated.46 Lamotrigine also lacks most of the side effects associated with the antidepressants developed for use in major depressive disorder. Several recent placebo-controlled studies have shown lamotrigine to have both acute and prophylactic benefits for bipolar depression,47,48 suggesting that this agent is an alternative to the more traditional antidepressants in the management of bipolar depression.

The most frequent adverse events leading to discontinuation in controlled trials have been skin rashes. Indeed, reports of toxic epidermal necrolysis or Stevens-Johnson syndrome have made some clinicians reluctant to use lamotrigine. An expert panel estimated that rashes occur in approximately 10% of patients given lamotrigine and that those severe enough to result in hospitalization occur in 0.3% of adults and 1% of children.46 Established risk factors for lamotrigine-induced rash are use in childhood, use in combination with valproate, and most importantly, a rapid progression in dose. Recognition of this last risk factor led to revisions in the recommended dose-progression.49 A large-scale comparison of rates before and after the adoption of these revisions shows that the risk for severe rash (associated with systemic disturbances) was seemingly eliminated, though the risk for nonserious rashes remained at 9%.49


Only a few medicines have demonstrated effectiveness in the maintenance of bipolar affective disorder. Because of this, and the fact that most patients with bipolar illness require maintenance for an indefinite period, side effects should be managed with particular care to prevent the unnecessary abandonment of a potentially valuable treatment.

Treatment options fall into four categories. The most obvious category is dose adjustment to titrate symptom prophylaxis against side effects within therapeutic plasma level ranges. An often neglected but frequently rewarding intervention is the trial elimination of concomitant medications which may no longer be necessary. The optimization of thyroid status may improve cognitive slowing or fatigue, particularly during lithium maintenance. Emphasis on a regular exercise program is often preferable to switching medication in the face of weight gain. Finally, modest doses of adjunctive medication have been reported as useful in the management of certain side effects. Most of these apply to lithium side effects, doubtless because lithium has been in use far longer than the alternatives.


1.    Persson G. Lithium side effects in relation to dose and to levels and gradients of lithium in plasma. Acta Psychiatr Scand. 1977;55:208-213.
2.    Persson G. Plasma lithium levels and side effects during administration of a slow release lithium sulphate preparation and lithium carbonate tablets. Acta Psychiatr Scand. 1974;50:174-182.
3.    Maj M, Starace F, Nolfe G, Kemali D. Minimum plasma lithium levels required for effective prophylaxis in DSM-III bipolar disorder. Pharmacopsychiatry. 1986;9:420-423.
4.    Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321:1489-1493.
5.    Kirk L, Baastrup PC, Schou M. Propranolol treatment of lithium-induced tremor [letter]. Lancet. 1973;2:1086-1087.
6.    Lapierre YD. Control of lithium tremor with propranolol. Can Med Assoc J. 1976;114:619-624.
7.    Zubenko GS, Cohen BM, Lipinski JF. Comparison of metoprolol and propranolol in the treatment of lithium tremor. Psychiatry Res. 1984;11:163-164.
8.    Dave M. Treatment of lithium induced tremor with atenolol. Can J Psychiatry. 1989;34:132-133.
9.    Smigan L, Bucht G, von Knorring L, Perris C, Wahlin A. Long-term lithium treatment and renal functions. Neuropsychobiology. 1984;11:33-38.
10.    Plenge P, Mellerup ET, Bolwig TG, et al. Lithium treatment: does the kidney prefer one daily dose instead of two? Acta Psychiatr Scand. 1982;66:121-128.
11.    Bowen RC, Grof P, Grof E. Less frequent lithium administration and lower urine volume. Am J Psychiatry. 1991;148:189-192.
12.    Hetmar O, Brun C, Ladefoged H, Larsen S, Bolwig TG. Long-term effects of lithium on the kidney: functional-morphological correlations. J Psychiatr Res. 1989;23:285-297.
13.    Hetmar O, Povlsen UJ, Ladefoged J, Bolwig TG. Lithium: long-term effects on the kidney. Br J Psychiatry. 1991;158:53-58.
14.    Perry PJ, Dunner FJ, Hahn RL, Tsuang MT, Berg MJ. Lithium kinetics in single daily dosing. Acta Psychiatr Scand. 1981;64:281-294.
15.    O’Donovan C, Hawkes J, Bowen R. Effect of lithium dosing schedule on urinary output. Acta Psychiatr Scand. 1993;87:92-95.
16.    Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med. 1985;312:408-414.
17.    Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57:481-489.
18.    Coxhead N, Silverstone T, Cookson J. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Acta Psychiatr Scand. 1992;85:114-118.
19.    Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med. 2000;62:633-638.
20.    Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990.
21.    Judd LL, Hubbard B, Janowsky DS, Huey YH, Attewell PA. The effect of lithium carbonate on affect, mood, and personality of normal subjects. Arch Gen Psychiatry. 1977;34:346-351.
22.    Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI. The effect of lithium carbonate on the cognitive function of normal subjects. Arch Gen Psychiatry. 1977; 34:355-357.
23.    Amdisen A, Andersen CJ. Lithium treatment and thyroid function: a survey of 237 patients in long-term lithium treatment. Pharmacopsychiatry. 1982;15:149-155.
24.    Frye MA, Denicoff KD, Bryan AL, et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry. 1999;156:1909-1914.
25.    Joffe RT, Levitt AJ. Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 1992;17:215-221.
26.    Joffe RT, Marriott M. Thyroid hormone levels and recurrence of major depression. Am J Psychiatry. 2000;157:1689-1691.
27.    Prohaska ML, Stern RA, Mason GA, Nevels CT, Prange AJ. Thyroid hormones and lithium-related neuropsychological deficits: A preliminary test of the lithium-thyroid interactive hypothesis. J Int Neuropsychol Soc. 1995;1:134.
28.    Prohaska ML, Stern RA, Nevels CT, Mason GA, Prange AJ. The relationship between thyroid status and neuropsychological performance in psychiatric outpatients maintained on lithium. Neuropsychiatry Neuropsychol Behav Neurol. 1996;9:30-34.
29.    Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatr Res. 1990;32:241-251.
30.    Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424-429.
31.    Bowden CL, Janicak PG, Orsulak P, et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry. 1996;153:765-770.
32.    Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(5 suppl 2):S53-67.
33.    Zarate CA, Tohen M, Narendran R, et al. The adverse affect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study. J Clin Psychiatry. 1999;60:232-236.
34.    Stoll AL, Vuckovic A, McElroy SL. Histamine subscript 2-receptor antagonists for the treatment of valproate induced gastrointestinal distress. Ann Clin Psychiatry. 1991;3:301-304.
35.    Placidi GF, Lenzi A, Lazzerini F, Cassano GB, Akiskal HS. The comparative efficacy and safety of carbamazepine versus lithium: a randomized, double-blind 3-year trial in 83 patients.
J Clin Psychiatry. 1986;47:490-494.
36.    Isojarvi JI, Rattya J, Myllyla VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol. 1998;43:446-451.
37.    Kifune A, Kubota F, Shibata N, Akata T, Kikuchi S. Valproic acid-induced hyperammonemic encephalopathy with triphasic waves. Epilepsia. 2000;41:909-912.
38.    Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49:1358-1359.
39.    Hjelm M, Oberholzer V, Seakins J, Thomas S. Valproate-induced inhibition of urea syntheseis and hyperammonaemia in healthy subjects [letter]. Lancet. 1986;2:859.
40.    Raby WN. Carnitine for valproic acid-induced hyperammonemia [letter]. Am J Psychiatry. 1997;154:1168-1169.
41.    Tohen M, Castillo J, Baldessarini RJ, Zarate C, Kando JC. Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk. Am J Psychiatry. 1995;152:413-418.
42.    Joffe RT, Post RM, Roy-Byrne PP, Uhde TW. Hematological effects of carbamazepine in patients with affective illness. Am J Psychiatry. 1985;142:1196-1199.
43.    Brewerton TD. Lithium counteracts carbamazepine-induced leukopenia while increasing its therapeutic effect. Biol Psychiatry. 1986;21:677-685.
44.    Yassa R, Iskandar H, Nastase C, Camille Y. Carbamazepine and hyponatremia in patients with affective disorder. Am J Psychiatry. 1988;145:339-342.
45.    Frye MA, Ketter TA, Kimbrell TA, et al.
A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.
46.    Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40:985-991.
47.    Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of the lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
48.    Calabrese JR, Suppes T, Bowden CL, et al.
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61:841-850.
49.    Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother. 1999;33:1037-1042.


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Andrew Farah, MD

Primary Psychiatry. 2002;9(12):30-35

Dr. Farah is medical director of behavioral services at High Point Regional Health System in High Point, North Carolina.

Disclosure: The author has received grants and/or consultant fees from Forest Laboratories.



What are the therapeutic advantages of escitalopram, the purified S-enantiomer of the racemate citalopram? The biological activity and therapeutic effects of citalopram, which has been used for over a decade to effectively treat depression and other psychiatric disorders, have been shown to reside exclusively in escitalopram. Escitalopram has been shown in vitro to be more than twice as potent as citalopram in the inhibition of serotonin uptake. It is the most selective agent in its class, with virtually no affinity for other neurotransmitters. The efficacy of escitalopram in the treatment of depression has been demonstrated in several clinical trials. Sustained improvement in symptoms of depression was first seen at 1–2 weeks, and continuing improvement and effective prevention of depressive relapse were observed during long-term studies. Further, escitalopram has also been shown to be an effective treatment for anxiety disorders such as panic disorder, generalized anxiety disorder, and social anxiety disorder. Escitalopram was safe and well-tolerated in these studies, with a low rate of discontinuation due to adverse events. Finally, escitalopram has the lowest propensity of all the selective serotonin reuptake inhibitors, including citalopram, for drug-drug interactions mediated by cytochrome P450. Together, these properties make escitalopram an ideal choice for the treatment of depression and other psychiatric disorders in primary care patients, in the elderly, and in patients with comorbid illness.



The selective serotonin reuptake inhibitors (SSRIs) are widely accepted as first-line therapy for depression, as well as for anxiety disorders such as panic disorder (PD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). In addition, they have demonstrated utility in a variety of other conditions such as premenstrual dysphoric disorder, and some chronic pain syndromes and impulse control disorders. Thus, SSRIs are among the most prescribed pharmaceutical agents.1

Despite the great utility of the available SSRIs, research to develop improved antidepressants continues. Reported response rates in clinical trials with the older SSRIs have ranged from 50% to 60%, meaning that a proportion of patients may not adequately respond to the first drug they try.2-4 Additional areas of unmet clinical need include better tolerability and long-term efficacy, faster onset of action, and better efficacy for difficult-to-treat conditions such as severe depression.5

One current area of research focuses on developing single-isomer products from racemic compounds. Approximately 80% of available medications are racemic compounds—mixtures of enantiomers, or stereoisomers that are nonsuperimposable images of one another. As one might expect, the biological activity of a compound is influenced by its stereochemical properties. For example, since many drugs act by adhering to specific receptors, it is no surprise a left-oriented isomer (“S”) may be a better fit in a particular receptor than a right-oriented isomer (“R”), or vice versa. Thus, single-isomer agents have the potential for an improved therapeutic index resulting from higher potency and selectivity, while removing any undesirable effects attributable to the less active enantiomer. This can result in a faster onset of action, improved duration of action, and decreased potential for drug-drug interactions. Other benefits could include a less complicated pharmacokinetic profile and a simplified relationship between plasma concentration and clinical effect.

Escitalopram oxalate is the S-enantiomer of the racemic SSRI antidepressant, citalopram hydrobromide. Citalopram has been demonstrated to effectively treat depression, PD, premenstrual dysphoric disorder, and obsessive-compulsive disorder.6-8 The biological activity and therapeutic effects of citalopram have been shown to reside exclusively in escitalopram. At physiologic concentrations, the R-enantiomer of citalopram has no activity to inhibit serotonin reuptake—the presumed mechanism underlying the antidepressant effect of citalopram. However, the R-isomer has been shown to have a weak affinity for histamine H1 receptors, and the demethyl metabolite of R-citalopram weakly inhibits cytochrome P450 (CYP) 2D6.9-12

This review summarizes published escitalopram data demonstrating the drug’s safety and efficacy in the treatment of depression and anxiety disorders, as well as its potential advantages over older SSRIs.


Escitalopram is more than twice as potent as citalopram in the inhibition of serotonin uptake in in vitro binding studies10 and is the most selective agent of its class.9-11,13,14 Escitalopram shows virtually no affinity for serotonin, norepinephrine, muscarinic, histaminic, and dopamine receptors (Table 1).








Escitalopram has been shown to be active in several animal models of depression. For example, chronic mild stress induces anhedonia in rats, as measured by a significant decrease in sucrose intake. Both escitalopram and citalopram reversed the effects of chronic mild stress, and the onset of effect in the escitalopram group was faster than in the citalopram group.15 Further, escitalopram and citalopram produced dose-dependant effects, while R-citalopram was inactive, as seen in Porsolt’s forced swim test in mice.9 Finally, escitalopram was at least twice as potent as citalopram in reducing aggressive behavior in an antagonistic behavior model in the rat.16

The anxiolytic activity of escitalopram has also been demonstrated using animal models.16-18 In the first model, stimulation of the dorsal periaqueductal grey matter in the rat leads to a panic-like aversive reaction that is considered one the most reliable models of panic anxiety.18 In the second, foot shock induced ultrasonic vocalization in adult rats reflects aspects of panic disorder.17 Finally, the two-compartment black and white box test in mice and rats represents aspects of GAD.17 Escitalopram produced potent, dose-dependent anxiolytic-like effects in all three models, while R-citalopram was either inactive or showed weak activity.


Metabolism of escitalopram to S-demethylcitalopram is meditated by three CYP isoforms in parallel (3A4, 2D6, and 2C19), with 3A4 becoming more dominant as escitalopram doses increase.12 Biotransformation of demethylcitalopram to didemethylcitalopram is mediated by CYP 2D6 and an unknown non-CYP-mediated reaction.12 The metabolites of escitalopram do not contribute to the clinical effects of the SSRI as they are present at much lower concentrations and are much weaker inhibitors of serotonin reuptake in vitro.12 Escitalopram is absorbed rapidly, with an average time to peak plasma concentration or serum concentrations of 4 hours. Food does not affect escitalopram absorption. Escitalopram does not bind strongly to plasma proteins, with approximately 56% of the compound being protein bound.19

Escitalopram exhibits linear kinetics that are dose-proportional across the therapeutic range. Terminal half-life in young healthy subjects is about 27–32 hours, consistent with once-a-day dosing.19 The metabolites of escitalopram do not have extended half-lives, so increased accumulation of drug is not observed. Steady state levels of escitalopram are achieved within 10 days. In a cross-over study comparing the single-dose pharmacokinetics of escitalopram 20 mg to those of citalopram 40 mg, the two SSRIs and their primary metabolites were found to be bioequivalent.20

The pharmacokinetics of escitalopram in elderly subjects (≥65 years) are similar to those observed in younger subjects, although the area under the curve (AUC) and half-life were increased by about 50%. Thus, 10 mg/day is the recommended dose for elderly patients. Escitalopram has not been evaluated in pediatric patients. No dosage adjustment is recommended for patients with reduced hepatic function, moderate renal function impairment, or on the basis of gender.21

Efficacy in Depression

Data from several large, randomized, placebo-controlled clinical trials indicate that escitalopram is effective in the treatment of depression. These studies also indicate that the starting dose of 10 mg/day is an effective dose to which most patients respond, and that escitalopram treatment was significantly superior to placebo in as little as 1–2 weeks.


The safety and efficacy of escitalopram has been demonstrated in two fixed-dose studies.22,23 In the first, an 8-week, placebo-controlled study conducted in the United States, 491 depressed outpatients were randomized to escitalopram 10 mg/day, escitalopram 20 mg/day, citalopram 40 mg/day, or placebo.22 At both doses, escitalopram significantly improved depressive symptoms compared to placebo as measured by the Montgomery-Asberg Depression Rating Scale (MADRS), the 24-item Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI) scales, and patient-rated quality of life (QOL) scales. Significant separation of escitalopram from placebo was observed within 1 week of double-blind treatment, as measured by the CGI-Improvement scale (Figure 1, P<.01). Citalopram also significantly improved depressive symptoms; however escitalopram 10 mg/day was at least as effective as citalopram 40 mg/day at endpoint. Anxiety symptoms and QOL were also significantly improved by escitalopram compared to placebo.










Another fixed-dose, 8-week, placebo-controlled, double-blind European trial (N=380) demonstrated that escitalopram 10 mg/day can be effectively used to treat depressed patients in a primary care setting.23 Escitalopram-treated patients experienced significant improvement by study endpoint relative to placebo on the MADRS total score (P=.002). Further, escitalopram showed onset of action that was statistically superior to placebo from week 1 onward as measured by the CGI-Improvement scale, at week 2 as measured by MADRS total score, and from week 3 onward as measured by CGI-Severity (CGI-S) scale. Response rates (defined as at least a 50% reduction in MADRS total score) were 55% for the escitalopram group versus 42% for placebo.

Montgomery and colleagues15 published results from the first 4 weeks of a European 8-week flexible-dose study conducted in primary care centers, during which the escitalopram and citalopram doses were fixed at 10 mg/day and 20 mg/day, respectively. At week 4, mean change in MADRS total score for escitalopram patients was significantly decreased versus placebo (P=.002), and escitalopram was statistically superior to placebo on both CGI subscales. Further, escitalopram but not citalopram produced a significantly superior effect versus placebo by week 1 on both the MADRS (P=.023) and CGI (P≤.05), which was sustained throughout the study.

Flexible Dose

Trivedi and Lepola24 reported the combined results of two 8-week, double-blind, placebo-controlled studies (including 8-week results from the European study described above15 and a study in the US of almost identical design) conducted by both specialists and primary care physicians.24 In these studies, 844 depressed outpatients were randomized to receive placebo, escitalopram 10–20 mg/day, or citalopram 20–40 mg/day. Both active treatment groups experienced significant changes from baseline in MADRS total score. Similar to the fixed-dose studies, the onset of action in the escitalopram group (1 week) was significantly faster than the citalopram group, and changes in mean MADRS scores were larger for escitalopram than citalopram throughout the study. The mean change from baseline in CGI-S was significant for escitalopram at week 1 (P<.05). By study end, 60% of escitalopram patients, 54% of citalopram patients, and 46% of placebo patients were classified as responders (patients achieving a reduction in MADRS total score of at least 50%).

Pooled Analysis

Results from the previously described studies demonstrate that escitalopram at doses of 10–20 mg/day effectively treats depression. However, none of the three studies employing both placebo- and citalopram-comparator arms22,24 was of sufficient sample size to detect a difference between active treatments. Therefore, Gorman25 examined pooled data from the three trials that included a citalopram arm in order to determine whether escitalopram represents an improved treatment for depression relative to citalopram. The similar design features (eg, patient characteristics, symptom measurement scales) of the three studies allowed for the pooling of data to provide a sample size adequate for statistical comparisons between the two active treatment groups.

At study endpoint, both the escitalopram 10–20 mg/day group (n=520) and the citalopram 20–40 mg/day group (n=403) experienced significantly improved depressive symptoms versus placebo (P≤.001). Escitalopram treatment significantly improved MADRS (Figure 2) and CGI scores within 1 week. At week 1 and week 8, escitalopram treatment led to statistically significantly greater improvement on the MADRS than citalopram treatment (Figure 2). Approximately 60% of patients treated with escitalopram were responders (defined as at least a 50% reduction in MADRS total score), while the response rates for citalopram and placebo were 53% and 41%, respectively.










Relapse Prevention

Continuation treatment with escitalopram in a long-term, double-blind, placebo-controlled study effectively prevented relapse and provided further improvement in depressive symptoms.26 Two hundred seventy-four patients who had completed 8 weeks of double-blind treatment with escitalopram, citalopram, or placebo were enrolled in this long-term extension study. The first phase of the continuation treatment was an 8-week, flexible-dose, open-label period in which all patients received escitalopram 10–20 mg/day (patients who had received escitalopram in the double-blind lead-in trials actually received a total of 16 weeks of escitalopram treatment prior to entering the placebo-controlled withdrawal phase). Responders during this 8-week treatment period were randomized in a 2:1 ratio to double-blind treatment with either escitalopram (at the same dose to which they had responded, n=181) or placebo (n=93) for 36 weeks (placebo-controlled withdrawal phase of the study). In the escitalopram group, time to relapse (defined as a MADRS total score ≥22, or discontinuation due to an insufficient therapeutic response) was significantly longer, and cumulative relapse rate was significantly lower than with placebo. In addition, continuing treatment with escitalopram produced further improvement in depression scores versus placebo.

Efficacy in Anxiety Disorders

Several animal models indicate that escitalopram has anxiolytic properties. Further, in clinical trials comparing the efficacy of escitalopram and citalopram in relieving anxiety symptoms associated with depression, escitalopram also had a rapid onset of action,27 which is consistent with the other efficacy findings determined for escitalopram in the treatment of depression. Results demonstrating the efficacy of escitalopram in the treatment of GAD, PD, and SAD are discussed in the following section.

Escitalopram 10–20 mg/day significantly improved symptoms of GAD in an 8-week, randomized, double-blind, placebo-controlled trial (N=252).28 The escitalopram-treated group experienced significant improvement over placebo on efficacy measures including the Hamilton Rating Scale for Anxiety (HAM-A) and the HAM-A psychic anxiety subscale, the Hospital Anxiety and Depression (HAD) subscale, and the CGI-Severity scale. Further, QOL measures improved, with statistically significant improvement observed in both the total scale and in individual items assessing overall life satisfaction and contentment, ability to function in daily life, and mood and overall sense of well being.

Escitalopram treatment (10–20 mg/day) significantly improved QOL and PD symptoms in a 10-week, randomized, placebo-controlled, double-blind trial (N=247).29 Several validated panic and anxiety assessment tools, as well as the CGI and two patient-rated QOL scales, indicated that escitalopram significantly improved PD symptoms compared to placebo. At weeks 8 and 10, significantly more escitalopram-treated patients achieved full remission (defined as no panic attacks in the previous week and a CGI-I score of 1; Figure 3). In addition, significant improvement was observed in QOL scores for escitalopram patients compared to placebo patients, as well as in individual items, including overall life satisfaction, social and family relationships, ability to function in daily life, and overall sense of well being.








 Escitalopram 10–20 mg/day was effective in the treatment of SAD in a 12-week, placebo-controlled, double-blind, multicenter, study (N=358).30 Escitalopram was significantly superior to placebo (P<.01) on the primary efficacy parameter—mean change in Liebowitz Social Anxiety Score (LSAS) from baseline to endpoint. Superior therapeutic efficacy for the escitalopram group relative to placebo was also observed as measured by CGI scores, LSAS avoidance and fear/anxiety subscale scores, and the work and social life items on the Sheehan Disability Scale.

Safety and Tolerability

Adverse-Event Profile

Escitalopram is safe and well tolerated, with a low rate of discontinuation due to adverse events. According to a comprehensive safety database31 that include depressed patients from the efficacy studies described previously, the rates of discontinuation due to adverse events for escitalopram 10–20 mg/day (n=715) and placebo (n=592) are statistically indistinguishable (5.9% and 2.2%, respectively), while the package inserts for other SSRIs, including citalopram, report discontinuation rates due to adverse events in worldwide clinical trials of 15% to 20%.

The adverse events most commonly reported by escitalopram-treated patients in the safety database are shown in Table 2.31 Only one adverse event, nausea, occurred in >10% of patients treated with escitalopram and more frequently than with placebo. Point of prevalence estimates of nausea per day show the difference between escitalopram and placebo leveling off after 3–4 weeks of double-blind treatment.23 Escitalopram was not associated with central nervous system stimulant effects, as the only activation adverse event to occur at a rate greater than placebo was insomnia (9% versus 4%). Incidence of ejaculation disorder for male patients in the safety database is approximately 9% for escitalopram, and is similar to that reported for citalopram.31 Other sexual adverse events, such as decreased libido, impotence, and anorgasmia, were reported at 4%, 3%, and 2%, respectively.21







In all the studies reviewed, no clinically significant changes were noted for clinical laboratory parameters, electrocardiogram, or vital signs. Escitalopram treatment had no effect on body weight, unlike other SSRIs.

Patients can be reassured that, in cases where escitalopram data are limited, any concerns about tolerability or safety can be addressed by referring to published data on the racemate citalopram. For example, while there currently are no published data on the effects of escitalopram treatment during pregnancy, delivery outcomes recorded by the Swedish Birth Registry of women reporting the use of antidepressants (including citalopram, n=375) in early pregnancy were not significantly different from the rest of the registry, with the exception of a slightly shorter gestational duration.32

Drug-Drug Interactions

Inhibition of the CYP enzymes, which metabolize the majority of available medications, underlies many drug-drug interactions. According to in vitro and in vivo data, escitalopram has little or no effect on the CYP pathways 1A2, 2C9, 2C19, 2D6, 3A4, and, 2E1 (Table 3).12 The weak inhibitory activity of citalopram observed in vitro has been attributed to the demethyl metabolite of R-citalopram. In vivo data on the drug interaction potential of escitalopram are limited; however, co-administration of escitalopram and ritonavir, a potent inhibitor of CYP 34A, in 21 healthy male and females produced no clinically significant effect.33









Although in vitro data indicate that escitalopram does not inhibit CYP 2D6, co-administration of a single dose of the 2D6 substrate, desipramine (50 mg), and escitalopram 20 mg/day for 21 days resulted in 40% increase in Cmax and a 100% increase in AUC of desipramine.21 The clinical significance of these results is not known. Although coadministration of escitalopram doubled blood levels of metoprolol in one single-dose study, no clinically significant effects on blood pressure or heart rate were observed.21

Clinical experience with the racemate citalopram indicates that coadministration with a variety of known CYP substrates and/or inhibitors, including antipsychotics,34,35 tricyclic antidepressants,36,37 theophylline,38 carbamazepine,39 ketoconazole,40 and triazolam,41 does not produce significant interactions. Citalopram also has a relatively low potential for drug-drug interactions via other mechanisms, such as interference with protein binding or renal elimination.42,43

As with all SSRIs, escitalopram should not be co-administered with monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing an MAOI.

Dosage and Administration

Escitalopram should be administered once daily in the morning or evening with or without food at a starting dose of 10 mg/day. This is an effective dose to which most patients will respond; however, if needed, dosage can be increased to 20 mg/day. No adjustment of starting dose is required for special patient populations including elderly patients or those with renal or hepatic impairment. Escitalopram is available in 5-mg tablets and 10-mg or 20-mg scored tablets.

Formulary Considerations and Conclusions

Escitalopram 10 mg/day is a selective and potent SSRI with little or no affinity for other neurotransmitter receptors. Several placebo-controlled clinical trials have demonstrated the drug’s safety and efficacy in depression. Escitalopram also has been studied in the prevention of depression relapse, as well as anxiety disorders such as GAD, PD, and SAD. Sustained improvement in symptoms of depression was first seen at 1–2 weeks,22-25 and continuing improvement was noted during long-term studies.26 The drug is well tolerated, with rates of discontinuation due to adverse events that are indistinguishable from placebo. The low propensity of escitalopram for CYP-mediated drug-drug interactions is a potential advantage for the average adult patient, who will most likely take more than one medication in the course of long-term therapy. It also is an advantage for the elderly, who tend to take more than one medication on a regular basis, as well as for those with chronic medical illnesses, which often require extensive polypharmacy. In conclusion, the data presented here support the use of escitalopram as a first-line antidepressant.


1.    Kaufman D, Kelly J, Rosenberg L, Anderson T, Mitchell A. Recent patterns of medication use in the ambulatory adult population of the United States. JAMA. 2002;287:337-344.
2.    Charney DS BR, Miller H. Treatment of depression. In:Textbook of Psychopharmacology. Washington, DC:American Psychiatric Press; 1998.
3.    Depression. Clinical Practice Guideline, Number 5. Rockville, Md: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1993.
4.    Kasper S HA. Do SSRIs differ in their antidepressant efficacy? Hum Psychopharm 1995;10(suppl):163-172.
5.    Montgomery S. New developments in the treatment of depression. J Clin Psychiatry. 1999;60(suppl 14):10-15.
6.    Willets J, Lippa A, Beer b. Clinical development of citalopram. J Clin Psychopharmacol. 1999;19(suppl):36S-46S.
7.    Joubert A, Stein D. Citalopram and anxiety disorders. Rev Contemp Pharmacother. 1999;10:79-123.
8.    Keller M. Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. J Clin Psychiatry. 2000;61:896-908.
9.    Sanchez C, Hogg S. The antidepressant effect of citalopram resides in the S-enantiomer. Paper presented at: Annual Meeting of the New Clinical Drug Evaluation Unit; May 30, 2002; Boca Raton, Fla.
10.    Owens M, Knight D, Nemeroff C. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345-350.
11.    Hyttel J, Boges K, Perregaard J, et al. The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm Gen Sect. 1992;88:157-160.
12.    Von Moltke L, Greenblatt D, Giancarlo G, Granda B, Harmatz J, Shader R. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Disp. 2001;29:1102-1109.
13.    Bergqvist P, Sanchez C. Escitalopram mediated the pharmacological activity of citalopram. In vivo studies. Paper presented at: the annual meeting of the Scandanavian College of Neuropsychopharmacology; April 2001; Juan Les Pins, France.
14.    Sanchez C, Brennum L. Escitalopram is a highly selective and potent serotonin reuptake inhibitor. In vitro studies. Paper presented at : the Annual Meeting of the Scandanavian College of Neuropsychopharmacology; April 2001; Juan Les Pins, France.
15.    Montgomery S, Loft H, Sanchez C, Reines E, Papp M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol. 2001;88:282-286.
16.    Mitchell P, Hogg S. Behavioural effects of escitalopram predict potent antidepressant activity [abstract]. Biol Psychiatry. 2001;49(suppl 8):48S
17.    Sanchez C. Escitalopram has potent anxiolytic effects in rodent anxiety models. Paper presented at: Annual Meeting of the American Psychiatric Association; May 30, 2001; Boca Raton, Fla.
18.    Hogg S. dPag Stimulation: a model for panic anxiety. Paper presented at: the Annual Meeting of the Society of Biological Psychiatry; May 2002; Philadelphia, PA.
19.    Gutierrez M, Mengel H. Pharmacokinetics of escitalopram. Paper presented at: the Annual Meeting of the New Clinical Drug Evaluation Unit; June 2002; Boca Raton, Fla.


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Paul M. Thompson, PhD, Judith L. Rapoport, MD, Tyrone D. Cannon, PhD and Arthur W. Toga, PhD

Primary Psychiatry. 2002;9(11):40-47

Dr. Thompson is assistant professor of neurology at the University of California at Los Angeles (UCLA) School of Medicine and a member of the UCLA Laboratory of Neuro Imaging and Brain Mapping Division.

Dr. Rapoport is chief of the Child Psychiatry Branch at the National Institute of Mental Health, in Bethesda, MD, and professor of psychiatry and pediatrics at Georgetown University School of Medicine in Washington, DC.

Dr. Cannon is Staglin Family Professor and chair of the Psychology Department at the UCLA College of Letters and Science, and professor of psychiatry and human genetics at the UCLA School of Medicine.

Dr. Toga is professor of neurology, director of the Laboratory of Neuro Imaging, and codirector of the Brain Mapping Division at the UCLA School of Medicine.

Acknowledgments: This work was supported by National Institute of Mental Health (NIMH) Intramural funding to Dr. Rapoport, an NIMH research grant to Dr. Cannon, and research grants to Drs. Thompson and Toga from the National Center for Research Resources (P41 RR13642 and RR00865), the National Library of Medicine (LM/MH05639), National Institute of Neurological Disorders and Stroke (NS38753), the NIMH (MH65166), and the Human Brain Project (P20 MH/DA52176).



Schizophrenia is a chronic, debilitating psychiatric disorder that affects 0.2% to 2% of the world’s population. Often striking without warning in the late teens or early twenties, its symptoms include auditory and visual hallucinations, psychotic outbreaks, bizarre or disordered thinking, depression, and social withdrawal. To combat the disease, new antipsychotic drugs are emerging; these atypical neuroleptics target dopamine and serotonin pathways in the brain, offering increased therapeutic efficacy with fewer side effects. Despite their moderate success in controlling some patients’ symptoms, little is known about the causes of schizophrenia and what triggers the disease. Its peculiar age of onset raises key questions: What physical changes occur in the brain as a patient develops schizophrenia? Do these deficits spread in the brain, and can they be opposed? How do they relate to psychotic symptoms? As risk for the disease is genetically transmitted, do a patient’s relatives exhibit similar brain changes? Recent advances in brain imaging and genetics provide exciting insight on these questions. Neuroimaging can now chart the emergence and progression of deficits in the brain, providing an exceptionally sharp scalpel to dissect the effects of genetic risk, environmental triggers, and susceptibility genes. Visualizing the dynamics of the disease, these techniques also offer new strategies to evaluate drugs that combat the unrelenting symptoms of schizophrenia.



Schizophrenia is a chronic, disabling mental illness that devastates the lives of patients and their caregivers, and affects 0.2% to 2% of the world’s population. Newer medications, such as the atypical neuroleptics (eg, clozapine, olanzapine, risperidone, and quetiapine) offer patients improved symptom control with fewer neurologic side effects. Even so, many patients remain refractory to treatment, and symptoms persist for their entire lifetime.

What triggers schizophrenia still remains an enigma. The illness typically strikes in young adulthood, with an average age of onset between 25 and 30 in women and between 20 and 25 in men. Psychotic disturbances include delusions, hallucinations, and bizarre thoughts (so-called positive symptoms). Negative symptoms include chronic depression, flat affect, loss of motivation, and social decline. If untreated, the active phase of florid psychotic symptoms may last forever, or it may be controlled to a degree by neuroleptics. Even when medications are effective, psychotic outbreaks are often replaced by a residual phase of poverty of thought or blunted affect. Around 20% of patients have a single psychotic outbreak, and 35% have multiple episodes without severe functional or personality impairments.1 The remainder of patients have relatively static (10%) or progressive (35%) functional impairments between psychotic episodes.

The discovery of chlorpromazine in the 1950s revolutionized the treatment of schizophrenia. The drug and other classical neuroleptics like it (eg, haloperidol), alleviate positive symptoms by blocking dopamine D2 receptors in the limbic and prefrontal cortices of the brain. These systems regulate emotional behavior and executive function. Unfortunately, at effective doses, these drugs also block dopamine receptors in the caudate/putamen, often leading to neurologic side effects associated with dopamine depletion, and resembling Parkinson’s disease.

Newer atypical antipsychotics, including clozapine and olanzapine, have reduced motor side effects, in part due to their weaker affinity for the D2 receptor. They powerfully block the serotonin (5-HT)2 and dopamine (D)4 receptors, and tend to outperform haloperidol in reducing negative symptoms.2 In the 20% of patients who respond poorly to conventional drugs, 33% to 66% respond well to clozapine; however, the risk of neutropenia in 3.6% and agranulocytosis in 0.75% of patients on clozapine requires constant monitoring in patients taking the drug, and underscores the need for safer drugs.

The last 10 years have also seen a search for biological markers of schizophrenia in the brain. Advances in brain imaging and genetics, in particular, are clarifying how schizophrenia emerges, its progression, its genetic transmission, and its impact on relatives who are at genetic risk. The peculiar age of onset for schizophrenia raises key questions: What physical changes occur in the brain as a patient develops schizophrenia? Do these deficits spread in the brain, and can they be opposed? How do they relate to psychotic symptoms? Do a patient’s relatives exhibit similar brain changes? New brain-imaging approaches can now create dynamic maps of the disease spreading in the brain, along with genetic maps that uncover deficit patterns in relatives. We review these techniques and their current uses.

Brain Development and Schizophrenia

Many studies point to developmental abnormalities that confer a later risk for schizophrenia. Risk factors include obstetric complications such as fetal malnutrition, extreme prematurity, hypoxia, and ischemia.3,4 People who are born in winter months,5 and infants exposed to the influenza virus during their second trimester, have an increased incidence of schizophrenia. According to the “neurodevelopmental hypothesis,” disrupted brain development at this key phase could play a causative role in schizophrenia.

A key puzzle is why there is a long gap between an early cerebral insult and the emergence of symptoms 20 or more years later. To explain this, some favor a two-hit (or diathesis-stress) model, in which an early developmental or genetic anomaly must be compounded by psychological trauma, viral infection, or some currently unknown trigger later in life for the disease to be expressed. Renewed interest in this hypothesis comes from a recent wave of brain-imaging studies identifying features of brain maturation that occur well into adolescence and beyond. These brain-imaging studies visualize a sequence of growth spurts in myelination through childhood,6,7 and dramatic waves of gray matter loss believed to reflect synapse production and pruning in the teen years.8-10 Schizophrenia typically strikes at a time when these developmental changes are still occurring. In particular, a natural teenage process of synapse elimination, or pruning, may be accelerated or otherwise derailed in schizophrenia.11

Mapping Brain Development

Since 1992, Judith L. Rapoport, MD, and her colleagues at the National Institute of Mental Health (NIMH) in Bethesda, Md, have scanned over 1,000 children and adolescents with high-resolution brain magnetic resonance imaging (MRI). What makes this study unique is the fact that these children return to the clinic to be re-scanned every 2 years. Many children are now receiving their fifth scan, and have grown up sice the beginning of the study, leaving a time-lapse movie to record how their brain has developed. The resulting treasure-chest of brain scans charts brain growth in unprecedented detail. Growth spurts and losses can be mapped in individual children, and the resulting patterns can be compared in health and disease.7

Our recent studies of these scans, in collaboration with the NIMH group, have developed computerized methods to map subtle changes in the developing brain. The goal is to visualize where the brain is growing fastest, measure local growth rates and their statistics, and reveal where gray matter or other types of tissue are lost. Detailed color-coded maps that combine and compare data from multiple subjects show where, and how fast, these changes occur. They also pinpoint where brain changes are most prominent in disease (Figure 1). One surprise has been that many brain systems apparently lose tissue as a child develops. Parts of the basal ganglia, which control learned motor functions, lose up to 50% of their tissue in the 4-year period leading up to puberty.7













Early-Onset Schizophrenia

Among those patients scanned at the NIMH were 50 adolescents with early-onset schizophrenia (EOS), scanned every 2 years as their disorder developed. A review of 1,000 charts and follow-up screening of 300 families from the United States and Canada led to a sample of 50 subjects with EOS (30 boys, 20 girls). These patients had detailed cognitive and clinical evaluations; they satisfied Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for diagnosis of schizophrenia before 13 years of age.12 Rigorous study revealed that their symptoms are continuous with the adult disorder; many patients resemble poor-outcome adult cases. Their brain scans and repeated neuropsychiatric tests therefore hold key information on how schizophrenia develops in the teenage years.

Dynamic Wave of Gray-Matter Loss

In studying the schizophrenic patients, a spreading wave of tissue loss that began in a small region of the brain, the parietal cortices (Figure 1: top row, red colors) was apparent.10 This deficit pattern moved across the brain like a forest fire. It destroyed more tissue as the disease progressed (red colors, bottom row), and eventually engulfed the rest of the cortex after a period of 5 years. Video sequences were also computed from the brain images, to show the dynamics of this process. These maps are color-coded to show different degrees of change, revealing where gray matter is significantly reduced in disease, relative to healthy controls.

At each scan, 12 schizophrenic patients were compared with 12 healthy controls matched for age, gender, and demographics. In each scan, a measure of the local quantity of gray matter was made at each point on the cerebral cortex, and the average pattern of changes was mapped in both patients and controls. At their first scan (an average of 1.5 years after initial diagnosis), patients showed a 10% gray matter deficit in a small region of the cortex. This deficit, observed at 13 years of age, was initially confined to parietal brain regions involved in spatial association. Over the 5 succeeding years, this brain tissue loss swept forward into sensory and motor regions. By 18 years of age, it had moved into dorsolateral prefrontal, and temporal cortices, which were not initially affected.

This pattern was replicated in independent groups of male and female patients. Each showed a similar pattern of spreading deficits, reaching a 20% to 25% average loss in some regions. Overall, the loss corresponded with impairments in neuromotor, auditory, visual search, and frontal executive functions that characterize schizophrenia. The frontal eye fields lost tissue the fastest, at about 5% per year, perhaps consistent with the eye-tracking and smooth eye pursuit deficits often reported in patients. The mapping technique also agreed with more conventional methods, in which the total volume of gray matter in each lobe of the brain was measured and compared over time.13

An earlier study14 found that the healthy controls lost cortical gray matter in the frontal (2.6%) and parietal lobes (4.1%); patients had faster losses in frontal (10.9%) and parietal (8.5%) regions, and they also suffered a decrease in temporal gray volume (7%), which remained stable in the controls.

Total frontal loss rates correlated with negative symptoms (total score on the Scale for the Assessment of Negative Symptoms) at final scan (P<.038). This is consistent with the physiological hypothesis that negative symptoms of schizophrenia may partly derive from reduced dopaminergic activity in frontal cortices. Future studies in larger samples will assess how these loss profiles correlate with specific symptoms such as auditory or visual hallucinations. Visual hallucinations, for example, may originate from multiple brain regions, perhaps in parietal or occipital rather than temporal cortices, or, if within the temporal lobe, possibly from the small inferior/posterior visual association regions, such as Brodmann area 37. We are currently developing digital mapping methods to isolate which specific regional deficits (eg, dorsolateral prefrontal, temporal) link most tightly with symptoms and cognitive impairment.

Medication Effects

Since there is a possibility that drug treatment may have induced these patterns of gray matter loss in the schizophrenic patients, 10 IQ-matched, serially imaged nonschizophrenic subjects who received identical medication to the patients (primarily for control of chronic mood disorders and aggressive outbursts) were mapped as well. While the nonschizophrenic group showed some subtle but significant tissue loss, this was much less marked than for the schizophrenics, and was restricted to superior frontal cortices. No temporal lobe or pervasive frontal deficits were observed in the medication controls, suggesting that the wave of disease progression may be specific to schizophrenia, regardless of medication, gender, or IQ.

Normal Gray-Matter Pruning

The shifting pattern of deficits in patients with schizophrenia raises interesting questions. First, tight correlations between the pattern of loss and specific symptoms could point to underlying mechanisms. If the pathogenesis of schizophrenia is a dynamic, gradual process, a 5-year window may be available for drugs to oppose the wave of loss. Imaging strategies will be key tools in evaluating their efficacy.

Second, just what causes this progressive wave of tissue loss? Healthy adolescents also lose gray matter in parietal regions, at a more modest rate of approximately 1%/year.10 The cognitive effects of this process are unclear. Future brain-imaging studies will reveal whether the process of normal gray matter maturation, sometimes called “pruning,”8 obeys a similar shifting pattern. If so, this will clarify whether the schizophrenic wave of loss is an alteration or acceleration of a normal developmental process. An alternative view is that it is a separate process entirely that begins in the teenage years.

Genetic Risk for Schizophrenia

Genetic studies are greatly accelerating our understanding of schizophrenia (see Sawa and Snyder15 for a recent review). Relatives who are genetically closer to a schizophrenic patient are more likely to develop the disorder themselves, so there is great interest in determining individual relatives’ risk for the disease, as well as understanding its genetic transmission. Two key themes are dominant in the study of genetic risk: (1) twin or family studies of disease transmission; and (2) the search for susceptibility genes. Twin and family studies reveal that there is a genetically transmitted risk for schizophrenia: adoption studies confirm this, and also control for differences in family environment that could conceivably promote the disease. Siblings of patients have a 14% lifetime risk of developing schizophrenia, and monozygotic (MZ) twins of patients, who have identical genes, have a 48% risk. Thus, risk increases with increased proportion of genetic material in common with the patient. Intriguingly, an identical twin’s risk is not 100%, showing that genes are not all-important in producing the disease. Discordance studies, where just one of two identical twins has the disease, are designed to study nongenetic triggers that promote disease expression in some relatives but not others.

Risk Genes

Several candidate genes have recently been discovered that affect individual risk for schizophrenia.16 These DNA variations, passed on from parents to their offspring, modify behavioral traits, disease susceptibility, and even treatment response. If two randomly selected individuals’ genomes were aligned, 0.1% to 0.2% of the nucleotides would not match. About 85% of these sequence variations are single nucleotide polymorphisms (SNPs). These are sites where at least 1% of the entire human population has a different base, and they occur roughly every 350 to 1,000 base pairs along the genome. About 200,000 of these SNPs, or about half of the total, occur in protein coding regions or upstream regulatory sites. By altering a protein’s amino-acid sequence or expression pattern, these functional SNPs are likely to account for almost all human heritable variation, and contribute to common diseases such as Alzheimer’s disease, arthritis, and diabetes, as well as genetic risk for schizophrenia. To find susceptibility genes and quantitative trait loci, association studies can now identify genetic variation by genotyping individuals at thousands of these loci, using high-capacity SNP detection chips.

Genetic loci that appear to confer susceptibility to schizophrenia have been mapped to regions on chromosomes 1, 6, 8, 10, 13, and 18. No single genetic variation is found in all schizophrenia patients. Two percent of diagnosed patients, however, exhibit a deletion of chromosomal region 22q11. This 22q11 deletion confers a 25% to 30% risk of schizophrenia, and results in velocardiofacial syndrome—a disorder characterized by learning disabilities, cardiac defects, and hypernasal speech due to abnormalities of the palate. Remarkably, the gene encoding catechol-O-methyltransferase (COMT), which inactivates dopamine in the brain, is also localized to 22q11, and mice with targeted deletion of this gene have excess dopamine in the prefrontal cortex. The action of this candidate gene, which is altered in some patients, is consistent with the dopamine hypothesis. Genetic variations may impair neurotransmitter metabolism, and this feature is consistent with schizophrenia symptoms and how antipsychotic drugs work.

Mapping Genetic Risk

Brain imaging can identify deficit patterns associated with these genetic risks. Genetic brain maps, in particular (Figure 2), show which aspects of brain structure are under strongest genetic control.17 In disease studies,18 they reveal brain regions at genetic risk for deficits. Recently, we developed a technique to visualize genetic influences on brain structure.17,19 This technique determines which aspects of brain structure is inherited from parents: some features, such as the quantity of frontal gray matter, prove to be under tight genetic control, while others are not. Not every part of a brain’s structure is strongly predetermined by our genetic blueprint: temporal and hippocampal regions involved in learning and memory, and some cortical and cerebellar regions, appear to be under greater environmental influence.19,20 These genetic brain maps can be used to find structural features that are similar among family members, as we shall describe next.



To see how this approach works, consider the color brain maps in Figure 2. These are computed from magnetic resonance imaging scans of normal twins. Figure 2a shows the correlation in the amount of gray matter in identical (MZ) twins, who have exactly the same genes. Red colors denote regions where twins are extremely similar in their quantity of gray matter. The map of correlation coefficients effectively shows accurate it would be if the amount of gray matter in one twin was used to predict the amount of gray matter in the other. Figure 2b shows the gray matter correlations for fraternal (dizygotic [DZ]) twins, who share on average half their genes with each other. These correlations are substantially less. If only the environment is important, it should not matter whether the twins are identical or fraternal. However, the heritability map (Figure 2c) shows that gray matter volume in certain parts of the brain is statistically more closely matched in the identical twins than in twins who were less similar genetically. The high genetic control of frontal brain structure is intriguing, as these are regions where individual differences correlate with cognitive function (specifically IQ),17,21,22 and where family members have extremely similar brain structure.

To examine the genetic transmission of deficits in schizophrenia, we recently measured differences in cortical gray matter distribution between MZ twins discordant for schizophrenia.18 In the identical twins we examined, the schizophrenic member of each pair showed statistically significant deficits (between 5% and 8%) in superior parietal and dorsolateral prefrontal cortices, and in the left superior temporal gyrus (disease-specific map; Figure 2d). No significant differences were found between discordant co-twins in primary somatosensory or primary motor areas. Since the MZ twins were identical genetically, the early loss of parietal cortex in the EOS patients suggests an environmental rather than a genetic origin for the disease. In the frontal and temporal regions, however, where loss occurred relatively late in the EOS patients, deficits were found to be highly heritable (liability map; Figure 2d). The liability map shows regions where deficits were found in healthy relatives of patients. These deficits were statistically linked with the degree of genetic affinity to a patient (ie, worse deficits in MZ than DZ relatives). This shows that these particular deficits are mediated by genetic differences.

Brain imaging provides a biological marker for brain regions at risk in schizophrenia. Genetic brain maps can also be used to search for schizophrenia susceptibility loci, and may in the future map effects of candidate genes on brain structure. A first step in this quest will be extending “allele sharing” methods, used widely in statistical genetics, to create statistical brain maps of gene effects. Continued hybridization of methods from genetics and brain imaging will accelerate our knowledge of the mechanism of the disease, its genetic transmission, and ultimately a means to block it in individual families.


Several schizophrenia studies in which brain imaging visualizes the disease process and its genetic transmission were reviewed. With brain mapping approaches, differences in a diseased population, or one with known genetic risk, can be visualized by reference to a normative standard. A dynamic wave of gray matter loss in early-onset schizophrenia was recently detected. This process began in a brain region where deficits are not highly heritable, and subsequently invaded the frontal cortex, which is at significant genetic risk for developing deficits. Intriguingly, deficits moved in a shifting pattern, enveloping increasing amounts of cortex throughout adolescence. These deficits are severe and correlate strongly with symptom severity, but their progression does not appear to be complete until at least 7 years after symptom onset. This provides a window of opportunity for drug treatment to oppose the spread of the disease.

New imaging methods, including those linking brain deficits with specific risk genes, are likely to be at the forefront in discovering triggers and underlying risks for schizophrenia. Schizophrenia may be promoted or triggered by a nongenetic factor, including possibly psychological trauma, an infectious agent or virus, or an abnormal process that is currently unknown during pre- or postnatal development. Even so, the disease process has a strongly heritable component, and brain regions are subtly impaired in unaffected relatives. Imaging methods also show promise for early detection of the disease, especially in relatives who are at genetic risk; dynamic brain maps can also monitor disease progression, which may be advantageous in charting the effects of drugs in clinical trials.


1.    Green B. A review of schizophrenia. Psychiatry Online. Available at: Accessed October 2002.
2.    Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002;159:1018-1028.
3.    Dalman C, Allebeck P, Cullberg J, Grunewald C, Koster M. Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Arch Gen Psychiatry. 1999;56:234-240.
4.    Cannon TD, van Erp TG, Rosso IM, et al. Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 2002;59:35-41.
5.    Kirch DG. Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull. 1993;19:355-370.
6.    Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of neural pathways in children and adolescents: in vivo study. Science. 1999;19;283:1908-1911.
7.    Thompson PM, Giedd JN, Woods RP, et al. Growth patterns in the developing human brain detected using continuum-mechanical tensor mapping. Nature. 2000;404:190-193.
8.    Giedd JN, Blumenthal J, Jeffries NO, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2:861-863.
9.    Sowell ER, Thompson PM, Holmes CJ, et al. Progression of structural changes in the human brain during the first three decades of life: in vivo evidence for post-adolescent frontal and striatal maturation. Nat Neurosci. 1999;2:859-861.
10.    Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci. 2001;98:11650-11655.
11.    Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982;17:319-334.
12.    Rapoport JL, Inoff-Germain G. Update on childhood-onset schizophrenia. Curr Psychiatry Rep. 2000;2:410-415.
13.    Giedd JN, Jeffries NO, Blumenthal J, et al. Childhood-onset schizophrenia: progressive brain changes during adolescence. Biol Psychiatry. 1999;46:892-898.
14.    Rapoport JL, Giedd JN, Blumenthal J, et al. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry. 1999;56:649-654.
15.    Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease. Science. 2002;296:692-695.
16.    Liu H, Heath SC, Sobin C, et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 2002;99:3717-3722.
17.    Thompson PM, Cannon TD, Narr KL, et al. Genetic influences on brain structure. Nat Neurosci. 2001;4:1253-1258.
18.    Cannon TD, Thompson PM, van Erp T, et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci U S A. 2002;99:3228-3233.
19.    Thompson PM, Cannon TD, Toga AW. Mapping genetic influences on human brain structure. Ann Med. 2002. In press.
20.    Giedd JN, Molloy E, Vaituzis AC, et al. Heritability of cerebral cortex morphometry during childhood and adolescence. Paper presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 12, 2001; Waikoloa Village, HI.
21.    Plomin R, Kosslyn SM. Genes, brain and cognition. Nat Neurosci. 2001;4:1153-1154.
22.    Posthuma D, De Geus EJ, Baare WF, et al. The association between brain volume and intelligence is of genetic origin. Nat Neurosci. 2002;5:83-84.


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Tony P. George, MD, Aisha A. Seyal, BS, Sara L. Dolan, MA, Melissa M. Dudas, BS, Angelo Termine, BS and Jennifer C. Vessicchio, MSW

Primary Psychiatry. 2002;9(11):48-53

Dr. George is director of the Program for Research in Smokers with Mental Illness (PRISM), Connecticut Mental Health Center, and assistant professor of psychiatry in the Department of Psychiatry at Yale University School of Medicine, both in New Haven, Connecticut.

Ms. Seyal is research assistant, Ms. Dolan is psychology fellow, Ms. Dudas is research assistant, Mr. Termine is research associate, and Ms. Vessicchio is research coordinator at PRISM, Connecticut Mental Health Center.

Acknowledgments: This work was supported in part by US Public Health Service grant Nos. R01-DA-13672, R01-DA-14039, and K12-DA-00167 and a NARSAD Young Investigator Award granted to Dr. George.



Why is it important to treat nicotine addiction in schizophrenia? The prevalence of smoking in schizophrenia, as in other mental disorders, is higher than in the general population. Smoking is also associated with higher rates of medical morbidity, including cardiovascular and lung diseases, and with higher mortality in schizophrenic patients. Schizophrenia is characterized by a constellation of clinical and cognitive deficits, and these patients may remediate such deficits by cigarette smoking. Genetic and environmental factors may also play a role in the high comorbid rates of smoking in schizophrenia. Preclinical and human laboratory studies have elucidated factors which may determine this comorbidity in schizophrenia, and recent treatments for both nicotine dependence (eg, nicotine replacement, bupropion) and schizophrenia (atypical antipsychotic drugs) may be useful for smoking reduction and cessation in this population. We review the biology of nicotine addiction in schizophrenia, and findings from the laboratory and clinic which suggest that: (1) there may be biological factors which explain the high rates of comorbid nicotine addiction in schizophrenic patients; and (2) based on an understanding of this neurobiology, effective treatment for nicotine addiction in these patients is possible. A clinical approach, including pharmacologic and behavioral treatments, is discussed.



Epidemiologic and clinical studies have consistently revealed remarkable results indicating that the prevalence of cigarette smoking is markedly elevated in patients suffering from mental illness. In schizophrenic populations alone, rates of cigarette smoking approach 90%, in comparison to 25% in the general United States population.1,2 Clinicians are well aware that tobacco smoking poses dangerous health risks such as cardiovascular disease and lung cancer. In spite of the long-term health hazards associated with cigarette smoking, nicotine dependence has been difficult to treat in the schizophrenic population.

It has been speculated that individuals with schizophrenic disorders may be utilizing nicotine administered through tobacco smoking to remediate clinical and cognitive deficits. Indeed, a growing number of studies have found evidence that there may be biological and psychosocial factors which may explain these high rates of smoking comorbidity in schizophrenic patients, and that based on such knowledge, effective pharmacologic and behavioral treatments can be developed for the treatment of nicotine addiction in schizophrenia. This article reviews the epidemiology, neurobiology, clinical impact, and approach to treatment for nicotine and tobacco addiction in patients with schizophrenic disorders.

Epidemiology of Smoking in Patients With Schizophrenia

The prevalence of smoking in clinical samples of patients with schizophrenia in Western countries ranges from 58% to 88%,3 and these rates may vary as a function of setting (inpatient versus outpatient treatment) and illness severity.4,5 Interestingly, a study of Chinese schizophrenic patients in Singapore reported that the rate of smoking in schizophrenics was 31.8%, as compared to a rate of 15% in the general population.6 Researchers speculate that the lower rates observed may have been a function of societal prohibitions on smoking in Singapore.6 Hughes and colleagues5 published a clinical survey of smoking prevalence in 277 psychiatric outpatients from Minnesota compared to local and national population-based control groups, which documented higher (1.6-fold overall) rates of smoking in a variety of psychiatric disorders. This study is one of the few that have controlled for important confounding variables such as age, sex, treatment with psychotropic medication, alcohol and caffeine use, and socioeconomic status.

A population-based study recently published by Lasser and colleagues7 examined smoking prevalence in various psychiatric patient groups using the National Comorbidity Study (NCS) database. This method probably gives a more accurate estimate of smoking prevalence in individuals with psychiatric disorders than data from surveys of clinical samples. In general, current (past 30 days) smoking rates were comparable to those obtained in studies of clinical samples including major depression (44.7%), bipolar disorder (60.6%), panic disorder (42.6%), and posttraumatic stress disorder (44.6%). The notable exception was in the schizophrenic disorders (defined loosely in this study as the “nonaffective psychoses”), which were found to be at lower rates (45.3%) compared to a composite rate derived from published studies from clinical samples (72.5%).2 The Figure depicts these higher rates of smoking in schizophrenics as compared to the general population (24.7%).1,2 In addition, lower quit rates in persons with mental illness compared to those without mental illness have been observed in clinical populations, and  were confirmed in this population-based study.










Neurobiology of Comorbid Nicotine Addiction in Schizophrenia

There has been an increasing understanding of both the neurobiology of schizophrenia and nicotine addiction in the past 20 years. For the purposes of this discussion, nicotine is assumed to be the active ingredient in tobacco and cigarette smoking that exerts psychopharmacologic effects, though other components of tobacco smoke may be active in this respect.8 There are three possible reasons for the high comorbid rates of nicotine addiction in schizophrenia: (1) self-medication of clinical and cognitive deficits associated with schizophrenia by tobacco use; (2) abnormalities in brain reward pathways in schizophrenia which make these patients vulnerable to tobacco (and other drug) use; and (3) common genetic and environmental factors that are independently associated with both smoking and schizophrenia. We briefly describe the pharmacologic effects of nicotine, and how these effects may link nicotine addiction with schizophrenia.

Nicotine alters the function of neurotransmitter systems implicated in the pathogenesis of major psychiatric disorders, including dopamine (DA), norepinephrine, serotonin, glutamate, γ-aminobutyric acid, and endogenous opioid peptides.9,10 Nicotine’s receptor in the brain is the nicotinic acetylcholine receptor (nAChR). Nicotine’s stimulation of presynaptic nAChRs on these neurons increases transmitter release and metabolism. Unlike most agonists, chronic nicotine administration leads to desensitization and inactivation of nAChRs,11 with subsequent upregulation of nAChR sites. This may explain why most smokers report that the most satisfying cigarette of the day is the first one in the morning.

Mesolimbic DA (reward pathway) neurons are of particular importance since these neurons project from the ventral tegmental area (VTA) in the midbrain to anterior limbic forebrain structures such as the nucleus accumbens and cingulate cortex, and may mediate the rewarding effects of nicotine since they have presynaptic nAChRs. These are the same subcortical DA pathways that are implicated in the expression of the positive symptoms of schizophrenia. Similarly, there are nAChRs present presynaptically on midbrain DA neurons which project from the VTA to the prefrontal cortex (PFC) that evoke DA release and metabolism when nAChRs are activated by nicotine (during smoking). The PFC is known to be dysregulated in schizophrenia—a finding possibly related to hypofunction of cortical DA and other transmitter systems.11 It is this hypofunction of PFC DA which is thought to mediate the cognitive deficits and negative symptoms associated with schizophrenia, and which may be ameliorated by cigarette smoking.12,13 Nicotine also stimulates glutamate release9 and could thereby alter abnormalities in central glutamatergic systems (eg, hypofunction) associated with schizophrenia.12

Effects of Smoking in Patients With Schizophrenia

Antipsychotic Blood Levels

There is strong evidence that tobacco smoking induces cytochrome P450 (CYP) 1A2 enzyme system in the liver—a major route for the metabolism of antipsychotic drugs such as haloperidol, chlorpromazine, olanzapine, and clozapine.2 Thus, given the same daily dose of antipsychotic drug, antipsychotic blood levels have been found to be lower in smokers versus nonsmokers with schizophrenia.14,15 Accordingly, smoking cessation would be expected to lead to increases in plasma concentrations of antipsychotic drugs metabolized by the CYP 1A2 system. Such an increase in circulating levels would be expected to increase the likelihood of extrapyramidal symptoms and other antipsychotic drug side effects (sedation, anticholinergic side effects),16 but evidence for an increase in antipsychotic side effects has not been demonstrated in controlled smoking cessation studies.17-19 Nonetheless, adjustment of antipsychotic drug in schizophrenic patients who quit smoking may need to be considered, as well as close monitoring of plasma antipsychotic levels and extrapyramidal symptoms.

Positive and Negative
Symptoms of Schizophrenia

There is little evidence that smoking can significantly influence the positive and negative symptoms of schizophrenia. Several cross-sectional studies have examined the effects of cigarette smoking on psychotic symptoms in schizophrenic patients,4,20,21 with inconsistent results. Goff and colleagues20 found that schizophrenic smokers had higher total scores on the Brief Psychiatric Rating Scale than nonsmokers, and higher subscale scores for both positive and negative symptoms. Ziedonis and colleagues21 found increased positive symptoms, and reduced negative symptoms that varied by amount smoked. Hall and colleagues4 found that schizophrenics who were former smokers had fewer negative symptoms than current schizophrenic smokers.

However, recent prospective studies found no evidence for significant changes in psychotic symptoms with smoking abstinence in schizophrenic patients, suggesting the safety of smoking cessation in this population. Studies included a laboratory evaluation of tobacco abstinence in schizophrenics,22 and controlled smoking cessation trials using the nicotine patch17,18 and bupropion.19,23,24 The confounding effects of differences in other patient variables not related to smoking status may explain the differences in positive and negative symptoms between smoking and non-smoking schizophrenics found in cross-sectional studies.3,13

Movement Disorders

Cigarette smoking may reduce neuroleptic-induced parkinsonism25 and worsen symptoms of tardive dyskinesia,26 but these studies have been of cross-sectional designs. Smokers with schizophrenia are typically prescribed approximately twice the daily dose of neuroleptics compared to nonsmokers.20,25 The increased dosages are most likely due to the fact that smoking induces the metabolism of antipsychotic drugs and reduces therapeutic efficacy.27 Goff and colleagues20 found that while there was less neuroleptic-induced parkinsonism among schizophrenic smokers compared to nonsmokers, they had higher levels of akathisia. These effects may relate to nicotine’s enhancement of nigrostriatal DA systems.12,20

Neurocognitive Symptoms of Schizophrenia

Researchers have shown that a psychophysiological measure of auditory information processing (P50 responses, which involve “gating” of sensory inputs in response to two stimuli) is deficient in schizophrenic patients and their first-degree relatives compared to controls, and that nicotine and cigarette smoking transiently reverse these deficits.28-30 Animal studies suggest that P50 responses are related to low-affinity (α7) nAChR dysfunction in the hippocampus, and genetic studies have suggested that variations in regulatory regions of the α7 nAChR subunit gene on chromosome 15 may be a genetic marker for schizophrenia, and could explain high comorbid rates of nicotine use in schizophrenia.30 Interestingly, atypical antipsychotics, such as clozapine31 and olanzapine,32 may normalize P50 deficits in schizophrenic patients. This may be of importance for treatment of nicotine addiction in schizophrenia since clozapine has been shown to reduce smoking in schizophrenic patients,33,34 and atypical, compared to typical antipsychotic medications, have been shown to enhance smoking cessation rates when combined with nicotine patch in schizophrenic smokers.18

Regarding neuropsychological effects of smoking in schizophrenia, Levin and colleagues35 have demonstrated that nicotine patch can dose-dependently reverse haloperidol-induced deficits in working memory, attention, and the authors of this article have recently demonstrated that prolonged smoking abstinence is associated with worsening of deficits in spatial working memory in schizophrenic, but not control smokers.13

Effects of Antipsychotic Drugs on Smoking in Schizophrenia

Our research group has found that switching schizophrenic smokers from typical antipsychotic agents to clozapine leads to reductions in self-reported cigarette smoking, especially in heavier smokers.33 Similar findings were reported by McEvoy and colleagues,34,36 who found that the degree of reduction may be dependent on clozapine plasma levels. A related study found that the typical antipsychotic drug haloperidol leads to increased smoking in schizophrenics compared to a baseline medication-free condition.37 Most recently, two cross-sectional studies by Procyshyn and colleagues38 have found that schizophrenic patients treated with clozapine smoke less than those on depot neuroleptic agents, and that patients treated with the combination of clozapine plus risperidone smoke fewer cigarettes and have reduced carbon monoxide levels compared to patients treated with risperidone alone.39 Thus, a role for clozapine in reducing smoking behavior is suggested.

Use of the nicotine transdermal patch (NTP) is known to facilitate smoking reduction40 and cessation17,18 in schizophrenic smokers albeit at lower rates (36% to 42% at trial endpoint) than in healthy control smokers (50% to 70%).41 Nonetheless, nicotine patch use (at 21 mg/day) appears to effectively reduce cigarette smoking and nicotine withdrawal symptoms in schizophrenic smokers.17,18,22,40

Our recent studies indicate that in combination with the NTP, atypical antipsychotics, paricularly risperidone and olanzapine, may enhance smoking cessation rates compared to typical antipsychotic drugs, in schizophrenic smokers who had high motivation to quit smoking.18 Furthermore, recent data from a preliminary placebo-controlled trial comparing bupropion versus placebo in schizophrenic smokers suggests that atypical antipsychotic treatment significantly enhances smoking cessation responses to bupropion.19

We speculate that atypical antipsychotic drugs compared to typical neuroleptic agents may be helpful for smoking cessation in schizophrenics for the following reasons: (1) atypical agents produce fewer extrapyramidal side effects and improve negative symptoms, both of which may be improved by cigarette smoking; (2) treatment with atypical agents is associated with improvement in deficits in certain aspects of neuropsychological function (eg, spatial working memory, executive function) which also appear to be alleviated by smoking42; (3) sensory gating deficits (eg, P50 responses, prepulse inhibition) that are (transiently) normalized by nicotine administration or cigarette smoking are also ameliorated by some of the atypical antipsychotic drugs31,32 possibly by increasing acetylcholine release and α7 nAChR-mediated neurotransmission in the hippocampus; and (4) atypical agents are associated with augmentation of DA release in the prefrontal cortex in rodent studies,43 and may normalize presumed deficits in cortical DA function in schizophrenia, which may also be remediated by nicotine/cigarette smoking.13,18

A Clinical Approach to Smoking Cessation in Patients With Schizophrenia

The use of atypical agents and improvements in psychosocial and medical care probably affords an enhanced quality of life to individuals with schizophrenia. In addition, it is becoming increasingly apparent that cigarette smoking schizophrenic patients are more vulnerable to developing smoking-related morbidity and mortality, including an increased risk of cardiovascular disease and some forms of cancer compared to the general population of smokers.44,45

Previous epidemiological studies have suggested that schizophrenic smokers were protected against the development of malignancies,44,46 and this was thought to relate to neuroleptic drug exposure.47 In addition, there is evidence that urinary levels of the peptide bombesin, a possible marker of precancerous cigarette smoking-induced lung damage, are lower in schizophrenic patients compared to controls.48 This reduction in urinary bombesin levels is independent of smoking status in schizophrenic patients, supporting the notion that schizophrenic patients may be less vulnerable to the development of cancer. However, several subsequent epidemiological studies have found no evidence for a decreased (or increased) risk of malignancy in schizophrenic patients or other patients with serious mental illness.44,45,49,50 Previous studies may have been confounded by a selection bias where rates of these medical illnesses in older schizophrenics were lower since most of this cohort had died from other causes related to their psychiatric illness (eg, suicide) by the time they reached the age at which cancer risk is substantially increased (50 years or higher).51 Thus, disease prevention through smoking cessation/reduction in this population is an important public health issue, as schizophrenic patients comprise about 1% of the population in the United States.52

It appears that schizophrenic patients typically show low interest in quitting. However, based on ratings of motivational level on the Stages of Change scale (eg, preparation or action stages),53 there are approximately 20% to 40% whose desire to quit smoking is substantial.54-56 In many cases where smoking cessation is not possible, a reduction in smoking consumption (eg, a “harm reduction” approach) might accrue some health benefits for schizophrenic smokers,57,58 but no studies have been published to suggest that reducing smoking can reduce the risk of developing smoking-related illness in nonpsychiatric or schizophrenic smokers. Thus, an understanding of biological and psychosocial factors which render schizophrenic patients at high risk for developing nicotine addiction, as well as which contribute to their low intrinsic motivation to change smoking behaviors, are both critical to guiding efforts directed toward improving smoking cessation treatment in this population. A summary of patient and treatment factors which predict successful nicotine addiction treatment outcomes17-19,55,57 in patients with schizophrenia is presented in Table 1.








Psychosocial Interventions

Our experience in controlled treatment research studies for smoking cessation in schizophrenia has suggested the need to optimize both pharmacologic and psychosocial interventions.18,19,23

While atypical antipsychotic drugs may be one patient factor that predicts better smoking cessation/reduction outcomes, the reality is that schizophrenic patients need persistent, supportive efforts to encourage them to quit smoking, and subsequently maintain abstinence. It is notable that patients typically know very little about the dangers of smoking on their health, so education about the health risks related to tobacco smoking is an important first step in working with patients to motivate them to quit smoking. Psychoeducation, in combination with classical motivational enhancement techniques (MET), can be combined to move patients through the stages of change56 toward abstinence. For example, many patients come to our program in the “contemplation” stage. Our clinicians work with these patients to identify the pros and cons of quitting smoking.

Once patients achieve smoking abstinence, it becomes crucial to employ cognitive-behavioral coping skills techniques to reduce the likelihood of a relapse.18,55,59 Skills such as drug refusal and coping with cravings are especially important for schizophrenic patients, as they are often in environments with other smokers and peer pressure to smoke is strong. This treatment is done in a group setting, and we work from a social skills training model which encourages schizophrenic patients to practice skills which help facilitate social interaction and trust of fellow group attendees and therapists. We have found that this combination of education, MET, and skills training can be quite effective for helping schizophrenic patients quit smoking and, with classic relapse-prevention skills training, remain abstinent.

Pharmacologic Interventions

Standard Food and Drug Administration-approved smoking cessation pharmacotherapies like NTP17,18 and sustained-release bupropion19,23,24 appear to be safe and efficacious in schizophrenic patients during the course of controlled studies. Smoking cessation rates at the end of drug treatment with nicotine patch (36% to 42%)17,18 and bupropion (11% to 50%)19,23,24 in schizophrenic patients are modest compared to those achieved in nonschizophrenic control smokers (50% to 75%),41 but may be improved when patients are prescribed atypical antipsychotic agents.18,19 Differences in study design, patient selection (eg, level of motivation to quit smoking), medication dose (in the studies with bupropion, used at 150–300 mg/day) and criteria used to determine smoking abstinence may explain the variability in quit rates amongst these studies. In studies that have used NTP, patients are expected to stop all smoking when they begin NTP on the “quit date.”

When using the NTP, patients should be cautioned not to smoke while they are wearing the patch due to concerns about nicotine toxicity: symptoms include tremor, nausea, vomiting, dizziness, and, in very rare cases, seizures, arrhythmias, and death. In our research clinic, we have not encountered nicotine toxicity to be a significant problem, but patients are told that if they must smoke they should remove the patch and wait 1–2 hours before resuming smoking. Craving to smoke and continuing withdrawal symptoms typically indicates incomplete nicotine replacement, and if needed, another patch of 7–21 mg/day can be added to therapy with the 21 mg/day NTP.

For bupropion, controlled studies have started dosing at 150 mg PO daily with an increase to 150 mg BID by day 4 of treatment. The quit date is typically set once levels reach steady-state, usually 3–4 days after beginning the full dose of 300 mg/day. A history of seizures of any etiology is a contraindication to the use of bupropion as indicated by the product labeling, and we recommend not exceeding the dose of 300 mg/day, since most antipsychotic drugs reduce seizure threshold. At the same time, bupropion 150–300 mg/day does not appear to worsen positive symptoms of schizophrenia, and may reduce negative symptoms.19,23,24

The typical duration of therapy studied in schizophrenic patients with these agents is 8–12 weeks; studies with longer durations of treatment in this population have not yet been conducted. A summary of pharmacologic and behavioral treatment that have been evaluated in controlled studies of nicotine addiction is listed in Table 2.







The high rates of comorbid smoking in schizophrenic patients may relate to abnormal biology of nicotinic receptor systems and central dopamine pathways associated with this disorder. Hence, these patients may self-medicate clinical and cognitive deficits associated with schizophrenia that are nicotine-responsive. These findings have profound implications for understanding the neurobiology of schizophrenic disorders and for development of better treatments for nicotine addiction in this population, given that these patients appear to be at increased risk for developing smoking-related medical illnesses.

In addition, motivation to quit smoking is often low in schizophrenic patients and efforts need to be undertaken to increase the awareness of both patients and their clinicians of the dangers of habitual tobacco smoking. Psychoeducation, motivational enhancement, and relapse-prevention techniques are the mainstays of behavioral treatment for nicotine addiction in patients with schizophrenia.

Furthermore, there is increasing evidence from controlled studies that certain pharmacologic agents (eg, atypical antipsychotic drugs, nicotine replacement, and bupropion), in combination with behavioral support (eg, psychoeducation, MET, relapse-prevention, and social skills training), promote smoking reduction and cessation, and that these agents can be used safely for the treatment of cigarette smoking and nicotine dependence in clinically stable patients with schizophrenic disorders. While there is little evidence from controlled clinical studies that smoking cessation produces a deterioration of clinical function (eg, positive and negative symptoms) in stabilized patients, clinicians should not attempt to persuade patients to quit smoking when they are clinically unstable since the likelihood of success is low.


1.    Centers for Disease Control (2001). Cigarette smoking among adults in the United States. Morbidity and Mortality World Report (MMWR). 1999;40:869-873.
2.    George TP, Vessicchio JC. Nicotine addiction and schizophrenia. Psychiatr Times. 2001;18:39-42.
4.    Hall RG, Duhamel M, McClanahan R, et al. Level of functioning, severity of illness, and smoking status among chronic psychiatric patients. J Nerv Ment Dis. 1995;183:468-471.
5.    Hughes JR, Hatsukami DK, Mitchell JE, Dahlgreen LA. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:993-997.
6.    Chong SA, Choo HL. Smoking among Chinese patients with schizophrenia. Aust N Z J Psychiatry. 1996;30:350-353.
7.    Lasser K, Boyd JW, Woolhander S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: a population-based prevalence study. J Am Med Assoc. 2000;284:2606-2610.
8.    Fowler JS, Volkow ND, Wang GJ. et al. Brain monoamine oxidase A: inhibition by cigarette smoke. Proc Natl Acad Sci USA. 1996;93:14065-14069.
9.    McGehee DS, Heath MJ, Gelber S, Devay P, Role LW. Nicotinic enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science. 1995;269:1692-1696.
10.    Picciotto MR, Caldarone BJ, King SL, Zachariou V. Nicotinic receptors in the brain: links between molecular biology and behavior. Neuropsychopharmacology. 2000;22:451-465.
11.    Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol. 1997;11:123-131.
12.    Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence and schizophrenia: clinical phenomenon and laboratory findings. Am J Psychiatry. 1998;155:1490-1501.
13.    George TP, Vessicchio JC, Termine A, et al. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology. 2002;26:75-85.
14.    Perry PJ, Miller DD, Arndt SV, Smith DA, Holman TL. Haloperidol dosing requirements: the contributions of smoking and nonlinear pharmacokinetics. J Clin Psychopharmacol. 1993;13:46-51.
15.    Seppala NH, Leinonen EV, Lehtonen ML, Kivisto KT. Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharmacol Toxicol. 1999;85:244-246.
16.    Meyer JM. Individual changes in clozapine levels after smoking cessation: results and a predictive model. J Clin Psychopharmacol. 2001;21:569-574.
17.    Addington J, el-Guebaly N, Campbell W, Hodgins DC, Addington D. Smoking cessation treatment for patients with schizophrenia. Am J Psychiatry. 1998;155:974-976.
18.    George TP, Zeidonis DM, Feingold A, et al. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry. 2000;157:1835-1842.
19.    George TP, Vessicchio JC, Termine A, et al. A placebo-controlled study of bupropion for smoking cessation in schizophrenia. Biol Psychiatry. 2002;52:53-62.
20.    Goff DC, Henderson DC, Amico E. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry. 1992;149:1189-1194.
21.    Ziedonis DM, Kosten TR, Glazer WM, Frances RJ. Nicotine dependence and schizophrenia. Hosp Comm Psychiatry. 1994;45:204-206.
22.    Dalack GW, Becks L, Hill E, Pomerleau OF, Meador-Woodruff JH. Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia. Neuropsychopharmacology. 1999;21:195-202.
23.    Evins AE, Mays VK, Rigotti NA, Tisdale T, Cather C, Goff DC. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tob Res. 2001;3:397-403.
24.    Weiner E, Ball MP, Summerfelt A, Gold J, Buchanan RW. Effects of sustained-release bupropion and supportive group therapy on cigarette consumption in patients with schizophrenia. Am J Psychiatry. 2001;158:635-637.
25.    Decina P, Caracci G, Sandik R, Berman W, Mukerjee S, Scapicchio P. Cigarette smoking and neuroleptic-induced parkinsonism. Biol Psychiatry. 1990;28:502-508.
26.    Yassa R, Lal S, Korpassy A, Ally J. Nicotine exposure and tardive dyskinesia. Biol Psychiatry. 1987;30:109-115.
27.    Vinarova E, Vinar O, Kalvach Z. Smokers need higher doses of neuroleptic drugs. Biol Psychiatry. 1984;19:1265-1268.
28.    Adler LE, Hoffer LD, Wiser A, Freedman R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856-1861.
29.    Adler LE, Olincy A, Waldo M, et al. Schizophrenia, sensory gating and nicotinic receptors. Schizophr Bull. 1998;24:189-202.
30.    Freedman R, Coon H, Myles-Worsley M, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Nat Acad Sci. 1997;94:587-592.
31.    Nagamoto HT, Adler LE, Waldo MC, Griffith JM, McRae KA, Freedman R. Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry. 1996;40:181-188.
32.    Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL. Normal P50 supression in schizophrenia patients treated with atypical antipsychotic drugs. Am J Psychiatry. 2000;157:767-771.
33.    George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1995;56:344-346.
34.    McEvoy J, Freudenreich O, McGee M, VanderZwaag C, Levin E, Rose J. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry. 1995;37:550-552.
35.    Levin ED, Wilson W, Rose J, McEvoy J. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology. 1996;15:429-436.
36.    McEvoy JP, Freudenreich O, Wilson WH. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;46:125-129.
37.    McEvoy J, Freudenreich O, Levin E, Rose
J. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology. 1995;119:124-126.
38.    Procyshyn RM, Ihsan N, Thompson D. A comparison of smoking behaviours between patients treated with clozapine and depot neuroleptics. Int Clin Psychopharmacol. 2001;16:291-294.
39.    Procyshyn RM, Tse G, Sin O, Flynn S. Concomitant clozapine reduces smoking in patients treated with risperidone. Eur Neuropsychopharmacol. 2002;12:77-80.
40.    Dalack GW, Meador-Woodruff JH. Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia. Nicotine Tob Res. 1999;1:53-57.
41.    Hughes JR, Goldstein MG, Hurt RD, Shiffman S. Recent advances in the pharmacotherapy of smoking. J Am Med Assoc. 1999;281:72-76.
42.    Meltzer HY, Park S, Kessler R. Cognition, schizophrenia, and the atypical antipsychotic drugs. Proc Natl Acad Sci USA. 1999;96:13591-13593.
43.    Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:1521-1531.
44.    Tsuang MT, Perkins K, Simpson JC. Physical diseases in schizophrenia and affective disorder. J Clin Psychiatry. 1983;44:42-46.
45.    Lichtermann D, Ekelund E, Pukkala E, Tanskanen A, Lonnqvist J. Incidence of cancer among persons with schizophrenia and their relatives. Arch Gen Psychiatry. 2001;58:573-578.
46.    Tsuang MT, Woolson RF, Fleming JA. Premature deaths in schizophrenia and affective disorders: an analysis of survival curves and variables affecting the shortened survival. Arch Gen Psychiatry. 1980;37:979-983.
47.    Mortensen PB. Neuroleptic medication and other factors modifying cancer risk in schizophrenic patients. Acta Psychiatr Scand. 1987;75:585-590.
48.    Olincy A, Leonard S, Young DA, Sullivan B, Freedman R. Decreased bombesin peptide response to cigarette smoking in schizophrenia. Neuropsychopharmacology. 1999;20:52-59.
49.    Masterson E, O’Shea B. Smoking and malignancy in schizophrenia. Br J Psychiatry. 1984;145:429-432.
50.    Saku M, Tokudome S, Ikeda M, et al. Mortality in psychiatric patients, with a specific focus on cancer mortality associated with schizophrenia. Int J Epidemiol. 1995;24:366-372.
51.    Allebeck P. Schizophrenia: a life-shortening disease. Schizophr Bull. 1989;15:81-89.
52.    Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. J Am Med Assoc. 1990;264:2511-2518.
53.    Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychology. 1983;51:390-395.
54.    Addington J, el-Guebaly N, Addington D, Hodgins D. Readiness to stop smoking in schizophrenia. Can J Psychiatry. 1997;42:49-52.
55.    Addington J, el-Guebaly N, Duchak V, Hodgins D. Using measures of readiness to change in individuals with schizophrenia. Am J Drug Alcohol Abuse. 1999;25:151-161.
56.    Ziedonis DM, George TP. Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues. Schizophr Bull. 1997;23:247-254.
57.    McChargue DE, Gulliver SB, Hitsman B. Would smokers with schizophrenia benefit from a more flexible approach to smoking treatment? Addiction. 2002;97:795-800.
58.    Hughes JR. Harm-reduction approaches to smoking: the need for data. Am J Prev Med. 1998;15:9-16.
59.    Addington J. Group treatment for smoking cessation among persons with schizophrenia. Psychiatr Serv. 1998;49:925-928.

Dr. Davis is Gilman Professor and Ms. Chen is a research data analyst in the Department of Psychiatry at the University of Illinois in Chicago.

Acknowledgments: The authors wish to thank Michael E. Bennett for his assistance in the preparation of this manuscript. 



Should all second-generation antipsychotics (SGAs) be treated as a homogenous group? This article focuses on efficacy differences using results from a meta-analysis of 124 randomized, controlled studies comparing an SGA with a first-generation antipsychotic. Results from a meta-analyses on olanzapine and risperidone registrational trials is discussed. While the focus of this article is on efficacy differences among SGAs, a brief discussion of side effects is included as well. Using evidence-based medicine, the assumption that SGAs constitute a homogenous group is called into question. Since SGAs differ in efficacy and all the major side effects, there is really no property in which they are clearly homogeneous and the choice of antipsychotic medication should be tailored toward individual patients.



This article evaluates the centrally important issues regarding the choice of antipsychotic for schizophrenia through the use of evidence-based medicine. With the development of the second-generation antipsychotics (SGAs) clinicians have considerable choice in which antipsychotic to prescribe (Table 1) and revision of old assumptions and practices are necessary. In our view, double-blind, random-assignment, controlled clinical trials provide quantitative evidence largely free of bias, while most existing guidelines, meta-analyses, and narrative reviews are vague and contradictory. Most guidelines discuss SGAs as a homogenous group (Table 2),1-7 and data will be presented to show that this is not the case.


In the 1960s, the manufacturers of each antipsychotic advertised its drug to be particularly useful for certain symptoms of schizophrenia. At that time, we reviewed the evidence and found that typical, or first-generation antipsychotics (FGAs), have identical efficacy and spectrum of action and generally similar side-effect profiles.8 While this similarity has established a tradition of lumping drugs together, we feel that SGAs differ from each other in almost all respects, and therefore need to be individually characterized.



We performed a comprehensive meta-analysis of 124 randomized, controlled studies that compared SGAs with FGAs in schizophrenia or schizoaffective patients. Using a search strategy similar to that employed in Cochrane reviews, we located studies by searching MEDLINE, International Pharmaceutical Abstracts, CINAHL, PsychINFO, and the Cochrane Database of Systematic Reviews. We also searched reference lists in journal articles, and included data from the Food and Drug Administration Web site. Other sources of data include poster presentations, and unpublished data from Cochrane Database reviews or other meta-analyses, conference abstracts, and manuscripts submitted for publications. We queried investigators to locate additional studies and contacted manufacturers to obtain company monographs. In addition, we performed a meta-analysis9 using pooled raw data from four registrational trials of olanzapine.10-13 We also analyzed the raw data from the two registrational studies of risperidone conducted in the United States and Canada.14-16


Evaluation of Schizophrenia Symptoms

The development of the Positive and Negative Symptom Scale for Schizophrenia (PANSS),17 a 30-symptom scale which replaced the 18-symptom Brief Psychiatric Rating Scale (BPRS)18 has facilitated examination of schizophrenia symptom clusters. The PANSS is divided into three subscales based on theoretical grounds: positive symptoms, negative symptoms, and the general psychopathology. Using the PANSS for assessment of symptoms, Crow and colleagues19 showed that schizophrenia patients with negative symptoms have enlarged ventricles—a finding which has withstood the test of time. In the US, Lindenmayer and colleagues20 carried out a number of factor analyses demonstrating that there are really five clusters of symptoms that best characterize the PANSS items. This was an important extension of our knowledge on schizophrenic symptoms and has withstood verification. A review by Marder and colleagues21 found the same five factors in schizophrenia patients in many countries where translations of the PANSS are used.



Janssen Pharmaceuticals developed specific type-2 serotonin (5-HT2) antagonists, based on evidence linking hallucinogens to serotonin receptors and on increasing knowledge of the biology of serotonin. These 5-HT2 antagonists proved to be helpful with negative and depressive symptoms, but ineffective with the positive symptoms of schizophrenia. These findings led Janssen to consider that dopamine (D)-blocking properties were also necessary for antipsychotics and to focus on risperidone, which blocks both D2 receptors and 5-HT2 receptors.

In our opinion, the best studies of risperidone efficacy in acute patients were a US registrational trial conducted by Marder and Meibach15 and a Canadian study conducted by Chouinard and colleagues.16 Our meta-analysis of the combined raw data from these two studies focused on a more detailed differential efficacy analysis.14 The larger sample size of the combined data sets allowed for a detailed examination of individual symptoms and clusters of symptoms. We factor-analyzed the PANSS with a focus on the dimensions of schizophrenia. In the combined data set, the active comparator was haloperidol—the FGA comparator used in almost all contemporary clinical trials. While the theoretically postulated positive symptoms and negative symptoms scales were approximately correct in that most of these symptoms cluster in the appropriate subscales, not all items clustered in the theoretically defined scale. Therefore, the traditionally defined scales were not fully accurate in terms of their factor structure.

Analysis of the five factors of the PANSS showed that haloperidol produced more improvement than placebo on positive symptoms, and had some modest benefits on the cognitive (thought disorder) factor. However, haloperidol was ineffective on the negative symptoms, impulsivity/hostility, and anxiety/depression factors.

Risperidone 6 mg/day was substantially more effective than placebo on all five factors. Since all FGAs and SGAs are superior to placebo, the real question is how they compare with each other. Risperidone at 6 mg/day (or the pooled 6-, 10-, and 16-mg/day doses) proved to be more efficacious than haloperidol on all five factors (Figure 1). The best overall effect is observed at the 6-mg risperidone dose. It is unclear whether the lower optimum response at the 10 and 16 mg/day doses is due to statistical variation or reflects a real fall-off of efficacy at higher doses.

There is clear evidence that risperidone doses of 4–6 mg/day are clearly optimal doses and Patient Outcomes Research Team (PORT) guidelines recommend a daily dose of 4–10 mg.6 There has been some discussion among psychiatrists that the dose range may be between 2–4 mg/day, but certainly for elderly and first admission patients, one should use target doses of 2–4 mg/day.22 Our analysis of adult schizophrenics shows that the efficacy at the 2-mg dose is 50% less than the efficacy at the 6-mg dose. For the typical adult schizophrenic patient we believe decreasing the dose to 2 mg/day would be too low a dose to be fully effective for most patients.

On a descriptive level, risperidone was better than haloperidol for positive symptoms, although haloperidol was also effective. Risperidone was also quite effective in treating negative symptoms, anxiety/depression, and impulsivity/hostility, while haloperidol was not effective at all. Haloperidol showed some modest benefit in the cognitive (thought disorder) factor, but risperidone was more effective. We also compared risperidone and haloperidol on each of the 30 individual schizophrenia symptoms tested on the PANSS. Risperidone showed greater improvement than haloperidol on the majority of symptoms. Many of the symptoms were not improved by haloperidol.

To further define the spectrum of action of these drugs, we developed a haloperidol-responsive scale and a haloperidol-nonresponsive scale based on items of which haloperidol was shown to be effective or ineffective. The scales are described in a previous publication.14 About two thirds of the better improvement was achieved on the haloperidol-nonresponsive scale. We emphasize that risperidone produces a wider range of effects than haloperidol. Many of these symptoms are important for function in the community. Those who focus on positive symptoms, but recognize that drugs such as risperidone affect negative and affective symptoms, hold a somewhat similar position to us. This is an important point to clarify so that disagreements are not merely semantic. It is possible that two antipsychotics could have the same overall efficacy but one could be better for positive symptoms at the expense of negative symptoms or vice versa. This was not the case for risperidone. Risperidone was better than haloperidol on symptoms that improved with haloperidol. One third of risperidone’s increased efficacy was due to an even greater effect on symptoms already improved by haloperidol.


Speed of Action

The time course of improvement with risperidone and haloperidol is presented in Figure 2. Note that although risperidone at 6–16 mg/day produces a much better symptom reduction than haloperidol, the speed of action is not that different (Figure 3). Risperidone achieved almost its full effect by 2 weeks. SGAs have been described as having a slower onset of action than the FGAs, but inspection of the mean rate of response does not support this.




A large randomized, double-blind prospective study of maintenance treatment demonstrated that risperidone produced a greater decrease in relapse than haloperidol as well as a significantly greater improvement on all five factors of schizophrenia.23  In order to evaluate this finding and the findings from the pooled US and Canadian studies, a meta-analysis of all the randomized studies comparing risperidone to FGAs was performed. Risperidone was shown to be consistently more effective than FGAs on both total symptom reduction and on the traditional positive and negative scales. This finding indicates that the effect observed in both the North American clinical trials and the maintenance trial are consistently observed in most trials.



We did a meta-analysis of the registrational trials of olanzapine.9 Eli Lilly and Company has conducted four large trials using the following doses: (1) olanzapine at 1 and 10 mg/day versus placebo11; (2) olanzapine at 5, 10, and 15 mg/day versus haloperidol and placebo10; (3) olanzapine at 1, 5, 10, and 15 mg/day versus haloperidol12; and (4) a large flexible-dose international study of haloperidol versus olanzapine.10-13 In the 5-, 10-, and 15-mg/day dose studies, the clinicians could adjust the olanzapine dose by ±2.5 mg so that the average doses administered were approximately 7, 12, and 16 mg. Olanzapine was substantially more effective than haloperidol and significantly effective on most of the 30 schizophrenia symptoms.

Once again, the real question is how olanzapine compares with FGAs. The same approach used with risperidone was utilized. Factor analysis verified that the PANSS is best described by the same five factors. As with risperidone, olanzapine produces more improvement than haloperidol on all five factors and on most symptoms (Figure 4). We also identified haloperidol-responsive and haloperidol-nonresponsive scales, and showed that olanzapine was more efficacious than haloperidol on both the responsive and nonresponsive scales. While two thirds of olanzapine superiority was on the haloperidol nonresponsive scale, it was also clearly superior on the haloperidol-responsive scale. Thus, it can be said that olanzapine is a better haloperidol than haloperidol and clearly benefits many symptoms not improved at all by haloperidol.

The clinical profile of olanzapine and risperidone are similar. Both drugs produce significantly more improvement than FGAs on all five factors. However, there are two minor differences. First, while olanzapine produces significantly more improvement than haloperidol on the impulsivity/hostility factor, the magnitude of the difference is greater with risperidone 6 mg/day (Figures 1 and 4). Second, while risperidone produces more improvement than haloperidol on anxiety/depression, olanzapine produces a statistically greater superiority over haloperidol than risperidone. Whether the slight difference in the symptoms-improvement profile is real and can withstand the test of time remains to be determined.

It is our opinion that indirect comparisons of two drugs (in this case, olanzapine and risperidone) to a common third drug are not quantitative. Comparison of efficacy is a measure of relative difference, not an absolute difference, and the comparator is a flexible yardstick. Head-to-head trials are required for comparative efficacy. A meta-analysis of all the double-blind random-assignment studies comparing risperidone and olanzapine was performed, and a significant difference was not produced.


Speed of Action

Lilly has conducted several studies10-13 of intramuscular olanzapine compared to haloperidol or benzodiazepine in acutely ill patients. Olanzapine produces a rapid response in the first day or so. This is important because some have said that the onset of the beneficial effect of SGAs is gradual. We have plotted the time to response of olanzapine and haloperidol (Figure 5). There was no significant difference in response in the first 2 weeks, but olanzapine gradually proved to be superior to haloperidol (Figure 6). Since the nonsignificant trends favored olanzapine, it would be difficult to argue that olanzapine had a slower response rate. The acute intramuscular studies are critical in this respect. Olanzapine exhibited as rapid a response as haloperidol. Since there is evidence that benzodiazepines have considerable efficacy on schizophrenia symptoms in the first few days, we feel that benzodiazepine augmentation is often useful in the first few days, particularly for agitated patients.



While use of olanzapine during maintenance treatment has not been studied in a comparable comparative study, the follow-up of the acute study showed that olanzapine continues to be superior to haloperidol in this phase. As more haloperidol patients drop out, this study would tend to minimize the olanzapine superiority, yet olanzapine continued to be superior.


Dose Response

The best data on olanzapine dose-response came from the US trial10 because there was a placebo group for perspective. The rate of response is linear over time. The dose-response curve is a sigmoid curve where the curve levels off after the drug produces all possible effect. Olanzapine has not reached this leveling off yet. Since the goal of treatment is to achieve maximum efficacy, assuming the patients can tolerate the drug, the best dose is the point at which the response levels off. Interestingly, many practitioners are increasing the dose of olanzapine up to 20–30 mg/day, but there is little data from controlled studies on possible efficacy advantages and side-effect disadvantages on this dosing strategy.


Distribution of Outcome Variables

The degree of symptom reduction as measured by the PANSS or BPRS was normally distributed in the response to all the different drug groups in the pivotal studies of both olanzapine and risperidone (Figure 7). There was no evidence of a bimodal curve that would allow patients to be classified as responders or nonresponders based on how much they responded. Although the 20% criteria (of PANSS or BPRS reduction) is frequently used as a definition of responder, other cut-off points have also been chosen to favor one drug over another. An important problem with the arbitrary definition of responders is that a given manufacturer can choose the optimal cut-off point for their drug, which creates a systematic bias. If all studies consistently use the 20% criteria, the bias would be avoided. A better method of measuring improvement is the covariate-adjusted change from baseline (with baseline as covariate). When the underlying distribution is continuous, information is lost by setting an arbitrary dichotomy. Fifty percent of information is lost when both continuous variables of a correlation are dichotomized.



Although sertindole has been withdrawn from the market, it is of academic interest since its overall efficacy is identical to haloperidol. Sertindole exhibited a trend for better efficacy for negative symptoms and less optimal efficacy for positive symptoms. This illustrates the trade-off of one type of symptom for another. While a drug may be superior in one respect, it may be less effective in another, although overall efficacy may be identical to that of the FGAs.



Quetiapine has been investigated in four large randomized trials.24-27 While two of the studies found that the drug’s efficacy was identical to the FGAs,24,27 the other two found the drug to be slightly but not significantly different than the FGAs—one showed it to be more effective,26 while the other showed the drug to be less effective.25 Full data on quetiapine’s profile on positive or negative symptoms have not been systematically presented.



Ziprasidone is on the market in the US, but most of its efficacy studies have not been published. The FDA Web site probably has the best data on ziprasidone.28 Initially, ziprasidone was used at an overly low dose, so most of the registrational studies defined the dose-response curve against placebo. No data exist to indicate that ziprasidone has efficacy above placebo below a dose of 120 mg. The two 80-mg studies have shown somewhat disparate findings, indicating only that efficacy cannot be consistently displayed at the 80-mg dose in acute patients.28 Only at 120, 160, or 200 mg, is there clearly marked efficacy (highly significant) compared to placebo.28 One of these studies using an active comparator (haloperidol), demonstrated that ziprasidone was somewhat less efficacious than haloperidol.28 It is unclear whether this was statistically significant. Another study29 showed that the ziprasidone and olanzapine did not differ greatly in efficacy. Therefore, we view ziprasidone to be at least as efficacious as FGAs. A large maintenance study demonstrated dose-related efficacy against placebo.28



All the planned registrational studies for aripiprazole are mostly completed and have been reported at meetings, but none have been published yet. Our impression is that aripiprazole has about the same efficacy as haloperidol. A study comparing the drug with risperidone showed aripiprazole to be slightly less efficacious than risperidone, but the difference was not significant.30 This would suggest that aripiprazole efficacy may fall between that of FGAs and risperidone or olanzapine. The dose-response curve indicated that the dose producing full efficacy plateaus at about 10 mg/day (possibly at a lower dose in one study).



Clozapine has been studied in double-blind studies with FGAs. Meta-analyses conducted by Wahlbeck and Colleagues,31 Leucht,32 Geddes and colleagues,33 and the authors of this article (unpublished data, 2002) demonstrated that clozapine is substantially more efficacious than FGAs. Weekly white blood cell monitoring has reduced the incidence of death from agranulocytosis to almost zero. Since clozapine has more side effects than the FGAs, it is clearly a second-line drug. Because it is the most efficacious drug, it should be considered in all patients with incomplete response.


Dose Effect of First-Generation Comparison Drug

The results of the meta-analysis by Geddes and colleagues33 showed that the SGAs olanzapine, amisulpride, risperidone, and clozapine were more effective than FGAs. However, Geddes and colleagues concluded that the observed efficacy advantage of the SGAs was only observed in studies where excessively high haloperidol doses were used as comparison, thus there is no real evidence that show SGAs to be more efficacious than FGAs.

Our meta-analysis of 124 randomized double-blind studies failed to replicate the finding of Geddes and colleagues.33 We observed that many clozapine trials used higher comparison doses and clozapine was substantially more effective than FGA. In contrast, sertindole and quetiapine, which were approximately equally effective to their FGA comparison drug, used lower doses of the comparison drug. We suspect that the observed association of high dose comparator with a greater SGA-FGA effect found by Geddes and colleagues33 was due to clozapine efficacy and the reverse due to the lesser efficacy of quetiapine and sertindole. When we examined each individual SGA versus FGA, we found no tendency for higher doses of the comparison drug to be less efficacious. We feel that the hypothesis presented by Geddes and colleagues is not supported by empirical evidence.


Side Effects

There are qualitative differences in side effects among SGAs. Clinicians need to balance the frequency, reversibility, and seriousness of side effects for each patient. Common side effects can be assessed in controlled clinical trials, but rare side effects are difficult to quantify. The FGAs produce a high incidence of acute extrapyramidal symptoms (EPS), which can be troubling, and dystonia, which can be alarming and painful. Tardive dyskinesias (TD) develops in about 3% to 4% of patients per year, each in a cumulative fashion. Severe cases can be socially disfiguring and irreversible.

The introduction of the newer SGAs (eg, olanzapine, risperidone) marks a major advance in the safety of antipsychotics. The major side effects of these drugs are extrapyramidal symptoms and tardive dyskinesia. With drug-induced movement disorders reduced to virtually zero, treatment is greatly simplified. Yet, as with any group of new drugs, other problems emerge. In our discussion of side effects we will emphasize our meta-analyses as they contribute to the understanding of the risks and benefits of these new drugs.

While the SGAs clearly cause less EPS than the FGAs by some margin, they differ among themselves in the occurrence of all the major side effects including parkinsonian symptoms, TD, prolactin elevation, weight gain, diabetes, sedation, and QT prolongation.34 Low-dose clozapine can help dopa-induced hallucinations in parkinsonian patients without aggravating their parkinsonism. Therefore, an argument can be made that clozapine does not cause EPS. Furthermore, since there is an extensive knowledge base on clozapine worldwide, any EPS associated with its use would be well documented by now. We feel the time has come to conclude that clozapine does not cause EPS.

In blinded clinical trials, it has been shown that a number of patients randomized to placebo have EPS ratings greater than zero.9,14 It is unclear whether this observation is some sort of persistent parkinsonian symptom that continues for some months despite placebo treatment. We feel a good possibility may be rater error. Close examination of normal individuals reveals the presence of some mild degree of movement disorder. Even world-class marksmen have some degree of essential tremor. The amount of movement disorder observed in normal subjects increase with age. Therefore, a rating on an EPS scale above zero does not mean that the drug causes EPS. It reflects a background frequency of EPS seen in normal people. There are even some subtle signs of TD-like symptoms in normal elderly patients. Thus, it is difficult to conclude that a new drug does not cause EPS. Scores on standard scales such as the Barnes Akathisia Scale and the Simpson-Angus Scale are not zero, but change from baseline show a decrease of the scores.

Review of our analysis of the combined olanzapine data set showed no significant difference in side effect from placebo. Data from two registrational studies10,11 where olanzapine was compared against placebo were pooled. Haloperidol showed a definite increase in EPS ratings, which was massively statistically significant. The most interesting comparison was with olanzapine and placebo. Ratings of both Simpson-Angus EPS and the Barnes Akathisia scales dropped below baseline with olanzapine and placebo. There was no statistically reliable difference between olanzapine and placebo on either scale. We could demonstrate no dose-related EPS on the Simpson-Angus Scale or akathisia on the Barnes Akathisia Scale. Even when we combined data from two large studies we were unable to demonstrate statistically that olanzapine caused any EPS or akathisia. However, this does not mean that olanzapine does not cause the side effect, it only means that it could not be measured even in the pooled large sample studies.

It is also possible that a clinician could see clearly in a case with definite symptoms that which is hidden behind the noise of rating scale evaluations. There is some evidence that olanzapine may not be useful in treating dopa-induced hallucinations in patients with Parkinson’s disease, but large scale studies are absent. We feel there is a qualitative difference between olanzapine and risperidone on the ability to produce EPS. With risperidone there is a very low level, which may not be clearly statistically distinguishable at doses of 4–6 mg but is distinguishable at higher doses. In addition, dystonias, characteristic of EPS, clearly occur with risperidone. It is difficult to evaluate TD because it is necessary to have large sample sizes over a number of years. Individual cases are not very helpful because most patients have been treated with many drugs and unusual circumstances can complicate an individual case. Given that risperidone has been used for close to a decade and olanzapine for several years, the absence of TD reported in large-scale studies or a large number of case reports suggest some degree of safety.

Risperidone causes EPS but its incidence is markedly lower than that of FGAs, such that at low doses it is not statistically distinguishable from placebo.8,9 Compared with FGAs, risperidone showed slightly greater elevation in prolactin levels, whereas most of the other SGAs have a favorable prolactin profile. While olanzapine and risperidone clearly cause weight gain,34 some of the newer SGAs may not cause weight gain.

There is a substantial interest in new onset diabetes associated with olanzapine and clozapine use, which is under active investigation at this time. Wirshing and colleagues35 were the first to describe an increase in incidence of new onset diabetes with SGAs. Another study by Wirshing and colleagues36 found that triglyceride levels were statistically significantly increased in olanzapine and clozapine patients. Consequently, there is no doubt from case reports and administrative databases that cases of new-onset diabetes are occurring in SGAs such as clozapine and olanzapine. A popular journal article will generate increased number of reports to public databases, such as the FDA. One cannot exactly quantitate the incidence of side effect from such data. How much of the incidence of new-onset diabetes is attributable to weight gain awaits further investigation.

Gianfrancesco and colleagues37 analyzed a claims-based database and found a statistically significant increase in reimbursement claims for new-onset diabetes following the use of clozapine (odds ratio [OR]=7.4), olanzapine (OR=3.1; relationship was found to be dose-related), low-potency FGAs (OR=3.5), and high-potency FGAs (OR=2.1). The authors failed to find a significant increase in diabetes with risperidone. Patients on antipsychotics should be weighed at each visit and if weight gain is observed, it should be managed by diet and exercise, and/or the patient should be switched to a different drug with a lower propensity for weight gain. Because psychiatrists now have to deal with weight gain as a possible side effect of antipsychotic use, they need to join with internists in helping patients maintain normal weight in the prevention of cardiovascular disease and stroke.

Ziprasidone causes a modest increase in QT interval, which raises the possibility of the propensity for sudden death, particularly in patients with long QT syndrome or in patients taking drugs which also prolong the QT interval.38 Ziprasidone has been on the market for a while, and the absence of such reports is reassuring. It is important to recognize that with rare side effects it is difficult to be sure that a drug does or does not cause a side effect, particularly in the absence of any systematic surveillance.

Since the SGAs are not a homogeneous group, there may be tradeoffs. The clinician may trade a minor difference in efficacy for an advantage in side effects, or choose a slightly higher incidence of one side effect in order to avoid another. Because EPS and TD are serious side effects associated with FGAs, it can be said that the SGAs as a group have a superior safety profile. However, the classes of drugs differ from each other qualitatively, thus the clinician may wish to balance differences in efficacy and in side-effect protocols when deciding on a drug for a given patient.



While side-effect profile of a drug is probably the most important criterion when choosing an antipsychotic, there are important differences with regard to efficacy of these drugs as well. Efficacy differences of SGAs, in particular, have not been fully appreciated. Differences in both side effects and efficacy necessitate that SGAs not be treated as a homogeneous group. The clinician should evaluate SGAs individually for each patient.  PP



1.    Bhanji NH, Tempier R. Managing schizophrenia during the stable phase: is there consensus among practice guidelines? Can J Psychiatry. 2002;47:76-80.
2.    Practice guideline for the treatment of patients with schizophrenia. American Psychiatric Association. Am J Psychiatry. 1997;154(suppl 4):1-63.
3.    Canadian clinical practice guidelines for the treatment of schizophrenia. The Canadian Psychiatric Association. Can J Psychiatry. 1998;43(suppl 2):25-40.
4.    McEvoy JP, Scheifler PI, Frances A. The Expert Consensus Guideline Series: treatment of schizophrenia 1999. J Clin Psychiatry. 1999;60(suppl 11):4-80.
5.    Agence National Pour le Development de L Evaluation Medicale. Strategies Therapeutiques a Long Terme Dans les Psychoses Schizophreniques. Text du Consensus. Paris: Agence Nationale pour le Development de L Evaluation Medicale; 1994.
6.    Lehman AF, Steinwachs DM. Translating research into practice: the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations. Schizophrenia Bulletin. 1998;24:1-10.
7.    Miller AL, Chiles JA, Chiles JK, Crimson ML, Rush JA, Shon SP. The Texas Medication Algorithms Project (TMAP) schizophrenia algorithms. J Clin Psychiatry. 1999;60:649-657.
8.    Klein DF, Davis JM. Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore, Md: Williams & Wilkins; 1969.
9.    Davis JM, Chen N. The effects of olanzapine on the 5 dimensions of schizophrenia derived by factor analysis: combined results of the North American and international trials. J Clin Psychiatry. 2001;62:757-771.
10.    Beasley CM Jr, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111-123.
11.    Beasley CM Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology. 1996;124:159-167.
12.    Beasley CM Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol. 1997;7:125-137.
13.    Tollefson GD, Beasley CM Jr, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry. 1997;154:457-465.
14.    Davis JM, Chen N. Clinical profile of an atypical antipsychotic: risperidone. Schizophr Bull. 2002;28:43-61.
15.    Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151:825-835.
16.    Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol. 1993;13:25-40.
17.    Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261-276.
18.    Overall J, Gorham D. The Brief Psychiatric Rating Scale. Psychological Reports. 1962;10:799-813.
19.    Crow TJ, MacMillan JF, Johnson AL, Johnstone EC. A randomised controlled trial of prophylactic neuroleptic treatment. Br J Psychiatry. 1986;148:120-127.
20.    Lindenmayer JP, Bernstein-Hyman R, Grochowski S. A new five factor model of schizophrenia. Psychiatr Q. 1994;65:299-322.
21.    Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American Trials. J Clin Psychiatry. 1997;58:538-546.
22.    Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Risperidone Working Group. Schizophr Bull. 1999;25:721-729.
23.    Csernansky JG, Mahmoud R, Brenner R. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Eng J Med. 2002;346:16-22.
24.    Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42:233-246.
25.    Copolov DL, Link CGG, Kowalcyk B. A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, ‘seroquel’) and haloperidol in schizophrenia. Psychol Med. 2000;30:95-105.
26.    Emsley RA, Raniwalla J, Bailey, Jones AM. A comparison of the effects of quetiapine (‘seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group. Int Clin Psychopharmacol. 2000;15:121-131.
27.    Peuskens J, Link CG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand. 1997;96:265-273.
28.    NDA 20-919: Zeldox (ziprasidone mesylate IM, Pfizer.). Pfizer Global Research & Development. Available at: ac/01/briefing/3685b2.htm. Accessed May 2002.
29.    Simpson G, Romano SJ, Horne RL, Weiden P, Pigott T, Bari M. Ziprasidone vs olanzapine in schizophrenia: results of a double-blind trial. Paper presented at: Annual Meeting of the  American Psychiatric Association; May 15-21, 2001; New Orleans, LA.
30.    Carson WH, Saha A, Ali M, Dunbar GC, Ingenito G. Aripiprazole and risperidone vs. placebo in schizophrenia and schizoaffective disorder. Paper presented at: Annual Meetin g of theAmerican Psychiatric Association; May 5-10, 2001; New Orleans, LA.
31.    Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry. 1999;156:990-999.
32.    Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res. 1999;35:51-68.
33.    Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antpsychotics in the treatment of schizophrenia systematic overview and meta-regression analysis. BMJ. 2000;321:1371-1376.
34.    Marder SR, Essock SM, Miller AL, et al. The Mount Sinai conference on the pharmacotherapy of schizophrenia. Schizophr Bull. 2002;28:5-16.
35.    Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry. 1998;44:778-783.
36.    Wirshing DA, Boyd JA, Meng LR, Ballon BA, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002;63:856-865.
37.    Gianfancesco FD, Grogg AL, Mahmoud RA, Wang R-H, Nasrallah HA. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry. 2002;63:920-930.
38.    Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. 2001;158:1774-1782.


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Jean-Pierre Lindenmayer, MD, Victoria E. Cosgrove, BA

Primary Psychiatry. 2002;9(11):31-39

Dr. Lindenmayer is director and Ms. Cosgrove is a research scientist at the Psychopharmacology Research Unit, Manhattan Psychiatric Center-Nathan Kline Institute for Psychiatric Research in New York City.

Acknowledgments: The authors report no financial, academic, or other support of this work. 



What are the best pharmacologic treatment strategies for schizophrenia? Adequate diagnostic assessment must precede any treatment plan. For acute schizophrenic patients presenting in a psychiatric inpatient setting, pharmacologic choices depend on the patient’s medication history and current level of agitation or aggression. The pharmacologic choices have been greatly expanded with the availability of the atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone. Maintenance treatment, often lifelong, requires psychoeducational interventions and side-effect management to ensure adherence to an optimal treatment regimen. Coexisting syndromes must be treated in concordance with the patient’s clinical presentation. For treatment-resistant patients, atypical compounds are generally more effective than their typical counterparts. Since response rates in resistant patients are often low, medication augmentation strategies are frequently recommended.


The pharmacologic treatment of schizophrenia has significantly evolved with the introduction of the newer atypical antipsychotics. These compounds produce fewer side effects, increase  treatment adherence for patients, and have a broader profile in effectiveness compared to traditional antipsychotics. In addition, different treatment algorithms have been developed which have contributed to a body of best practices in the treatment of this complex disorder.

This article will provide an overview of the assessment and pharmacologic strategies for the different stages of schizophrenia, including the acute phase, the postacute/maintenance phase, and treatment-resistant situations.


Assessment of patients with schizophrenia must be adequately completed before initiation of any treatment plan. The starting point is always a careful and comprehensive psychiatric interview, which should be supplemented by information from relatives or friends of the patient. This is particularly important with schizophrenia patients as their ability to communicate coherently might be impaired or their awareness of reality might be distorted. An obligatory part of the interview will be a mental status examination. It is also helpful to determine distinct domains of psychopathology which make up the clinical presentation of the patient, as they may present differential responsiveness to pharmacotherapy. Several authors have reliably identified five domains: the positive symptom domain (eg, delusions and hallucinations); the negative domain (eg, blunted affect and social withdrawal); the cognitive domain (eg, thought disorder and stereotyped thinking); the excitement domain (eg, uncooperativeness and poor impulse control); and the depression/anxiety domain (eg, depression and tension).1

In addition, clinicians need to determine the presence of comorbid psychopathology, common in patients suffering from schizophrenia. One of the more frequently comorbid conditions is substance abuse. Overall, the outcome for schizophrenic patients with comorbid psychopathology is less favorable than for those without comorbid disorders. Finally, when patients fail to respond to various treatments, a thorough diagnostic reevaluation is required, which also considers medical underlying factors contributing to nonresponse (Table 1).







Conditions, such as medication-induced delirium, seizure disorders, and other disorders of the central nervous system, may occasionally present with schizophrenia-like symptoms. In addition, medical conditions, such as cardiac disorders, ophthalmologic conditions, hepatic disorders, obesity, neurological conditions, or diabetes, may influence medication choice.

Since schizophrenia is a chronic condition with periodic psychotic decompensations, patients often have extensive medication histories. Initial assessment must include a thorough review of the adequacy and effectiveness of previous mediation trials, adherence patterns, and adequacy of dosing regimens. Patients themselves may be able to describe which medications have been intolerable in the past. Ultimately, choosing medications that patients believe will be helpful to them ensures adherence.

It is essential to assess past and present medication adherence as well as reasons for nonadherence. Patients neglect medication for many reasons—side effects, substance abuse, and cognitive impairments as manifested by unawareness of mental illness and stigma. There has been evidence to suggest that adherence is better for clozapine than other typical and atypical antipsychotics.2,3 Long-acting depot preparations, which avoid the burden of daily dosing, represent an important route of medication administration for patients with adherence problems. Other ways to ensure adherence is to tailor the medication regimen to the specific needs of the patient and through participation in illness education groups. The regimen should be as simple as possible (QD or BID). Side effects should be minimized; however, patients should be aware that some side effects might be inevitable. Through psychoeducational interventions emphasis should be placed on the long-term necessity for medication treatment in order to avoid discontinuation and psychotic relapse. In addition, a patient’s adherence increases as his level of services increases. Introduction of intensive case managers or supportive housing is helpful.

Finally, diagnostic and laboratory tests may be indicated depending on clinical circumstances (Table 2). For new patients, clinicians should assess blood chemistry and hematology including prolactin levels, urinalysis with toxicology, electrocardiogram, vital signs, and extrapyramidal symptoms.









Management of Acute Schizophrenia

Most treatment episodes for acute schizophrenia take place in a psychiatric inpatient setting. This allows time for the clinician to conduct a full diagnostic assessment, evaluate differential diagnostic considerations, and initiate an aggressive psychopharmacologic treatment plan. However, at times, this treatment plan may have to be shaped in order to satisfy the constraints of length of stay requirements. In fact, the average length of stay at this time for an acute schizophrenic inpatient episode has been reported to be ≤1 week, which will only allow for rapid stabilization.4 It will also mean that the continuation of treatment will occur in the outpatient setting.

The aim of treatment is the stabilization of acute psychotic symptoms, the control of agitation, the resolution of self destructive or aggressive behavior, and the transition to safe outpatient treatment. On occasion, the treatment of an acute episode may be accomplished in an outpatient setting, where consistent monitoring and supervision are available. The involvement of intensive case managers or of assertive community treatment may be particularly helpful in these situations.5 Outpatient treatment may be possible in situations of incipient acute psychotic decompensation or transitional environmental stress. In general, we recommend the use of a medication that had been effective in the past, had no/minimal side effects, and that is supported by patient preference.

Once acute hospitalization has been considered as the initial treatment location, the next issue to consider is whether the admission will take place under voluntary or involuntary conditions. Local regulations will determine the criteria for each of the two conditions. In general, involuntary admission can be considered in situations of presence of mental illness and imminent self-harm, danger to others, or inability to take care of oneself due to the mental illness. For voluntary admission, the patient has to be willing to sign him/herself into the hospital and the admission must be approved by the administration.6

If the present episode is a first episode or if the treatment history is not known, one would start with one of the atypical compounds, such as olanzapine 15–20 mg/day PO or risperidone 3–6 mg/day PO. The following are common dosage ranges, which have to be individualized for each patient. Alternative compounds are quetiapine 200–400 mg/day PO or ziprasidone 120–160 mg/day PO. Use of typical antipsychotics would include haloperidol 10–15 mg/day. The question of how to determine when the duration of a trial is sufficient in case of lack of response is influenced by the choice of outcome measures and the availability of support postdischarge. In the inpatient setting, switching to another compound could be considered after 1 week, if there is no hint of a response.7

Treatment of Acute Agitation and Aggression

An important associated symptom during the acute phase is agitation and aggressive behavior. Short-acting benzodiazepines (lorazepam or midazolam) are extremely helpful in the acute management of agitation and aggressive behavior. Based on a double-blind study comparing lorazepam 2 mg intramuscular (IM) and haloperidol 5 mg IM as a PRN medication for the control of assaultive or aggressive behavior, Salzman and colleagues8 found that both compounds were equally effective in controlling aggressive and psychotic symptoms, but that patients on haloperidol had significantly more extrapyramidal symptoms (EPS). Lorazepam may be particularly useful because of its short half-life and the availability of IM, intravenous (IV), and PO forms. Given that haloperidol can cause significant EPS and can worsen phencyclidine intoxications, it is generally preferable to use parenteral lorazepam in most emergency situations. Recommended dosages for haloperidol are 5 mg IM every 1–4 hours together with lorazepam 2 mg IM or chlorpromazine 25–50 mg IM every 1–4 hours. Another alternate form of administration is oral concentrate of an antipsychotic mixed in orange juice, which is at times more acceptable to patients.

Second-generation antipsychotics are clearly superior to typicals in terms of their lesser propensity to EPS and other more beneficial side-effect profiles (Table 3). Although there is currently only one available atypical in IM form, short-acting ziprasidone (dose for ziprasidone IM is 5–20 mg9), there may soon be an olanzapine IM form available.10 There are also two other atypical compound administrations that may be useful for emergency situations: a liquid risperidone form and a rapidly dissolving oral olanzapine form.







Rapid neuroleptization, which was at one time favored by physicians treating acutely psychotic patients who also were agitated, is no longer advisable. The duration of onset of action and effectiveness is not superior to traditional dosage techniques.11

In the case of agitation and violence in the context of drug withdrawal from hypnotics or sedatives, antipsychotics are contraindicated because they lower the seizure threshold. Benzodiazepines are the treatment of choice in these situations. High potency antipsychotics or benzodiazepines are preferable to low potency compounds in the treatment of agitation and violence in patients with delirium. Low potency antipsychotics, due to sedating and anticholinergic properties, may worsen the delirious states in these patients. In particular, dosages of antipsychotics need to be adjusted in situations with elderly patients or with patients who have cerebrovascular problems. Haloperidol 0.5–2.0 mg IM every 30–60 minutes can be given until the patient is calm.

Barbiturates are less frequently used, since safe and effective benzodiazepines have displaced them in the treatment of acute agitation and aggression. Barbiturates also have a high potential for abuse and dependence, and are therefore less favored. However, they can still be useful in patients who do not respond to benzodiazepines. Compounds with a shorter half-life such as sodium amytal 250 mg IM every 4 hours is preferable in order to avoid accumulation of the drug over time.

In situations of persistent agitation, it is important to rule out the presence of akathisia. This extrapyramidal motor side effect consists of objective motor hyperactivity and a subjective sense of restlessness. It often cannot be distinguished from agitated anxiety. A frequent practice is to combine a high-potency antipsychotic with a short-acting benzodiazepine (eg, lorazepam). This adjunctive treatment offers sedation, treatment for possible acute EPS (eg, acute dystonic reaction), and may also treat akathisia. Often, an anticholinergic is added later for the treatment of EPS. Another treatment intervention for akathisia is the use of β-blockers, eg, propranolol (40–60 mg/day PO).

With patients who present acutely psychotic and persistently aggressive, the clinician may want to combine the antipsychotic treatment with depakote. A recent double-blind study combining either olanzapine or risperidone with depakote in acutely psychotic patients showed that those on the combination regimen improved faster on a number of psychosis symptoms, including excitement and uncooperativeness.12

Another longer-term option to consider for persistently aggressive psychotic patients is clozapine. This atypical compound has been found in a number of open-label and one double-blind study to significantly reduce hostility, the number of violent episodes, and the need for seclusion.13

Management of Postacute Schizophrenia

It is important to remember that maintenance therapy for schizophrenia will be long-term and often life-long. However, while the preponderance of evidence supports the recommendation of long-term pharmacotherapy for schizophrenia, every patient will decide whether or not he or she will continue to take a prescribed medication. It is the job of the psychiatrist to foster a collaborative relationship in which the patient feels free to share his or her personal experience, personal opinions, and experiences with side effects regarding the prescribed medication. Psychoeducational interventions with patients and their families are helpful in setting the stage for long-term treatment. Some general guidelines for the duration of maintenance treatment are listed in Table 4.







In terms of general guidelines for dosing during the maintenance phase, recommended doses are presented in Table 5. In general, the minimum effective dose that gives the best efficacy and the lowest levels of side effects should be used. This minimum effective dose will change over time, and ongoing efforts should be made to find the minimum effective dose.







Duration of Medication Trials

In general, specific medication trials should be within recommended duration in order to ensure that the patient has had an adequate trial and that ineffective medications are discontinued in a timely fashion. Recommended trial durations are 4–12 weeks for atypical antipsychotics, 4–12 weeks for typical antipsychotics, and 3–12 months for clozapine. In the case of intolerable side effects, antipsychotics can be discontinued at any point during a trial. A special situation applies to the acute inpatient setting, where discontinuation of an antipsychotic trial could be considered after 1 week if there is no hint of a response.

Side-Effect Management

Side effects can have a number of adverse effects on treatment, including decreasing the therapeutic alliance, causing medication nonadherence, and contributing to serious morbidity and mortality. However, if side effects are managed in a collaborative manner with the patient, it can offer an opportunity to build the therapeutic alliance, support illness self-management, and minimize the risk of adverse outcomes. In general, one of the first strategies is to reduce the dose. If this fails, an additional compound can be added to reduce the side effect in question (Table 6). If this intervention fails, one should switch to a medication with a more favorable side-effect profile.



During the maintenance phase, patients are seen over several years by psychiatrists who monitor their clinical response to drugs, including vulnerability to side effects. In order to facilitate the monitoring, we have summarized some of the most important measures, which clinicians should examine and which will rapidly and efficiently yield data on side effects (Table 7).



Treatment Strategies for Coexisting Syndromes

During the maintenance phase, coexisting syndromes may emerge and may respond to the antipsychotic treatment in progress. However, some may require treatment with an augmenting strategy as outlined below in Table 8.



Treatment Strategies for Partial/Nonresponders

The traditional definition of treatment nonresponse in the past was pharmacologically driven and relatively narrow in scope; its criteria included two failed treatment trials with two different classes of neuroleptic agents and persistent illness for at least 5 years. However, the greater and wider-ranging efficacy of atypical antipsychotic agents has compelled a broader and a multidimensional definition. This new definition of treatment resistance uses (1) the concept of discrete domains of psychopathology, which can be treatment resistant; and (2) the concept response, which often is only partial. The discrete domains of psychopathology include persistent positive symptoms, persistent negative symptoms, persistent depressive-anxiety symptoms (including suicidality), persistent excitement symptoms (including aggressive behavior), and persistent cognitive symptoms. Also included are functional-disability symptoms such as social-function deficits (eg, inability to live independently in the community) and occupational deficits (eg, inability to perform adequately in a work or academic setting). Finally, continuous hospitalization or frequent rehospitalization is also included in this definition.

The atypical antipsychotic agents, clozapine, olanzapine, risperidone, and quetiapine, play an important role in the treatment of these patients. The role of ziprasidone is not yet clear, as data on its effects on partial responders is not available yet.


The first breakthrough in the treatment of refractory schizophrenia came when Kane and colleagues14 reported that clozapine, the prototypical atypical antipsychotic agent, was superior to chlorpromazine in a group of patients who met rigorous criteria for treatment resistance. In this study, 30% of clozapine-treated patients fulfilled a priori response criteria, compared with only 4% of chlorpromazine-treated patients. These results have been confirmed in a number of other comparative studies.

In a recent review by Wahlbeck and colleagues15 on clozapine’s effectiveness in schizophrenia, the drug was found to be superior in clinical improvement (Brief Psychiatric Rating Scale [BPRS] standard mean difference=0.7, 95% CI=0.5–0.9).

The one study in which results ran somewhat counter to these positive ones was a more recent trial by Rosenheck and colleagues.16 In this 1-year, randomized, double-blind trial, clozapine 100–900 mg/day was compared to haloperidol 5–30 mg/day in 205 and 218 patients, respectively, with treatment-refractory schizophrenia. Clozapine performed better than haloperidol in several aspects of the study. For example, clozapine-treated patients were significantly more likely than were haloperidol-treated patients to continue their assigned treatment for the full year (57% versus 28%; P<.001). In addition, compared to haloperidol-treated patients, clozapine-treated patients had a significantly better quality of life (P=.003), less tardive dyskinesia (P=.005), fewer EPS (P<.001), and fewer mean days of psychiatric hospitalization (144 days versus 168 days, P=.03). However, the difference between the two groups was far more modest than had been shown in previous studies, at just 5% (mean scores at endpoint: 79 with clozapine versus 84 with haloperidol; P=.02). Nevertheless, the preponderance of research evidence shows that clozapine is substantially more effective than typical neuroleptics in treatment-resistant schizophrenia.


In a study that compared risperidone to typical antipsychotics in treatment-resistant patients, Wirshing and colleagues17 reported on 67 medication-unresponsive subjects with schizophrenia who were randomly assigned to either risperidone 6 mg/day or haloperidol 15 mg/day for a fixed dose during a 4-week period and for a flexible dose for a 4-week period (mean risperidone 7.5 mg/day and mean haloperidol 19.4 mg/day). Risperidone demonstrated clinical efficacy superior (as measured with the Positive and Negative Symptom Scale for Schizophrenia [PANSS]) to that of haloperidol after the first 4 weeks of treatment, which was lost after an additional 4 weeks of treatment. Risperidone-treated patients needed significantly less concomitant anticholinergic medication, showed less akathisia, and less severe tardive dyskinesia than haloperidol-treated patients.


A subpopulation of 526 patients selected from a larger multicenter study and meeting treatment-resistant criteria (including failure to respond to a trial of at least 8 weeks’ duration of one or more conventional neuroleptics during the previous 2 years) were randomized to receive either olanzapine (mean dose, 11.1 mg/day) or haloperidol (mean dose, 10 mg/day).18 A greater proportion of patients in the olanzapine group than in the haloperidol group completed the study, and fewer olanzapine-treated patients discontinued due to of lack of efficacy. Looking at patients who completed the trial, the olanzapine-treated patients achieved significantly greater mean improvement compared with the haloperidol-treated group for all symptom measures, including BPRS total (P=.006), PANSS total (P=.005), PANSS positive symptoms (P=.017), PANSS negative symptoms (P<.001), and Montgomery-Asberg Depression Rating Scale total (P=.019).

In contrast to these positive results, Conley and colleagues19 showed that olanzapine was no better than chlorpromazine. In a controlled double-blind study, these authors compared the effect of olanzapine (25 mg/day) to chlorpromazine (1,200 mg/day) in an 8-week study of treatment-resistant schizophrenia patients. The results showed that olanzapine was therapeutically not superior to chlorpromazine, showing a response rate of only 7%.


Emsley and colleagues20 reported on an 8-week study of quetiapine 600 mg/day compared to haloperidol 20 mg/day in a group of treatment-refractory schizophrenic patients who had been included in the study after showing partial or no response after a prospective 4-week trial of 20 mg/day of fluphenazine. Significantly more patients on quetiapine (52%) than on haloperidol (38%) achieved a clinical response of at least 20% reduction of PANSS total score (P<.05). In summary, the data on clozapine, risperidone, olanzapine, and quetiapine show significant superiority over typicals in treatment-resistant patients.

Comparisons Among Atypical Agents

How do atypical agents compare to each other in terms of efficacy in treatment-resistant patients? Few controlled studies are available in this area. Bondolfi and colleagues21 compared the atypical agent risperidone to clozapine in an 8-week, randomized, double-blind trial of 86 inpatients with chronic schizophrenia who were resistant to or intolerant of at least two different classes of conventional neuroleptics. Both atypical agents significantly ameliorated symptoms of schizophrenia (P<.001 versus baseline); 67% of risperidone-treated patients and 65% of clozapine-treated patients were clinically improved at endpoint according to total PANSS criteria, and there was no statistically significant difference between the two agents. It may be notable that the dose of clozapine was rather low (291.2 mg/day clozapine versus risperidone 6.4 mg/day), which may have put clozapine at a disadvantage. Another comparative trial examined the effects of clozapine (mean daily dose 403.6 mg) and risperidone (mean daily dose 5.9 mg) in partially responding schizophrenia patients using a double-blind, 8-week design after a baseline fluphenazine treatment period.22 Clozapine proved to be superior to risperidone only in positive symptoms and parkinsonian side effects. The two compounds were comparable in their effects on negative symptoms, depressive symptoms, and BPRS total scores.

Olanzapine has also been compared to clozapine in treatment-resistant patients. In a double-blind, randomized 18-week trial, Beuzen and colleagues23 compared clozapine to olanzapine in 180 patients with schizophrenia who were deemed treatment refractory by virtue of having failed to respond to at least two previous adequate antipsychotic trials. Once again, both agents were effective, but the differences between the two did not reach statistical significance. The results numerically favored olanzapine, which decreased total PANSS scores by 25.6, compared with 22.1 for clozapine.

In a well-designed, double-blind, 14-week study comparing risperidone, olanzapine, and clozapine with haloperidol in well-defined treatment-refractory patients with schizophrenia, Volavka and colleagues24 reported significant superiority on the PANSS of clozapine and olanzapine over haloperidol.

Most recently, clozapine emerged as significantly more effective than olanzapine in the prevention of suicidal behavior in patients with a history of suicide attempts. It was also more effective than hospitalization in preventing suicide attempts within the previous 36 months, and moderate to severe suicidal ideation or command hallucinations for self-harm in the week prior to enrollment. The 2-year study included patients with schizophrenia or schizoaffective disorder (N=980) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.25

Switching or Augmentation

An important clinical concern is what type of strategy should be used in the group of patients with treatment-refractory schizophrenia who have not responded to atypicals. Is it helpful to switch patients who have failed on one atypical to another one? This question has been examined in two recent studies.26,27

Our group conducted a study in 43 inpatients who were highly treatment resistant to adequate trials of typical neuroleptics and to either clozapine or risperidone.26 All patients were switched to olanzapine 10–40 mg/day for 14 weeks after a cross taper, in an open-label, prospective trial. Results on the PANSS showed a minimal nonsignificant improvement in positive and negative symptoms, but a significant improvement in cognitive symptoms (P=.001) and depression/anxiety symptoms (P=.042). Examining improvement using the categorical approach, we found seven patients who were classified as improvers (20% decrease in BPRS), representing an improvement rate of 16.6%.

Another study examined the response of patients who had failed on olanzapine and were switched to clozapine.27 Of the 39 patients who had failed an 8-week trial with olanzapine, 21 were treated with clozapine. Of this group of patients, 52% was classified as responders with at least a 20% decrease in BPRS score. In summary, it appears that a switch from a failed trial with olanzapine to clozapine can be considered, while the reverse may not be very advantageous.

Finally, a number of augmentation strategies have been suggested for patients who have failed a trial with an atypical agent. Unfortunately, only few controlled double-blind studies are available in this very challenging area. Henderson and Goff28 reported on an open study using risperidone as an adjunct to clozapine in a 12-week trial of treatment-refractory outpatients with schizophrenia. BPRS scores decreased significantly in this group and 10 of the 12 patients improved on the BPRS.

In a retrospective study by Friedman and colleagues,29 clozapine augmentation of pimozide for partial clozapine responders was helpful in reducing mean BPRS scores from 51 to 27 in two schizoaffective and five schizophrenic patients. Another augmentation report utilized loxitane in chronic schizophrenic patients who still continued to show substantial impairment in functioning while taking clozapine.30 These patients received adjunctive loxitane lasting 18–50 weeks. All patients improved as measured by BPRS ratings ranging from 19 to 38 points, with two patients improving remarkably.

The guiding principle of augmentation strategies is to first determine the main treatment-resistant syndrome within the overall clinical presentation of the patient. Each of these persistent clinical syndromes can then become a treatment target for a specific augmentation strategy that is added to a stable atypical antipsychotic regimen (Table 5).


Schizophrenia is a severe and chronic illness that requires careful, ongoing pharmacologic management. Treatment guidelines such as those presented here help to inform clinical decisions regarding choice of medication. Second-generation atypical antipsychotics have provided clinicians with better tolerated alternatives to older typical antipsychotics. However, levels of efficacy are still widely variable among patients.


1.    Lindenmayer JP, Bernstein-Hyman R, Grochowski S, Bark N. Psychopathology of schizophrenia: initial validation of a 5-factor model. Psychopathology. 1995;28:22-31.
2.    Rosenheck R, Chang S, Choe Y, et al. Medication continuation and compliance: a comparison of patients treated with clozapine and haloperidol. J Clin Psychiatry. 2000;61:382-386.
3.    Naber D. Optimizing clozapine treatment. J Clin Psychiatry. 1999;12:35-38.
4.    Osser DN, Sigadel R. Short-term inpatient pharmacotherapy of schizophrenia. Harv Rev Psychiatry. 2001;9:89-104.
5.    Jones A. Assertive community treatment: development of the team, selection of clients, and impact on length of hospital stay. J Psychiatr Ment Health Nurs. 2002; 9:261-270.
6.    New York Mental Hygiene Law § 9.13 McKinney 2002
7.    American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. American Psychiatric Publishing, Inc.: Washington, DC; 1997.
8.    Salzman C, Solomon D, Miyawaki E, et al. Parental lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. J Clin Psychiatry. 1991;52:177-180.
9    Brook S, Lucey JV, Gunn KP. Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone IM Study Group. J Clin Psychiatry. 2000;61:933-941.
10.    Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam or placebo in threatening acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001;21:389-397.
11.    Donlon PT, Hopkin JT, Tupin JT, et al. Haloperidol for acute schizophrenic patients: an evaluation of three oral regimens. Arch Gen Psychiatry. 1980;37:691-695.
12.    Citrome LL, Daniel DG, Wassef AA, Tracy KA, Wozniak P, Casey D. Antipsychotic monotherapy versus combination treatment with valproate in hospitalized patients with acute schizophrenia: a double-blind, multi-center study. Poster presented at: Annual Meeting of the American Psychiatric Association; May 2002; Philadelphia, Pa.
13.    Citrome L, Volavka J, Czobor P, et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv. 2001;52:1510-1514.
14.    Kane J, Honigfeld G, Singer J, Meltzer H, Group at CCS. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789-796.
15.    Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry. 1999;156:990-999.
16.    Rosenheck R, Cramer J, Xu W, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med. 1997;337:809-815.
17.    Wirshing D, Marshall B, Green M, Mintz J, Marder S, Wirshing W. Risperidone in treatment-refractory schizophrenia. Am J Psychiatry. 1999;156:1374-1379.
18.    Breier A, Hamilton SH. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol Psychiatry. 1999;45:403-411.
19.    Conley RR, Tamminga CA, Bartko JJ, et al. Olanzapine compared with chlorpromazine in treatment resistant schizophrenia. Am J Psychiatry. 1998;155:914-920.
20.    Emsley R. Partial response to antipsychotic treatment: the patient with enduring symptoms. J Clin Psychiatry. 1999;60(suppl 23):10-13.
21.    Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry. 1998;155:499-504.
22.    Breier A, Malhotra A, Su TP, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry. 1999;156:294-296.
23.    Buezen JN, Birkett MA, Kiesler GM, Tollefson GD, Wood AJ, Beasley CW. Olanzapine versus clozapine: an international double-blind study in the treatment of resistant schizophrenia. Paper presented at: The 37th Annual Meeting of the American College of Neuropsychopharmacology; Dec 14-18; San Juan, Puerto Rico.
24.    Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002;159:255-262.
25.    Meltzer HY. Suicidality in schizophrenia: a review of the evidence for risk factors and treatment options. Curr Psychiatry Rep. 2002;4:279-283.
26.    Lindenmayer JP, Volavka J, Lieberman J, et al. Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial. J Clin Psychopharmacol. 2001;21:448-453.
27.    Conley RR, Tamminga CA, Kelly DL, Richardson CM. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry. 1999;46:73-77.
28.    Henderson DC, Goff DC. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry. 1996;57:395-397.
29.    Friedman J, Ault K, Powchik P. Pimozide Augmentation for the treatment of schizophrenia patients who are partial responders to clozapine. Biol Psychiatry. 1997;42:522-523.
30.    Mowerman S, Siris S. Adjunctive loxapine in a clozapine resistant cohort of schizophrenic patients. Ann Clin Psychiatry. 1996;8:193-197.

Dr. Verovsky is a research pharmacist at the Maryland Psychiatric Research Center in the Department of Psychiatry at the University of Maryland.

Dr. Thaker is professor of psychiatry and chief of the Schizophrenia Related Disorders Program at the Maryland Psychiatric Research Center in the Department of Psychiatry at the University of Maryland.

Acknowledgments: This work was supported by grant nos. MH40279 and MH49826 from the National Institute of Health, and a grant from the Stanley Medical Research Institute. 



The advent of antipsychotic drugs in the 1950s revolutionized the treatment of schizophrenia. However, serious motor side effects such as akathisia and tardive dyskinesia raised concerns. Most studies found older women to be more at risk for motor side effects. Sedation, slowed motor speed, and anticholinergic effects produced cognitive and functional problems in some patients. These side effects acted partly as a catalyst in the search for new antipsychotic agents. The new-generation antipsychotic agents are less likely to cause these troublesome motor effects but have different side effects, the most troubling of which are metabolic. Many first-generation antipsychotics and some second-generation antipsychotics affect hormones, especially prolactin. These hormonal side effects likely affect reproductivity in women. Further studies are needed to determine if gender differences affect risk and incidence rates of antipsychotic side effects.



Since the 1950s, the use of antipsychotic drugs has revolutionized the treatment of patients who are chronically mentally ill. However, use of these drugs over the past 4 decades has produced significant side effects in many patients.1-6 Women exposed to antipsychotic agents are at risk for almost all of these side effects, although the risks for some of the side effects are known to vary according to gender.7 Women may be more vulnerable to the long-term motor side effects and the endocrinological side effects, which are particularly distressing to younger women.7,8 However, there is a general lack of data regarding the effects of gender on the risk, course, and management of antipsychotic drug side effects. Since many of the side effects are infrequent, large numbers of patients taking medications are needed in order to obtain reliable estimates of the prevalence rates. Many large sample studies that have examined side-effect profiles of antipsychotic agents were conducted at Veteran’s Administration facilities, which have mostly male patients.9

Many side effects emerge with the initiation of antipsychotic treatment, while others are more insidious in onset, perhaps emerging after years of treatment. The early-onset side effects include cardiovascular effects such as orthostatic hypotension, hypertension, and cardiac rhythm anomalies; anticholinergic effects such as dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment; sedation and slowness in processing information; motor side effects such as tremors, slowness, limitation of voluntary movements and other associated parkinsonian symptoms; and motor restlessness (akathisia).10 Other side effects that may be apparent after weeks to months of antipsychotic treatment include weight gain, lactation, gynecomastia in males, breast enlargement in females, changes in libido, and disturbances in menstruation in females. Late-onset side effects occurring after months to years of antipsychotic treatment include choreoathetoid and dystonic involuntary movements of tardive dyskinesia, skin pigmentation changes, rare lenticular opacities, and morbidity secondary to weight gain. There are some rare but serious side effects associated with a particular antipsychotic drug. Examples include agranulocytosis with clozapine and cardiac conductivity changes with some low potency drugs.10

The side-effect profiles vary with dose and antipsychotic agent. Risks for immediate motor side effects are common with high potency first-generation antipsychotic drugs, and less common with low potency first-generation drugs. Risks for tardive dyskinesia, one of the serious adverse effects of antipsychotic drug use, are similar for all first-generation antipsychotics. Motor side effects, particularly dyskinesia, were one of the major catalysts for the search for drugs that could ameliorate psychotic symptoms with fewer side effects.11 The results were the second-generation antipsychotic agents that were introduced for clinical use: clozapine (1990), risperidone (1994), olanzapine (1996), quetiapine (1997), and ziprasidone (2001). These drugs have fewer motor side effects, but have much higher risks for weight gain, hyperlipidemia, and diabetes mellitus secondary to the weight gain or through other mechanisms, when compared to the first-generation antipsychotics. It is important to note that tardive dyskinesia only became a public health concern in the late 70s and 80s after a large number of patients took these drugs for a long time. Similarly, one would anticipate that the full impact of chronic weight gain and hyperlipidemia associated with second-generation antipsychotics will become apparent in the future as data regarding associated morbidity and mortality are compiled. Furthermore, there is considerable interindividual variability that the clinician can take advantage of when choosing a drug to treat psychosis. Side-effect vulnerability in the patient can be predicted by sex, age, or other clinical variables. In the near future, pharmacogenetic data will drive many of the drug-selection decisions made by clinicians.

Motor Side Effects of Antipsychotic Agents

Within hours to days of starting antipsychotic drugs, particularly high potency first-generation antipsychotic drugs, women are less vulnerable to developing acute dystonic reactions.12 Spasm and abnormal posturing of the neck muscles (torticolis), tongue, ocular muscles (oculogyric crisis), and back muscles are some of the common regions involved in acute dystonia.13 The reaction quickly responds to anticholinergic treatment. Motor symptoms mimicking Parkinson’s disease emerge within days to weeks of starting first-generation antipsychotics, and to a much lesser extent, second-generation antipsychotic treatment. Tremors affecting the extremities and other regions, hypokinesia, bradykinesia, shuffling gait, and masked facies are common clinical manifestations.13 Akathisia is perhaps one of the most troubling subchronic motor side effects associated with first-generation antipsychotics as well as some of the second-generation agents.

The prevalence rates of such extrapyramidal symptoms (EPS) vary from sample to sample depending on the drugs used, their doses, and duration of treatment. A large sample study (N=1,559) reported a prevalence rate of 29.4% for EPS in patients who had a long history of receiving antipsychotic drugs.7 Most common symptoms were parkinsonian (66% of those with EPS), and akathisia (32%). Least common were acute dystonia (2%). Women were at a higher risk for EPS in this study, although this has not been a consistent finding in the literature.

Akathisia is one of the most troubling side effects for patients and one of the leading causes of noncompliance due to the uncomfortable subjective feelings of motor restlessness.14 In addition, successful management of akathisia is difficult. In spite of high prevalence rates, parkinsonian symptoms have not been very troubling for the therapeutics of chronic psychoses because these symptoms are easily managed.9 The symptoms are reversible when the antipsychotic drug is discontinued; anticholinergic and other agents are effective in reversing the symptoms in most cases and patients develop tolerance after continued use of antipsychotic medications and reduction of parkinsonian symptoms.

In contrast to EPS, the recognition that the emergence of involuntary choreoathetoid and dystonic movements of tardive dyskinesia was linked to antipsychotic use in a large proportion of chronically-treated psychotic patients, caused a major public health concern. This is because dyskinetic movements are not easily reversible unless a long-term antipsychotic drug-free period is implemented, and even with that, the movements may be irreversible in some patients. Treatments of dyskinesia are difficult. The iatrogenic syndrome, although mild to moderate in most patients, progresses in a minority of patients, affecting most of the body regions and causing serious disability. Complications such as weight loss, arthritis, and disfiguring facial hypertrophy due to constant muscle spasms, dysarthria, and visual and mobility problems due to focal dystonia occur in about 15% of patients with tardive dyskinesia.15 Data from our clinic shows that the distribution of severity of dyskinesia is similar in men and women3 (Figure 1). Also, there is no effect of gender on the body distribution of dyskinetic symptoms (Figure 2).

 Several studies have found that women are at greater risk for tardive dyskinesia than men.16,17 In one of the few prospective studies, Kane and colleagues1 observed an incidence rate of about 4% to 5% per treatment year with first-generation agents. Women were at slightly increased risk, and as women aged, the risk increased. Other independent risk factors are cumulative dose of the first-generation antidepressant drugs, affective disorders, diabetes mellitus, and organic brain syndrome. The reason for the increased risk of tardive dyskinesia in women is unclear. This may be influenced by the fact that women are diagnosed with major depression and seek treatment more often than men.


Casey and colleagues9 examined the relationship between mood disorder and tardive dyskinesia. They noted that prevalence rates of tardive dyskinesia for those with affective disorders ranged from 30% to 83% and were consistently higher than for patients diagnosed with schizophrenia (25% to 30%). The higher risk for tardive dyskinesia in women was apparent both in affective disorders as well as nonaffective disorder cohorts.

Research on tardive dyskinesia has focused on the natural history of the illness and its prognostic indicators in adults.2,18 These studies have found that the course of tardive dyskinesia depend to a large extent, on the dose of antipsychotic prescribed. Switching to clozapine, and perhaps other second-generation antidepressant agents, is likely to reduce the severity of dyskinesia.19 The effects of sex on outcome have not been extensively looked at the literature. Data from a large cohort of patients that were followed for 1–15 years in our clinic showed that women show a slight but significant improvement in tardive dyskinesia, whereas men do not (Figure 3). These findings were observed even after controlling for age and duration of follow-up. With increasing use of second-generation agents to treat psychoses, new cases of tardive dyskinesia are less and less likely. However, there is still a large segment of women with psychoses who were previously treated with first-generation agents and experienced persistent tardive dyskinesia.

Treatment of tardive dyskinesia includes withdrawal from the antipsychotic agent if clinically feasible, switching to clozapine or another second-generation drug, and, in select cases, benzodiazepines to provide temporary symptom relief.20 One may want to consider Vitamin E treatment, although findings from several studies are mixed.21

Metabolic Side Effects of Antipsychotic Agents

While the concerns regarding tardive dyskinesia may be fading with the use of second-generation antidepressants, other side effects such as weight gain and hyperlipidemia may have serious health implications in chronic mentally ill population. Weight gain has been associated with antipsychotic treatment since chlorpromazine was introduced in the 1950s, but recent concerns about the propensity of the second-generation medications to cause obesity has promoted new interest.3,22 Obesity is a known risk factor for many health problems including diabetes mellitus, coronary artery disease, and hypertension. With the recent trend of using second-generation antidepressants in young women, not uncommonly in children and adolescents, and frequently for nonpsychotic illnesses, the complications associated with the side effects of second-generation antidepressants are likely to become a major public health issue of the future.

The mean weight gain associated with second-generation antidepressant treatment varies with the drug used. In general, clozapine and olanzapine are associated with about 10–20 lbs of weight gain for the first year.3 Weight gain usually plateaus by the end of the first year, but can continue, especially with clozapine, at the rate of about 4 lbs/year. Risperidone and quetiapine are less likely to cause severe weight gain, although moderate gain in the range of 5–10 lbs is not uncommon.3 Patients taking lithium and valproate concurrently with second-generation antidepressants are likely to experience two to three times the amount of weight gain as those who were not taking one of these mood stabilizers.3 Even before the advent of second-generation agents, women with schizophrenia had body mass index distributions in the overweight and obese spectrum compared to their counterparts in the general medical population.4 This trend is likely to worsen with increased use of second-generation antidepressants. Although mechanisms underlying weight gain in these patients is likely to be complex, suppression of satiety through brain neurotransmitter systems, mediated through the blockade of histamine H1 receptors and/or serotonergic 5-HT2c receptors, are likely to be implicated.

Following several case reports of increased triglycerides associated with second-generation antidepressants, several investigators prospectively examined the issue. Most of these were carried out based on a naturalistic study design and noted a significant increase in serum triglyceride levels.22-24 These studies had sample sizes ranging from 25 to 82 patients that were monitored for periods of 3 months to 5 years, and noted increases in triglycerides of about 60–100 mg/dL. In general, there was no significant increase in cholesterol levels. Increases in triglycerides were associated with clozapine, olanzapine, and, to a lesser extent, risperidone. In contrast to these findings, Lund and colleagues25 found no significant differences in diabetes, hyperlipidemia, or hypertension among patients treated with first-generation antidepressants or clozapine. This was a much larger sample (N>3,000), but the data set was based on medical and pharmacy claims which may not be sensitive in identifying diseases. For example, patients may experience increased serum triglycerides or glucose levels without being coded as having hyperlipidemia or diabetes. However, these authors noted an increase in relative risks of hyperlipidemia (relative risks of 2.4) and diabetes (relative risks of 2.5) associated with clozapine treatment in a young cohort (20–34 years of age).

Among these reports of metabolic side effects of second-generation antidepressants, the most disconcerting finding was that about one out of three patients who were initiated on clozapine were later diagnosed with adult-onset type 2 diabetes mellitus within the 5-year follow-up.24 In spite of the lack of rigorous study design, these observations based on a naturalistic study demand a closer look. The issue of type 2 diabetes mellitus and schizophrenia is complex as suggested by findings of abnormal glucose regulation in schizophrenia in the preantipsychotic drug era.26,27 The use of first-generation agents, particularly phenothiazines, may have further contributed to the risk of diabetes.28 Recently, there have been multiple reports of hyperglycemia, exacerbation of existing diabetes mellitus, and diabetic ketoacidosis with second-generation antidepressants.5,29 The increase in weight gain and abdominal adiposity associated with second-generation antidepressants may contribute to hyperglycemia by decreasing skeletal muscle insulin sensitivity. However, other independent adverse effects of these drugs are likely as numerous clinical reports have observed abnormal glucose regulation independent of weight gain.30,31 This assertion was further supported by a study by Newcomer and colleagues32 showing abnormal glucose tolerance tests in patients treated with olanzapine and clozapine. Being a female of African American ethnicity may also be risk factors for the hyperglycemic effects of second-generation antipsychotics.29

Hormonal Side Effects of Antipsychotic Agents

Hormonal side effects of antipsychotic agents may not have received its deserved attention from clinicians. These drugs elevate prolactin levels through blockade of dopamine D2 receptors on the lactotrophs in the anterior pituitary gland. The dopamine-inhibiting effect on prolactin release is diminished or gone, leading to hyperprolactinemia. This increase in prolactin levels is correlated with the degree of suppression of the hypothalamic pituitary axis and subsequent hypogonadal state.6 As a result, women experience serious consequences such as menstrual irregularities, sexual dysfunction, galactorrhea, and infertility. In addition, hyperprolactinemia decreases bone density directly or indirectly by decreasing ovarian estrogen secretion.33 This is a particular concern since women with schizophrenia are already candidates for osteoporosis because they tend to have other risk factors such as sedentary lifestyles, smoking, poor nutrition, and pathological water drinking.6,8,34 Another potential consequence of chronic low estrogen levels is increase in cardiovascular risk.8

Prolactin levels in patients with schizophrenia are generally within normal range prior to receiving treatment for the psychosis.35 Antipsychotic agents vary in their propensity to cause this side effect depending on the potency and/or transiency of D2 receptor blocking effects. In general, first-generation antipsychotics are more likely to cause serum prolactin elevations; among second-generation agents, risperidone causes hyperprolactinemia. The prolactin-elevating effect is more frequent and occurs at a lower daily dose of antipsychotic agents in women than in men.36 The effects of second-generation antipsychotics (other than risperidone) on prolactin levels are negligible. For example, in a fixed dose study in 361 patients with schizophrenia, the prolactin levels remained essentially flat from baseline to endpoint with quetiapine even at the highest dosage range, while marked elevations were found with haloperidol.37 There may be a transient increase with olanzapine in the first few weeks of use, but levels tend to remain within the normal range and then return to baseline levels or even lower.

Switching from typical to atypical agents can normalize prolactin levels. In addition, once the patient’s prolactin level returns to normal, the associated symptoms should resolve. In women, menses will resume, libido should increase, and fertility may return to normal for the patient’s age and health. Estrogen levels should return to age-appropriate levels, thereby reducing the risk of decreased bone mineral density and cardiovascular disease.38


Drug treatment of psychoses results in several side effects. Women, particularly those who are elderly, are more vulnerable to tardive dyskinesia and hyperprolactinemia. There is a large variability among available antipsychotic agents in their propensity to produce different side effects. Thus, clinicians should be able to switch from one medication, or one class of drugs, to another in order to manage many of these side effects. Patient characteristics, such as age, may also help in selecting a particular drug to prevent emergence of side effects. In this context, pharmacogenetics are beginning to emerge which will allow the clinicians in the near future to customize drug treatment based on genotype information.39


1.    Kane JM, Woerner M, Lieberman J. Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol. 1988;8(suppl 4):52S-56S.
2.    Gardos G, Perenyi A, Cole JO, Samu I, Kocsis E, Casey DE. Seven-year follow-up of tardive dyskinesia in Hungarian outpatients. Neuropsychopharmacology. 1988;1:169-172.
3.    Meyer JM. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry. 2001;62(suppl 27):27-34.
4.    Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686-1696.
5.    Haupt DW, Newcomer JW. Hyperglycemia and antipsychotic medications. J Clin Psychiatry. 2001;62(suppl 27):15-26.
6.    Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol. 2002;22:109-114.
7.    Muscettola G, Barbato G, Pampallona S, Casiello M, Bollini P. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. J Clin Psychopharmacol. 1999;19:203-208.
8.    Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res. 1999;35:(suppl):S75-S86.
9.    Casey DE, Keepers GA. Neuroleptic side effects: acute extrapyramidal syndromes and tardive dyskinesia. Psychopharmacol Ser. 1988;5:74-93.
10.    Physician’s Desk Reference. 53rd ed. Montvale, NJ:?Medical Economics, Inc; 1999.
11.    Glick ID, Murray SR, Vasudevan P, Marder SR, Hu RJ. Treatment with atypical antipsychotics:?new indications and new populations. J Psych Res. 2001;35:187-191.
12.    Keepers GA, Casey DE. Prediction of neuroleptic-induced dystonia. J Clin Psychopharmacol. 1987;7:342-345.
13.    Kaplan H,. Freedman AM, Sadock BJ. Comprehensive Textbook of Psychiatry/III. Vol 2. Baltimore, Md: Williams & Wilkins; 1980.
14.    Fleischhacker WW, Meise U, Gunther V, Kurz M. Compliance with antipsychotic drug treatment: influence of side effects. Acta Psychiatr Scand Suppl. 1994;382:11-15.
15.    Cassady SL, Thaker GK, Summerfelt A, Tamminga CA. The Maryland Psychatric Research Center scale for the characterization of involuntary movements. Psychiatry Res. 1997;70:21-37.
16.    Casey DE. Tardive dyskinesia–animal models. Psychopharmacol Bull. 1984;20:376-379.
17.    Casey DE. Neuroleptic-induced parkinsonism increases with repeated treatment in monkeys. Psychopharmacol Ser. 1987;3:243-247.
18.    Gardos G, Cole JO, Haskell D, Marby D, Paine SS, Moore P. The natural history of tardive dyskinesia. J Clin Psychopharmacol. 1988;8(suppl 4):31S-37S.
19.    Tamminga CA, Thaker GK, Moran M, Kakigi T, Gao XM. Clozapine in tardive dyskinesia: observations from human and animal model studies. J Clin Psychiatry. 1994;(suppl 55):102-106.
20.    Thaker GK, Nguyen JA, Strauss ME, Jacobson R, Kaup BA, Tamminga CA. Clonazepam treatment of tardive dyskinesia: a practical GABAmimetic strategy. Am J Psychiatry. 1990;147:445-451.
21.    Gardos G. Managing antipsychotic-induced tardive dyskinesia. Drug Saf. 1999;20:187-193.
22.    Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry. 2002;63:425-433.
23.    Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry. 1999;60:767-770.
24.    Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry. 2000;157:975-981.
25.    Lund BC, Perry PJ, Brooks JM, Arndt S. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry. 2001;58:1172-1176.
26.    Kasnin J. The blood sugar curve in mental disease. Arch Neurol Psychiatry. 1926;16:414-416.
27.    Braceland FJ, Meduna LJ, Vaichulis JA. Delayed action of insulin in schizophrenia. Am J Psychiatry. 1945;102:108-110.
28.    Thonnard-Neumann E. Phenothiazines and diabetes in hospitalized women. Am J Psychiatry. 1968;124:978-982.
29.    Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry. 2001;62(suppl 23):30-38.
30.    Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry. 1998;44:778-783.
31.    Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE. Clozapine and associated diabetes mellitus. J Clin Psychiatry. 1997;58:108-111.
32.    Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry. 2002;59:337-345.
33.    Ataya K, Mercado A, Kartaginer J, Abbasi A, Moghissi KS. Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinemia. Fertil Steril. 1988;50:876-881.
34.    Halbreich U, Palter S. Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. Schizophr Bull. 1996;22:447-454.
35.    Kuruvilla A, Srikrishna G, Peedicayil J, Kuruvilla K, Kanagasabapathy AS. A study on serum prolactin levels in schizophrenia: correlation with positive and negative symptoms. Int Clin Psychopharmacol. 1993;8:177-179.
36.    Melkersson KI, Hulting AL, Rane AJ. Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses. Br J Clin Pharmacol. 2001;51:317-324.
37.    Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42:233-246.
38.    Dickson RA, Seeman MV, Corenblum B. Hormonal side effects in women: typical versus atypical antipsychotic treatment. J Clin Psychiatry. 2000;61(suppl 3):10-15.
39.    Basile VS, Masellis M, McIntyre RS, Meltzer HY, Lieberman JA, Kennedy JL. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry. 2001;62(suppl 23):45-66.

Dr. Stotland is professor in the Departments of Psychiatry and Obstetrics and Gynecology at Rush Medical College in Chicago.

Acknowledgments: The author reports no financial, academic, or other support of this work. 



Why are psychiatric issues so crucial in women’s reproductive health care? Reproductive issues provoke intense feelings and interpersonal conflicts. They range from problems with menarche to problems with menopause, through infertility, contraception, abortion, peripartum psychiatric illness, sexual dysfunction, and gynecologic malignancies. They include psychiatric illnesses specific to reproduction, such as premenstrual dysphoric disorder and postpartum depression, and psychiatric complications and implications of reproductive diseases, malfunctions, and care. The common thread for all of them is the centrality of reproduction in the patient’s identity and in the patient’s relationship with his or her significant other. Awareness of the psychological aspects of reproduction, with a few basic psychiatric tools, can equip the practitioner to deal with the otherwise overwhelming emotions and psychiatric crises that occur in the course of reproductive health care.



Female reproduction has been associated with mental illness, at least since the time of Hippocrates. The term “hysteria” is derived from Hippocrates’ conviction that “otherwise unexplained disorders of voluntary motion and special senses were due to the wanderings of an unmoored uterus.”1 Over the centuries, women’s emotional problems have been attributed to sexual repression, masturbation, the menstrual cycle, menopause, and childbearing.2 They have been treated with clitoridectomy and ovariectomy.3 A few of these relationships have been borne out by modern science, others have been discarded, and still others persist in our tradition despite the absence of a scientific basis. The ability to distinguish among them is important in clinical care.

The field of gender-based biology offers a whole new entrée to molecular medicine, with implications for clinical care that are beyond the scope of this article. There are two major clinical subdivisions under the topic of psychiatry and reproduction: psychological and psychiatric concomitants of reproductive conditions and treatments, and psychiatric diseases specific to women’s reproduction. The first category includes psychological aspects of infertility, contraception, abortion, reproductive technologies, reproductive malignancies, sexually transmitted diseases, hysterectomy, pregnancy, peripartum, and menopause. Menopause was once thought to be an etiologic factor in later life depression, but this presumption has not been borne out by empirical evidence.4 The second category includes premenstrual dysphorias and postpartum mood disorders. Pelvic pain and vulvodynia fall somewhere between the two categories. The psychological impact of reproductive events and treatments is highly dependent on the reactions and supports of family and friends. Women report that the reactions of male partners are particularly important, so we will briefly discuss the male perspective. Lesbian women often feel misunderstood by the healthcare system; however, their needs must be addressed as well. We will proceed in life-stage order.

Premenstrual Dysphorias

Concern about the relationship between the menstrual cycle and women’s moods, cognition, and behavior have existed for a long time, but the concept of severe premenstrual dysphoria as a psychiatric illness is relatively new; it formally debuted in the appendix of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised,5 22 years ago. For decades before that, there were no generally accepted criteria for premenstrual syndrome (PMS), for which~100 signs and symptoms were mentioned in the medical literature.6 A majority of women in studies in the United States indicated that they experienced mood changes over the menstrual cycle7; we do not know the relative importance of expectation and biology in that experience. Unfortunately, the possibility that women feel better than average at some point during the menstrual cycle has not been explored. Approximately 5% of women who menstruate report symptoms so severe that they interfere with their daily lives or cause them to seek medical care7; this syndrome is called premenstrual dysphoric disorder (PMDD). The diagnosis is made after 2 months/cycles of daily self-ratings. Diagnostic criteria require that five or more of the following symptoms be present during most of the menstrual cycles in a given year: markedly depressed mood, marked anxiety, marked affective lability, marked anger or irritability, decreased interest in activities, changes in appetite, changes in sleep, decreased energy, a sense of being overwhelmed or unable to concentrate, and physical symptoms.8

The average age range for PMS and PMDD onset is the mid-20s–30s. There is little data on the natural course of these conditions, but they are persistent. Although there are no proven treatments for PMS, most patients respond to good-sense measures such as eating a well-balanced diet (including proponents of Vitamin B compounds), minimizing or eliminating caffeine and nicotine, and engaging in regular exercise.

Selective serotonin reuptake inhibitors have demonstrated efficacy in PMDD; the US Food and Drug Administration lists PMDD as a specific indication for fluoxetine and sertraline, in usual doses.6 Although these medications require up to 4 weeks for the effective treatment of depression not related to the menstrual cycle, they apparently ameliorate PMDD when taken only in the first 1–2 weeks of the cycle. This means a great deal to some patients who fear becoming dependent on psychoactive medication. Patients with symptoms of PMDD do not differ from normal individuals in their levels of circulating hormones, and hormonal treatments are ineffective.6

Infertility and Reproductive Technology

Many women describe infertility as the most painful problem they have ever confronted in their lives. The ability to reproduce is a key element in gender and adult identity and in committed relationships. For most people, the prospect of parenthood is an intrinsic and central part of their life plans. Infertility, caused by the lack of or damage to a vital, evolutionary central bodily function, threatens those plans. Infertility is usually discovered in the context of a committed relationship, and threatens to deprive the partner and family of biological offspring. In general, men are not quite as upset by infertility as women, are less demonstrative about their disappointment, and are much less willing to discuss the situation with others. This gender difference in the reaction to infertility further strains the relationship, as does the expensive, inconvenient, psychologically and physically intrusive, and sometimes painful sequence of diagnostic tests and treatments.9


The use of donated or purchased gametes presents several challenges for the legal parents and the child. Often, one parent is genetically related to the child while the other is not. There is very little literature, and little discussion, about informing such children about their biological origins. Most families report that they do not intend to inform the children. It is easy to foresee situations in which the revelation can occur and be traumatic. DNA tests, which will become more available over time, and simple blood tests which a child can possibly encounter in a school laboratory experiment, would make it clear that the child could not be the genetic product of the legal parents. As these children become adults, they may advocate for mandatory disclosure, as have some adopted children. Even in the absence of an unexpected or delayed revelation, children are very sensitive to the existence of family secrets, and often imagine far worse scenarios than are actually the case. The parents must be constantly on their guard to evade others who comment on their resemblance to the children.10

An additional complication of well-publicized but unusual treatment successes is that women feel confident that they can postpone pregnancy nearly indefinitely and are not prepared for the unfavorable odds they face when attempting to become pregnant in their late 30s and beyond. In addition, women who do manage to become pregnant, carry to term, and deliver, sometimes report a sense of disappointment after their babies are born. No baby can live up to the expectations that have grown over the years of infertility and treatment.11 The fact that so many artificially-induced pregnancies are multiples exacerbates the situation; caring for more than one infant taxes the best of families, and the rates of health problems in the children rise with the number of fetuses gestated together.


The decrease in unplanned pregnancies has not kept pace with developments in contraception over the last several decades. The gap is a psychosocial one. Some women are afraid of hormonal contraceptives and intrauterine devices, some barrier methods are less effective than hormonal methods, and too many women have difficulty insisting that their male partners use condoms. Some women are unfamiliar and uncomfortable with their own reproductive anatomy. Discussions with physicians have been shown to increase the use of contraception and should be part of routine preventive care.

Abortion and Stillbirth

Unfortunately, the term “abortion” is often incorrectly used to describe spontaneous miscarriage and induced termination of pregnancy. The loss of a wanted pregnancy, whether spontaneously or induced for medical indications, is often not acknowledged in our society as a legitimate reason for grief: “You can have another” or “There must have been something wrong with it; you are lucky,” are common reactions to news of a friend or family member’s loss. Meanwhile, the bereaved woman feels as though her body has failed her. A wanted child becomes invested with parental hopes and expectations even before conception. The loss is real despite the fact that the parents have not actually seen the child. It is enormously helpful for the medical staff to allow the parents, if they wish, to see and hold the remains of what was to have been their child. Carefully wrapping the fetus in blankets can help to make the child more or less presentable. Photographs allow parents to look at a later date. Parents appreciate the opportunity to review autopsy or other findings with the medical team. Feelings of grief after a miscarriage or stillbirth can persist through life, but a woman should be able to resume basic activities within weeks and to feel some pleasure in life within months. Unresolved grief can turn into clinical depression.12

Induced abortion is a politicized topic in the United States. The risk factors for unplanned and unwanted pregnancy are the same as the risk factors for psychological difficulties following abortion: these include coercion, poverty, unrealistic demands, and existing psychiatric illness.13 Many women report some sadness and/or guilt following abortion, but very few experience new-onset psychiatric illness. Some women report that making the decision that they could not support a pregnancy and child responsibly was an important step in their maturation.13 Unfortunately, the experience of some women is complicated by an inability to find or pay for an abortion provider, or harassment at the clinic where the abortion is performed. The responsibility of the health care professional is to help a woman make a decision consonant with her own values and situation and to offer support for whichever decision she makes.14


Pseudocyesis, or “false pregnancy,” is a condition in which a woman believes she is pregnant and shows some physiological changes characteristic of pregnancy, but is not pregnant in reality. There is very little data on the causes or long-term outcomes of pseudocyesis. Demonstrating definitive evidence that there is no pregnancy, by doing an ultrasound for example, may briefly lead the patient toward the realization that she is not pregnant. However, her conviction that she is pregnant may recur. This delusion exists apart from generalized psychotic conditions such as schizophrenia; the patient, with her swollen belly and in her maternity clothes, can otherwise continue to function.

Hyperemesis Gravidarum

Hyperemesis gravidarum is diagnosed when the nausea and vomiting of pregnancy, which do not appear to be concentrated in the morning hours after all (“morning” sickness actually occurs throughout the day), cause metabolic derangements and other complications. Hyperemesis was long believed to be a psychological disease, and treatment consisted of a variety of psychosocial interventions, some of them punitive or humiliating, used together with rehydration and restoration of metabolites. It now appears that while psychosocial factors may play an ancillary etiologic role, hyperemesis is a hormonal one. However, a woman with hyperemesis may need psychosocial support to cope with the incessant vomiting.

Postpartum Mental Illness

Postpartum mental illnesses are generally broken up into three categories: baby blues, postpartum depression, and postpartum psychosis.15 These conditions may or may not exist on a continuous spectrum: As some cases of postpartum depression progress, psychotic features develop. “Baby blues” is an extremely common phenomenon. Within days after birth, the new mother becomes affectively labile. She may cry on the slightest whim or from no discernible provocation. Women do not describe this experience as simple depression, but rather as heightened awareness of, and sensitivity to, the ups and downs of human life. Although “baby blues” is usually understood as a byproduct of the abrupt hormonal changes peripartum, social factors may play a role. For example, it is probable that a new mother living in the United States is more likely to be expected to fend for herself and her baby than a new mother in many other countries; the United States offers less financial support to families with children than do most countries in Europe.

Social factors play a role in postpartum depression as well. Postpartum depression can begin 6–12 months after a baby is born. The basic symptoms are like those of any other depression. The mother’s depressive ideation centers around worries about the baby, insecurity about her capacity to mother, and fear that she will harm the baby. The mother is often increasingly agitated. The depressive symptoms of sleeplessness and fatigue are too often mistaken for normal concomitants of new parenthood; many women report that their concerns were ignored for a considerable time, and that they had to consult with several physicians before receiving effective care. Their psychic pain is compounded by others’ assertions, and their own beliefs, that the time period after having a baby should be the happiest time in a woman’s life and that they have no right to feel sad when they are lucky enough to have a healthy baby. Women who do not receive effective care early in the course of illness typically feel they have missed one of the major joys of life, and worry that their children have been negatively affected. There is evidence that serious maternal depression has a negative impact on a child’s development.

Many cases of postpartum depression are simply continuations of depressive episodes or long-standing depression that were present during pregnancy. Screening for depression during pregnancy is a high-yield investment. Mild to moderate cases of pre- or postpartum depression can be treated with psychotherapy or with medication. Cognitive-behavioral therapy has been best studied, but it is likely that other forms of therapy are effective as well. For more severe depression, medication is indicated. Several selective serotonin reuptake inhibitors appear to be relatively safe for the fetus and nursing infant. Although it would be desirable to have more data on the effects of pharmacotherapy on babies, it is not appropriate to reject the use of medication altogether.

The psychiatric and obstetrical risks of untreated depression are considerable and must be weighed against the possible unknown risks of adverse effects on the fetus and nursing baby. Weaning or not breastfeeding pose medical and psychological risks for the mother-child dyad as well. Timing medication dosage so that peak blood levels occur just after the infant has been fed seems to minimize infant exposure to medication. If the mother is already on antidepressants, they should be tapered gradually so as to avoid discontinuation syndromes. Some women prefer psychiatric hospitalization to the use of medication when they are pregnant or breastfeeding.

Postpartum psychosis is a medical emergency, as we have learned all too tragically from recent cases ending in fatalities. The case of Andrea Yates, a woman in Texas who killed her children, is one such example that has been widely reported and discussed in the media. In some other Western countries, infanticide by a new mother is dealt with differently than other murders; the role of hormonal changes and psychiatric illnesses is recognized, and punishments are relatively mild. In most cases, the mother who actually kills her child or children does so because of a delusional belief that sending them to heaven is the only way to protect them from a worse fate on earth. She often attempts to kill herself in order to go along with them. Neonaticide is sometimes the result of a pregnancy not acknowledged either by the pregnant woman or by her friends and relatives. The mother may confuse the contractions of labor with an urge to defecate, and deliver the baby into the toilet where it drowns, or she may hide the baby and dispose of it in the trash. These cases seem to occur when the patient feels that a pregnancy would be extremely unacceptable to her family and when she feels overwhelmed by the situation she is in. She finds other reasons for her nausea, amenorrhea, and expanding waistline. In the United States, these mothers are generally arrested, tried, and sent to prison, where no further psychiatric evaluation or treatment is provided.

Unfortunately, postpartum psychiatric illnesses have a strong tendency to recur after subsequent pregnancies. Fortunately, they generally respond quickly to whatever treatment was effective for the prior episode. The patient, family, and medical team need to have an aggressive detection, diagnosis, and treatment plan; they may choose to begin medication and/or psychotherapy before birth, or to institute treatment immediately after delivery or at the first sign of recurrence. If existing social supports are not adequate, a visiting nurse or other outside help can play a major role in recovery.

Hysterectomy and Gynecological Malignancies

There has been considerable dispute about the psychological impact of hysterectomy, with studies purporting to prove that the effect is negative, positive, and neutral. In sum, it is not possible to say with certainty that hysterectomy is generically psychologically beneficial or harmful; the impact depends on the woman and the circumstances.16 Nulliparous women are at increased risk of depression; those who have children but would like to have more are at somewhat increased risk as well. In some cultures, an intact uterus is essential to the identity of a “real woman.” Hysterectomies performed under emergency conditions do not allow patients to prepare themselves psychologically for the loss of their fertility. The potential for other women to serve as so-called surrogates and bear a patient’s genetic child may soften the blow for women whose ovaries have been preserved.

It should be noted that the term “hysterectomy,” as used in gynecology, includes the removal of the ovaries and fallopian tubes as well as the uterus. Patients may not know what procedure has been recommended or performed, and may have intense feelings both about an unexpected ovariectomy and about not being fully informed of the procedural details by their physicians.

Gynecologic malignancies pose particular psychological challenges for patients. Some patients with gynecologic malignancies feel that their diseases are punishments for past sexual behavior. They suffer through the removal of sexual organs, sometimes resulting in premature menopause. Resulting difficulties in resuming sexual relations can fuel problems with a significant other, who may already be concerned about “catching” the disease.17 Ovarian cancer is known to be potentially fatal and is therefore more frightening than some other malignancies. Cervical cancer, in its advanced forms, is known to be largely preventable with regular Pap (papanicolaou) smears, and therefore may be blamed on the woman who failed to seek that preventive care.


Menopause has been considered a precipitant for depression for centuries, but meta-analyses of more recent studies demonstrate serious methodological difficulties. For example, studies rarely confirmed the timing of menopause. The reported results of these studies are contradictory; some find an association between depression and menopause and others do not. Rather than mourning the loss of their fertility, most women are relieved to be free of monthly bleeding, the need for contraception, and the duties of caring for young children. Physical symptoms such as hot flashes, night sweats, and vaginal dryness may cause secondary fatigue, irritability, difficulty concentrating, and sexual dysfunction. Current thinking focuses on the possibility that some women are vulnerable to hormonal changes; it appears that the same women may experience depressive symptoms premenstrually, postpartum, and at menopause. Some patients report that exogenous hormones improve their mood and overall well-being, but hormones precipitate depression in others.18 The clinician and patient should carefully note the relationship between mood and hormones in each case, and proceed on the basis of their findings.

Negative feelings about menopause are related to fears of aging. The aging woman in American society is viewed as unattractive and undesirable. At the same time, women of menopausal age are subject to a variety of psychosocial stresses: domestic violence, abandonment by long-time partners, age discrimination, thus making it difficult for them to find and keep jobs, and demands of their adult children and grandchildren. These factors should be carefully explored before psychological problems are ascribed to the hormonal changes of menopause.

The Male Perspective

Every reproductive event for a woman is influenced by, and influences, the men in her life. Men often feel neglected by clinicians under these circumstances. Many men do not completely understand the details of female anatomy and physiology, and many more are not comfortable with the subject. With a patient’s permission, her partner may be present for her gynecological examination, and her condition explained to both of them.19 Unplanned and unwanted pregnancies, the discomforts of pregnancy and labor, and complications of the process often make men feel guilty. The guilt is exacerbated when they simultaneously feel resentment at their female partners for getting pregnant, changing shape, or failing to incubate and bring forth desired offspring. Rather than discussing their feelings with their partner, relatives, or close friends, they may throw themselves into their work and/or hobbies. This can make the woman feel that her partner does not care. Joint interviews can help the couple communicate.

Sexual Orientation

Lesbian women face a somewhat different constellation of challenges with respect to OB/GYN issues than do heterosexual women. On one hand, it is awkward, to say the least, when health care professionals assume that every woman is heterosexual: by referring to husbands or boyfriends, by asking about contraception when none is necessary, or by being surprised or judgmental when a patient informs them she is homosexual. On the other hand, health care professionals may forget that many lesbian women have, or have had, male partners. There is some evidence that lesbians avoid medical encounters and thus suffer the effects of diseases not caught in their early stages.20 It is useful to know a patient’s sexual orientation, but it is more important to know the nature of her sexual history and activities, including those she practices alone. The physician might say something to the effect of “Please tell me about your sexual life,” as an opener for conversation on the topic.

Psychiatric Referral

As noted above, many cases of psychiatric conditions associated with reproductive events can be readily treated by primary care physicians.21 The newer antidepressants, while no more effective than the old ones, are easier to prescribe, safer, and better tolerated by patients in clinical practice. The interest, skill, and time of primary clinicians in psychotherapy varies enormously. For the treatment of depression, the combination of medication and psychotherapy is most effective. Provision of both by the same clinician is optimal. Patients who are not responding to treatment, have dual or more diagnoses, or are suicidal should be seen by a psychiatrist. In the latter case, the patient should not be left alone until she is safely under psychiatric care. Access to mental health professionals, particularly psychiatrists, is limited in many public or private health plans. It is worthwhile to cultivate relationships in advance, and it is sometimes necessary to convince a third party payer to support the services to  which a patient is entitled.


Reproductive events throughout the life cycle are generally normal physiologic phenomena, but they are associated with intense psychological reactions and occasional psychiatric complications. Clinicians need to understand the emotional implications of reproductive events for both the female patient and her male or female partner.22 Most psychiatric complications can be readily diagnosed and treated by the clinician who is sensitive to them, alleviating terrible pain and preventing lasting damage to patients and their families. Serious and complicated cases should be referred to a psychiatrist.


1.    Pomeroy SB. Goddesses, Whores, Wives, and Slaves:?Women in Classical Antiquity. New York, NY: Schocken; 1975.
2.    Freud S. Female sexuality. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol. 21. London, England: Hogarth Press; 1961:223-243.
3.    Meigs C. Females and their diseases. In: Speert, ed. Obstetrics and Gynecology in America. Chicago, Il: American College of Obstetricians and Gynecologists; 1986.
4.    Avis N, Brambilla D, McKinlay SM, et al. A longitudinal analysis of association between menopause and depression: results from the Massachusetts women’s health study. Ann Epidemiol. 1994;4:15-21.
5.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1980.
6.    Miller LJ. Psychiatric disorders and the menstrual cycle. In: Stotland NL. Cutting Edge Medicine: What Psychiatrists Need to Know. Washington, DC: American Psychiatric Publishing; 2002:113-136.
7.    Stotland NL, Stewart DE. Psychological aspects of the menstrual cycle. In: Jensvold MF, Dan CE, eds. Psychological Aspects of Women’s Health Care. 2nd ed. Washington, DC: American Psychiatric Publishing Inc; 2001.
8.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:715-718.
9.    Wright J, Duchesne C, Sabourin S, et al. Psychosocial distress and infertility: men and women respond differently. Fertil Steril. 1991;55:100-108.
10.    Sokoloff BZ. Alternative methods of reproduction: effects on the child. Clin Pediatr. 1987;26:11-17.
11.    Shapiro CH. Is pregnancy after infertility a dubious joy? Social Casework. 1986;67:306-313.
12.    Leon IG. When a Baby Dies: Psychotherapy for Pregnancy and Newborn Loss. New Haven, Conn: Yale University Press; 1990.
13.    Adler NE, David HP, Major BN, et al. Psychological responses after abortion. Science. 1990;248:41-44.
14.    Stotland NL. Abortion Facts and Feelings: A Handbook for Women and the People Who Care About Them. Washington, DC: American Psychiatric Press Inc; 1998.
15.    Miller LJ. Postpartum Mood Disorders. Washington, DC: American Psychiatric Press Inc; 2000.
16.    Schofield MJ, Bennett A, Redman S, et al. Self-reported long-term outcomes of hysterectomy: a prospective study. Br J Obstet Gynaecol. 1991;98:1129-1126.
17.    Schover LR. Sexuality and Fertility After Cancer. New York, NY: John Wiley & Sons; 1997.
18.    Stewart DE, Robinson GE, eds. A Clinician’s Guide to Menopause. Washington, DC: American Psychiatric Press Inc; 1997.
19.    Lalos A, Lalos O. The partner’s view about hysterectomy. J Psychosom Obstet Gynaecol. 1996; 17:119-124.
20.    Banks A, Gartrell N. Lesbians in the medical setting. In: Cabaj RP, Stein TS, eds. Textbook of Homosexuality and Mental Health. Washington, DC: American Psychiatric Press Inc; 1996.
21.    Nickels MW, McIntyre JS. A model for psychiatic services in primary care settings. Psychiatr Serv. 1996;47:522-526.
22.    Stotland NL, Stewart DE. Psychological Aspects of Women’s Health Care: The Interface Between Psychiatry and Obstetrics and Gynecology. 2nd ed. Washington, DC: American Psychiatric Publishing Inc; 2001.

Dr. Seeman is professor emeritus in the Department of Psychiatry at the University of Toronto Centre for Addiction and Mental Health.

Acknowledgments: The author would like to thank the clients and staff of the Women’s Clinic for Psychosis for their invaluable input. The research work of the clinic has been financially supported by the Schizophrenia Society of Canada, the Bertha Rosenstadt Fund (University of Toronto), the Ontario Mental Health Foundation, the Canadian Psychiatric Research Foundation, Eli Lilly Pharmaceuticals, the Ian Douglas Bebensee Foundation, and the Donner Foundation.



What are the major issues faced by mothers who suffer from schizophrenia? This article reviews the literature and offers clinical opinions based on 7 years of experience in a specialized service for women with psychosis. The literature indicates that >50% of women with schizophrenia are mothers and approximately 50% of these mothers lose custody of their children at least temporarily. This usually has detrimental implications for both mother and child. Child and adult mental health service providers, as well as child protection workers and family lawyers, need to work cooperatively to ensure the safety and healthy functioning of the mother-child unit in the schizophrenia population.



An estimated 50% of North American women suffering from schizophrenia are parents—a percentage identical to that of the general population. A recent community survey in Great Britain suggested that the percentage of women with a psychotic illness who are mothers is as high as 63%.1 This proportion may be growing because psychotic illness is now treated in the community rather than in institutions, treatment outcomes are improving, and current antipsychotic medications no longer raise prolactin levels2 and thus do not interfere with conception.3,4

Since children of schizophrenic mothers face the prospect of serious psychiatric illness for environmental and genetic reasons, psychiatrists can play a major preventive role by engaging women with schizophrenia in discussions about protecting themselves from unwanted sexual advances, using effective contraception, and planning responsible parenthood (Table 1). By ensuring safe pregnancies and deliveries and preventing postpartum psychoses, mental health problems in the children can be diminished. Most important is providing ongoing support and treatment to the mothers and, at the same time, monitoring the well-being of the children.

Besides being vulnerable to episodic symptoms of psychosis, women who suffer from schizophrenia frequently experience interpersonal problems, mood problems, cognitive problems, and behavior problems that interfere with optimal parenting. The medications that help control psychotic symptoms induce sedation and passivity, further contributing to parenting difficulties.

Consequent to their illness, women with schizophrenia abuse alcohol and other substances more than women in the general population. They may continue to do this during pregnancy. They are often single mothers who are economically disadvantaged and alienated from families and former friends (Table 2). They do not readily make new friends. This means there is no one to help look after the children or offer respite during times of distress. In the British community study, 22% of women with children at home rated themselves as having problems obtaining child care. Thirty-seven percent expressed a need for company, and 29% for intimate relationships, which speaks to the loneliness of these women and their lack of social supports.1


To add to the problems of social isolation and poverty, mothers with schizophrenia give birth to children who may inherit genes for schizophrenia. This can lead to developmental delays in the child and increased parenting difficulty. Smoking, alcohol use, and drug use during mother’s pregnancy, as well as the likelihood of inadequate prenatal care, may predispose these children to behavioral difficulties even in the absence of genes that express a vulnerability to schizophrenia. About half of the children of women with schizophrenia are known to be born prior to the mother’s diagnosis.5 This may mean that the mothers are functioning well during their children’s early years. On the other hand, it may mean that some are already functioning poorly but have not yet come to psychiatric attention. The family physician is best placed to intervene in these instances.

Contributing to a lack of preparedness for parenthood, about half of the pregnancies in women with schizophrenia are unplanned. This statistic is similar to that of the average amount of unplanned pregnancies in the United States. In the schizophrenia population, 25% of unplanned pregnancies are terminated at the mother’s initiative.5 Relatively large percentages of schizophrenic mothers who choose to have their children lose custody of them to their own mothers, the child’s father, foster homes, or adoptive parents because of the multiple problems they encounter.6-8

Working in a clinic for women with psychosis9 has allowed a better understanding of the burdens of parenthood in this population, the deficiencies in mothering reported in the schizophrenia literature, the potential risks to children,10 and the intense desire on the part of these women to become competent parents.11-14

The Meaning of Parenthood

Several qualitative studies have explored the meaning of parenthood to women with schizophrenia. Sands15 interviewed individual mothers with chronic mental illness. The majority of participants in this study were African Americans from low-income households. They were asked about their experiences with motherhood and psychosis, specifically about how their mental illness affected their mothering. An emergent theme was the struggle to maintain custody of children despite major health problems and secondary effects of antipsychotic treatment.

Mowbray and colleagues16 report interviewing 24 mothers with serious mental illness. Half of the women acknowledged feeling badly about their illness. Parenthood was described ambivalently as both stressful and growth-promoting. One fourth of the mothers reported that disciplining the children was the number one challenge of motherhood. Nicholson and colleagues17 used focus groups to examine the experiences of severely mentally ill mothers with young children. They focused on the quality of social support the mothers received from family members. Results indicated that relationships with family were complicated, sometimes supportive, sometimes intrusive, and often perceived as negative. The major themes that emerged from focus groups with mentally ill mothers conducted by Bassett and colleagues18 in Australia were the traumas of loss of custody, hospitalization, social isolation, and stigma. Single parenthood was a significant theme. These mothers identified the need for substitute care, better access to community services, consistency in care provision, and improved relationships with their children.

A Canadian study used focus groups with 28 female participants diagnosed with schizophrenia and schizoaffective disorder found that these women felt isolated and could not initiate relationships.14 They understood that antipsychotic drugs could increase parenting problems and that there was a risk associated with taking them during pregnancy, but they were afraid to stop treatment. They reported personal benefits of being mothers (eg, love, purpose, identity, support), but these benefits were offset by stress, exhaustion, poverty, fear of losing their children, and fear that their children may develop schizophrenia. These mothers relayed feelings of enduring grief and anger following the loss of children to foster care or adoption. They expressed needs for support, information, and therapeutic programs that include social activities, substance abuse counseling, relationship and assertiveness groups, and family planning.14

Prevalence of Motherhood and Custody Loss

Several clinics have reported the prevalence of motherhood and custody loss among their clients. Ritsher and colleagues19 asked case managers to fill out questionnaires on their entire clinical population of 419 female clients. They found that half the women had children and half of those had retained custody of at least one child. Of those who were raising their children, 44% were single. Over 70% required assistance with child care.19 Joseph and colleagues20 administered a questionnaire to 32 women with schizophrenia. Sixty-one percent turned out to be mothers. While 20% of the mothers had retained full custody, only 12% were actually the primary caregivers. Hearle and colleagues21 reported that 59% of the 110 women in their clinic for schizophrenia were parents and, in 9% of these households, the partner also suffered from a serious mental illness. Forty-two percent of the children lived with their parents.

In a case-control study, Miller and Jacobsen22 found that significantly more mothers with schizophrenia than controls from similar socioeconomic and marital backgrounds had children in foster care (49% versus 2%) and significantly more of the mothers who had custody, in comparison to control mothers, had relegated the care of their children to others (36% versus 9%). These studies indicate that half the mothers with schizophrenia and related disorders who are in treatment have lost custody of their children at some point, producing discontinuities of upbringing for the children and intense distress for the mothers.

In the community study, a comparatively low figure (10%) of the women with children had a history of having had a child in the care of social services, even temporarily. This is a much smaller ratio of child loss than seen in the clinical samples. The reasons for the discrepancy are that the factors that mitigate against becoming a clinic client (higher socioeconomic bracket, intact marriage, supportive family, absence of substance abuse, absence of aggressive behavior) are the same factors that prevent children’s apprehension by child protecion agencies. Although primary care physicians can do little to change their patients’ financial or domestic situations, they can help to prevent substance abuse and they can help to diminish aggressive behavior through behavioral and pharmacologic means. They can also help by organizing, with child protection personnel, intensive home-based assistance for isolated mothers suffering from psychosis, thus maintaining family integrity in an environment that is safe for children.

Parenting Assessments

Custody decisions are based on parenting assessments requested by child protection agencies. Of all psychiatric diagnoses, schizophrenia is perhaps most associated with low mother-infant interaction scores on assessment scales designed to predict healthy development in neonates.23 Using the Global Rating Scales of Mother-Infant Interaction applied to videotaped interactions of mothers and 4-month old infants, mothers with schizophrenia were found to be more remote, silent, verbally and behaviorally intrusive, self-absorbed, flaccid, insensitive, and unresponsive than mothers in the contrast affective disorders group.24 Their infants were more avoidant and the mother-child interaction appeared less satisfying than that of the contrast group.24 Another recent study has underscored the impact of the negative symptoms of schizophrenia on mother-infant interaction.25 Antipsychotic medications may be contributory here.

Early parenting assessments are understandable from the perspective of child protection because adoption decisions are best made during infancy. However, evaluations carried out during the postpartum period put biological mothers at a disadvantage because all psychiatric syndromes, including schizophrenia, are prone to postpartum exacerbation. This means the mother will either be very ill or very medicated when assessed. This is not a time when her capacity to bond with her baby can be fairly judged.

Custody decisions made at later periods rely to some extent on how well the child is developing. Again, children of mothers with schizophrenia may suffer developmental lags and relative failure to thrive not because of poor parenting, but as a result of the partial expression of genetically-transmitted schizophrenia. Such children will benefit from extra stimulation and an enriched environment, but this does not necessitate taking the child away. Extras, such as day care centers and holiday camps, can be provided while keeping the child in the maternal home.

Outcomes in Children of Mothers With Schizophrenia

An early study where infants were assessed over a 4-year period suggested that the specific diagnosis of schizophrenia has less impact on the child’s development than social status and severity/chronicity of mother’s illness. In this study, children of mothers suffering from depression were found to be more impaired than children of mothers diagnosed with schizophrenia.26

A 3-year study testing young children of black, low income, single mothers, came to a somewhat different conclusion.27 Mothers were diagnosed with either schizophrenia, depression, or no mental illness. In most domains of functioning, the children of the mothers with schizophrenia had the most problems. The child-rearing environment of the children of mothers with schizophrenia was characterized by less play, fewer learning experiences, and less mother-child emotional and verbal involvement. Mothers of both illness groups were less effectively involved with their children than were well mothers. The following protective factors were identified: less severe illness, older age of mothers, higher education and IQ, a history of work experience, and the presence of another adult in the house.27 In a later report on this study, the authors stated that parenting practices, not mother’s diagnosis, were the key to healthy child development.28

In a more recent study, Yoshida and colleagues29 found that infants of mothers with schizophrenia had more motor and cognitive impairments at 2 and 7 months than infants of mothers with other diagnoses, but that this could be fully explained by the infant’s initial birth weight and the mother’s social class.

Perhaps the more important question is what happens to these children once they are adults. Results of the Copenhagen High-Risk Study (207 children of schizophrenic mothers and 104 control children followed since 1962) indicated that 16.2% of the high-risk children versus 1.9% of the control group developed schizophrenia, and another 4.6% developed a related illness (versus 0.9%).30 The rate of mood disorder was the same in the both groups. These findings are expected from what we know about the genetic transmission of schizophrenia.

Twenty-five of the Copenhagen children of mothers with schizophrenia who were reared with their mothers were compared to 25 who were reared apart. More psychopathology was found in those reared away from their mothers. Although the explanation may lie in the fact that more severely ill mothers were more likely to have lost custody so that the reared-apart children could be said to have inherited more severe psychopathology, this finding underscores the fact that rearing by a mother with schizophrenia does not necessarily lead to a greater incidence of adult psychiatric illness.31

How to Help

Psychiatric services can best serve mothers with schizophrenia and their children by instituting comprehensive intervention programs. Services need to be in place prior to the birth of the baby. For example, women with schizophrenia frequently do not avail themselves of prenatal care.32 Their risk for premature delivery and low birth weight is 50% greater than that of the general population.33,34 Adequate prenatal care can, at least theoretically, reduce the incidence of schizophrenia in these children.35 A comprehensive service should include diagnostic and treatment components; emergency, inpatient, and outpatient services; outreach to parents and children; linkages with schools, camps, extended families, child protection, and legal services; and obstetric and pediatric facilities. Among the required resources are case management outreach teams; neuropsychological assessors; parenting capacity assessors; therapeutic group leaders; child, adult, and family therapists; and pharmacotherapists. Interventions should include symptom management, parenting classes, addiction treatments, family planning education, therapeutic nurseries, support and information groups, occupational and vocational help, homemaking help, and respite opportunities (Table 3). Income supplementation and safe housing are also essential. Optimal care provision for the mother-child unit requires adult and child mental health, child protection, and legal service systems to work cooperatively and preventively toward resolving opposing perspectives and keeping families together whenever possible.36-38


Primary care physicians treat many women living in the community who suffer from psychotic illnesses. Some of these women live alone and may become pregnant or may already already caring for children at home. Some may have lost custody of their children and may be battling the family legal system for visiting rights or for regaining custody. The safety of children needs to be ensured. This may mean temporary removal of the child from the home until the mother’s illness is treated and until a thorough parenting assesessment rules out danger to children. Maintaining the integrity of the family unit then becomes the main priority.

Family integrity can be ensured by good symptom control of the mother’s psychotic illness (perhaps through home outreach programs), regular child monitoring (through the family or child protection staff), assurance of income supplementation and adequate housing for the family unit, and domestic and respite aid for the mother. The provision of parent skill teaching, troubleshooting techniques, and effective role modeling is important. Family counseling and support of family cohesion around the needs of the mother-child unit are crucial services that the primary care physician is best positioned to offer.


1.    Howard LM, Kumar R, Thornicroft G. Psychosocial characteristics and needs of mothers with psychotic disorders. Br J Psychiatry. 2001;178:427-432.
2.    Turrone P, Kapur S, Seeman MV, Flint A. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry. 2002;159:133-135.
3.    Miller LJ. Sexuality, reproduction, and family planning in women with schizophrenia. Schizophr Bull. 1997;23:623-635.
4.    McGrath JJ, Hearle J, Jenner L, et al. The fertility and fecundity of patients with psychoses. Acta Psychiatr Scand. 1999;99:441-446.
5.    Barkla J, Byrne L, Hearle J, et al. Pregnancy in women with psychotic disorders. Arch Women’s Mental Health. 2000;3:1-4.
6.    Nicholson J, Blanch A. Rehabilitation for parenting roles for people with serious mental illness. Psychosoc Rehab J. 1994;18:109-119.
7.    Nicholson J, Geller, JL, Fisher WH, Dion GL. State policies and programs that address the needs of mentally ill mothers in the public sector. Hosp Community Psychiatry. 1993;44:484-489.
8.    Oyserman D, Mowbray CT, Zemencuk JA. Resources and supports for mothers with severe mental illness. Health Soc Work. 1994;19:132-142.
9.    Seeman MV, Cohen R. A service for women with schizophrenia. Psychiatr Services. 1998;49:674-677.
10.    Oates M. Patients as parents: the risk to children. Br J Psychiatry. 1997;170:22-27.
11.    Mowbray CT, Oyserman D, Zemencuk JK, Ross SR. Motherhood for women with serious mental illness: pregnancy, childbirth, and the postpartum period. Am J Orthopsychiatry. 1995;65:21-38.
12.    Zemencuk J, Rogosch F, Mowbray CT. The seriously mentally ill woman in the role of parent: characteristics, parenting sensitivity, and service needs. Psychosocial Rehab J. 1995;18:79-92.
13.    Fox L. Missing out on motherhood. Psychiatr Services. 1999;50:193-194.
14.    Chernomas WM, Clarke DE, Chisholm F. Living with schizophrenia: the perspectives of women. Psychiatr Services. 2000;51:1517-1521.
15.    Sands RG. The parenting experience of low-income single women with serious mental disorders. J Contemp Human Services. 1995;76:86-96.
16.    Mowbray CT, Oyserman D, Ross S. Parenting and the significance of children for women with a serious mental illness. J Mental Health Admin. 1995;22:189-200.
17.    Nicholson J, Sweeney EM, Geller JL. Mothers with mental illness: II. Family relationships and the context of parenting. Psychiatr Serv. 1998;49:643-649.
18.    Bassett H, Lampe J, Lloyd C. Parenting: experiences and feelings of parents with a mental illness. J Mental Health. 1999;8:597-604.
19.    Ritsher JEB, Coursey RD, Farrell EW. A survey on issues in the lives of women with severe mental illness. Psychiatr Serv. 1997;48:1273-1282.
20.    Joseph JG, Joshi SV, Lewin AB, Abrams M. Characteristics and perceived needs of mothers with serious mental illness. Psychiatr Serv. 1999;50:1357-1359.
21.    Hearle J, Plant K, Jenner L, et al. A survey of contact with offspring and assistance with child care among parents with psychotic disorders. Psychiatr Serv. 1999;50:1354-1356.
22.    Miller LJ, Finnerty M. Sexuality, pregnancy, and childbearing among women with schizophrenia-spectrum disorders. Psychiatr Serv. 1996;47:502-505.
23.    Hipwell AE, Kumar R. Maternal psychopathology and prediction of outcome based on mother-infant interaction ratings (BMIS). Br J Psychiatry. 1996;169:655-661.
24.    Riordan D, Appleby L, Faragher B. Mother-infant interaction in post-partum women with schizophrenia and affective disorders. Psychol Med. 1999;29:991-995.
25.    Snellen M, Mack K, Trauer T. Schizophrenia, mental state, and mother-infant interaction: examining the relationship. Aust N Z J Psychiatry. 1999;33:902-911.
26.    Sameroff A, Seifer R, Zax M, Barocas R. Early indicators of developmental risk: Rochester longitudinal study. Schizophr Bull. 1987;13:383-394.
27.    Goodman SH. Emory University project on children of disturbed parents. Schizophr Bull. 1987;3:411-423.
28.    Goodman SH, Brumley HE. Schizophrenic and depressed mothers: relational deficits in parenting. Development Psychol. 1990;26:31-39.
29.    Yoshida K, Marks MN, Craggs M, et al. Sensorimotor and cognitive development of infants of mothers with schizophrenia. Br J Psychiatry. 1999;175:380-387.
30.    Parnas J, Cannon TD, Jacobsen B, et al. Lifetime DSM-III-R diagnostic outcomes in the offspring of schizophrenic mothers. Results from the Copenhagen High-Risk Study. Arch Gen Psychiatry. 1993;50:707-714.
31.    Higgins J, Gore R, Gutkind D, et al. Effects of child-rearing by schizophrenic mothers: a 25-year follow-up. Acta Psychiatr Scand. 1997;96:402-404.
32.    Kelly RH, Danielsen BH, Golding JM, et al. Adequacy of prenatal care among women with psychiatric diagnoses giving birth in California in 1994 and 1995. Psychiatr Serv. 1999;50:1584-1590.
33.    Bennesden BE, Mortensen PB, Olesen AV, et al. Preterm birth and intra-uterine growth retardation among children of women with schizophrenia. Br J Psychiatry. 1999;175:239-245.
34.    Sacker A, Done DJ, Crow TJ. Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case-control studies. Psychol Med. 1996;26:279-287.
35.    Warner R. The prevention of schizophrenia: what interventions are safe and effective? Schizophr Bull. 2001;27:551-562.
36.    Blanch A, Nicholson J, Purcell J. Parents with severe mental illness and their children: the need for human services integration. J Mental Health Admin. 1994;21:388-396.
37.    Cowling V. Meeting the support needs of families with dependent children where the parent has a mental illness. Family Matters. 1996;45:22-25.
38.    Göpfert M, Webster J, Seeman MV, eds. Parental Psychiatric Disorder: Distressed Parents and Their Families. Cambridge, UK: Cambridge University Press; 1996.

Dr. Hankin is assistant professor in the Department of Psychology at the University of Illinois in Chicago.

Acknowledgments: The author reports no financial, academic, or other support of this work. 



At what stage in life do more females become depressed than males, and why? This article reviews the gender difference in depression. On average, there is a 2:1 ratio of depressed females to males throughout the lifespan in terms of descriptive course, possible causes, and treatment response. More girls than boys begin to become depressed after 13 years of age (during puberty), and this gender divergence continues throughout adulthood. Many causal explanations for this difference have been investigated. A genetic liability for depression is stronger for pubertal girls than boys, but there is no gender difference in genetic vulnerability among children or adults.

At present, neither hormonal nor other biological factors have sufficiently explained the gender difference in depression. Females encounter more stressful negative events and sexual abuse than males. The stereotypical feminine gender role is associated with depression more than the masculine gender role. Compared with males, females have more negative cognitive vulnerabilities, and they tend to cope through rumination. These different causal explanations can be integrated into a developmental depression model to understand why more females are depressed than males. Males and females do not differ in treatment seeking or response for depression.



Depression, one of the most common psychiatric disorders, is prevalent in approximately twice as many women as men.1 However, childhood depression is more common in boys than in girls.2 With the transition to adolescence, depression becomes more prevalent in girls; this trend continues until middle to late adulthood. This descriptive timeline for the development of the gender difference in depression has been found across different countries and cultures.

There are two primary reasons why it is important to understand the development of the gender difference in depression. First, depression has substantial personal, interpersonal, familial, and economic costs. As a result of their increased depression, females experience significant decreases in their quality of life and productivity. Second, elucidating why more females are depressed than males can provide a window that may help advance scientific understanding of the causes of depression in general over the lifespan.

This article reviews how the gender difference in depression emerges over the lifetime and surveys explanations for why more females than males become depressed.1,3-6

Descriptive Epidemiology of Depression

An important issue concerning the gender difference in depression is the possibility that, in reality, males and females do not actually differ in the prevalence of depression but simply in their willingness to report depressive feelings, or in how they describe their emotions. However, evidence does not support the reporting bias hypothesis because males are as likely as females to report and discuss their depressive symptoms and negative emotions.1 Instead, research supports the fact that the observed gender difference in depression is real and not the result of a gender difference in expressing emotion.

For depressive mood and symptoms, many studies converge on the fact that more boys are depressed prior to 13 years of age, while more girls are depressed after 13 years of age. Multiple longitudinal studies,7-9 ones that have prospectively followed children from preadolescence to young adulthood, show that in girls, depressive mood and symptoms increase after 13–14 years of age, whereas in boys, depression levels remain constant or do not rise as rapidly. Approximately 25% to 40% of adolescent girls and 20% to 35% of adolescent boys experience elevated levels of depressed mood.10 After adolescence and throughout adulthood, this gender divergence in depressed mood continues with adult women experiencing more depressive mood and symptoms than adult men until middle–late adulthood.1,11

For depressive disorder, cross-sectional studies12-14 provide evidence for the transition to increased prevalence rates of depressive disorders among females >13 years of age. Prospective research2,15 shows that more females receive a diagnosis of clinical depression beginning after 13 years of age. For example, a prospective study of a community birth cohort2 found that both boys and girls become substantially more depressed from 15–18 years of age, and significantly more girls become clinically depressed in middle–late adolescence. Figure 1 displays a graph of the development by age and by gender.


A longitudinal study15 of the offspring of depressed parents indicated that more girls than boys become depressed around 13 years of age for both the high-risk group of children of depressed parents as well as the group of children of nondepressed parents. As with the adult studies of depressive symptoms, approximately twice as many adult women as men experience clinical depression from middle adolescence through middle–late adulthood (55–65 years of age), when there is no longer a gender difference in depression.1,4,11

These studies clearly showed that the gender difference in depression emerges after 13 years of age; however, chronological age may not be the best indicator of the point at which depression becomes more common in girls than boys. Research investigating pubertal development shows that more girls become depressed around mid-puberty (after Tanner stage III).12

Ethnicity also interacts with pubertal status.16 Caucasian adolescent girls who have experienced menarche report greater depressed mood compared with boys and same-aged premenarcheal Caucasian girls. In contrast, pubertal level was not associated with depression among Hispanic or African American adolescents.

In addition, research has examined whether there are systematic gender differences in the symptomatic expression of the depression syndrome. Overall, the symptom profile for males and females tends to be very similar.17,18 The only difference noted is that women more often experience somatic and anxious symptoms in conjunction with depression compared with men.17,18 Thus, women more likely present with symptoms of anxious, somatic depression (eg, fatigue, appetite changes, and sleep disturbance), whereas there is no gender difference in the presentation of other symptoms (eg, anhedonia, depressed mood, decreased concentration).

Finally, depressive disorders show substantial comorbidity with other psychiatric disorders (eg, anxiety and behavioral disorders). More females experience anxiety disorders than men, and girls typically develop anxiety disorders prior to depression.14 In contrast, behavioral and substance use disorders (especially alcohol) are more prevalent among males.19,20

Explanations for the Gender Difference in Depression

There are many different factors that have been hypothesized to contribute to the gender difference in depression at various points during the lifespan. To date, a significant limitation in the existing research base is that most studies have only examined one mechanism or factor as a putative explanation for the gender difference in depression. Very little research has examined gender differences among the elderly, so it is not known why the gender difference in depression disappears later in life. This section will briefly review the major genetic, biological, environmental, gender role, and cognitive explanations that have been studied to date with children, adolescents, and adults.

Genetic Explanations

Research with children and adults21,22 shows that latent genetic factors explain a modest amount of variability in depression, although these studies cannot determine which specific genes are implicated. It is important to examine behavioral genetic factors across age groups because the genetic liability to depression may change throughout the lifespan.

Some studies have not found any gender difference in heritability estimates for depression among children and adolescents21,23 or adults.22 This suggests that the latent genetic factors for depression are similarly important for females and males. However, other research24 with adolescents shows that the genetic contribution for depressed mood was greater in girls than boys.

A more detailed analysis25 from a large twin study of children and adolescents found that postmenarcheal adolescent girls had elevated heritability for depressive disorders compared with boys or premenarcheal adolescent girls. These investigators concluded that in adolescent pubertal girls, increased risk for depressive disorder was explained by an emerging genetic liability for depression combined with an increase in stressful life events, which are partially genetically mediated during adolescence. Taken together, these twin studies suggest that genetic factors are more strongly associated with depression among pubertal adolescent girls than boys, but there is no discernible gender difference in genetic liability to depression among prepubertal children or adults.

Biological Explanations

Very little evidence exists to support the hypothesis that female hormone levels (eg, progesterone, estrogen) account for the gender difference in depression.1,26,27 For example, the effect of sex hormone levels was minimal in explaining the gender difference in depression compared with the impact of social factors.28 Similarly, research has not found consistent gender differences in stress hormone levels (eg, cortisol) that could explain why more females are depressed than males.4,26,28 No gender difference has been found in the levels of neurotransmitters that are implicated in the pathophysiology of depression (eg, serotonin).29 Research examining the association of depression with the menstrual cycle has been inconsistent.26

Last, menopause and declining levels of estrogen among the elderly do not affect vulnerability to depression. Although the existing studies have not supported biological mechanisms as an account for the gender difference in depression,27 this conclusion should be balanced against the few studies, most with small samples that have investigated biological factors as an explanation for the gender difference in depression. Moreover, most studies have tested rather simple etiological models (eg, change in hormone level directly affecting mood) that do not adequately consider the known complexity of biological systems and adaptation to stress.30,31

Explanations for Stressful Negative Events

More females than males experience child sexual abuse, including 7% to 19% of girls and 3% to 7% of boys.32 Research has shown that history of child sexual abuse partly explains the increase in depression levels observed in adult women.33 However, females do not experience more overall childhood adversity (eg, more males experience physical abuse), so it is important to consider the specific type of negative environmental event. Research indicates that adult women experience significantly more daily stress compared with men.34 Moreover, child and adolescent studies show that girls experience more stress than boys, especially interpersonal negative events.35 Also, adolescent girls experience more discord and stress in the family than boys, and this additional discord explained the gender difference in depressive symptoms.36 Prospective research8 that tracked level of stressful events and depressive symptoms among children and adolescents found that girls experienced significantly more stressful events than boys after 13–14 years of age. This rise in negative events closely mirrors the development of the gender difference in depression. Depressed mood in girls, but not boys, was associated with this increase in stressful life events.8

Gender Role Explanations

The gender role explanation posits that females who identify with the stereotypical feminine gender role will become more depressed because some aspects of the feminine role (eg, importance of being thin and attractive, being passive, reduced social status) may be more associated with depression compared with the masculine gender role. Research with adolescents indicates that in girls, dissatisfaction with their body shape and/ or physical appearance is associated with increased depression and accounts for the gender difference in adolescent depression.7,37-40 In adults, gender role inequality in marital relationships explained why more adult women are depressed than adult men.41 Moreover, women experienced more chronic strain related to their gender role, and this elevation in stress accounted for the adult gender difference in depression.42

Although supportive of a gender role explanation, this research has been conducted primarily with Caucasian samples, so it is important to consider how the feminine gender role fits into the broader cultural and ethnic context. Only pubertal Caucasian girls report increased depression compared with Hispanic and African American girls.16 Other research43 shows that believing one does not have the ideal body shape is more disappointing for Caucasian girls than for African American girls. Thus, these findings most accurately suggest that the feminine gender role is a risk factor for depression for Caucasian females; further research is needed with more ethnically diverse populations.

Cognitive Explanations

Cognitive vulnerability for depression posits that some individuals have a more negative self-view and explain the causes and consequence of stressful events in more negative ways. This negative cognitive style is a risk factor for depression.44 Research has investigated whether there are gender differences in cognitive vulnerability that could explain why more females are depressed than males.6 Overall, the answer to this question depends on which aspect of cognitive vulnerability is tested. No gender difference has been found for negative schemas in adults or adolescents.45 In contrast, females have a more negative self-concept46 and have lower self-esteem, on average, than males.47 Adolescent girls are more likely than boys to attribute and explain the cause of events in a negative manner.48 Females are more likely to cope with depression by ruminating on their depressed mood, whereas males are more likely to problem-solve and distract themselves.42,49

Integrative Models

As noted above, most studies on the potential causes of the gender difference in depression have focused on single-factor explanations. To advance a more complete understanding, future studies need to consider more complete, integrated, and developmentally sensitive accounts of why more females become depressed than males. Two recently proposed integrative explanatory models are briefly reviewed here.6,50

Cyranowski and colleagues50 presented an interpersonal vulnerability-stress model that addresses specifically why more girls than boys become depressed in early adolescence. They focus on an interpersonal, affiliative need as a psychological vulnerability that places adolescent girls at particular risk, especially when they encounter interpersonal negative events. Further, they posit that the feminine gender role, higher anxiety levels, and hormonal changes at puberty (ie, oxytocin) will contribute to the increasing affiliative vulnerability to depression observed in girls.

Hankin and colleagues48 proposed an elaborated cognitive vulnerability-transactional stress model. Females encounter more negative life events than males, and this increase in stress leads to elevations in depressed mood. Females exhibit more cognitive vulnerability to depression than males. This greater cognitive vulnerability enhances the likelihood that females will experience depression when they encounter negative events. Interpersonally, depressed females seek reassurance in close relationships to relieve their depression, but friends’ and family’s withdrawal and rejection can transactionally lead to more negative events. Finally, certain personality traits (eg, neuroticism) and forms of childhood adversity (eg, sexual maltreatment) can lead to females experiencing more stress and exhibiting more cognitive vulnerability, and, ultimately, more depression, than males.

Gender Differences in Treatment of Depression

Gender does not affect the likelihood that a patient’s depressive disorder will be detected.51,52 Depressed men are equally as likely as women to consult a clinician for treatment of their depression. Moreover, once in treatment, men do not differ from women in their propensity for discussing negative emotions.1 However, practicing psychiatrists are less likely to inquire about women’s, compared with men’s, sexual functioning or the sexual side effects related to medication.51

Many treatment-outcome studies show that psychotherapy (eg, cognitive-behavioral treatment, interpersonal psychotherapy) and pharmacotherapy (eg, antidepressant medication) are effective in reducing depressive symptoms. Treatment studies have not found evidence for substantial gender differences in response to treatment.53,54 For example, the National Institute of Mental Health’s Treatment of Depression Collaborative Research Program54 shows that the depressed patient’s gender did not affect the process or outcome of treatment (psychotherapy or pharmacotherapy). Overall, there is currently little evidence that gender affects clinical assessment, management, or treatment of depression.


Depression is more prevalent in girls than in boys beginning after 13 years of age (or mid-puberty), and this gender difference continues until middle–late adulthood. Twin studies suggest that genetic factors are associated with depression more strongly among pubertal adolescent girls than boys, but no gender difference in genetics has been found in children or adults. Biological mechanisms have not been able to account for the gender difference in depression to date. Females experience more stressful, negative events and more childhood adversity than males. The feminine gender role is associated more with depression than the masculine gender role. Females have a more negative self-view, are more likely to ruminate, and explain the cause of stressful events in a more negative manner than males. Males and females are equally likely to seek treatment for depression and respond equally well to psychotherapy and antidepressant medication.


1.     Nolen-Hoeksema S. Sex Differences in Depression. Stanford, Conn: Stanford University Press; 1990.
2.    Hankin BL, Abramson LY, Moffitt TE, McGee R, Silva PA, Angell KE. Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm Psychol. 1998;107:128-140.
3.    Nolen-Hoeksema S, Girgus JS. The emergence of gender differences in depression during adolescence. Psychol Bull. 1994;115:424-443.
4.     Bebbington PE. Sex and depression. Psychol Med. 1998;28:1-8.
5.     Hankin BL, Abramson LY. Development of gender differences in depression: description and possible explanations. Ann Med. 1999;31:372-379.
6.     Hankin BL, Abramson LY. Development of gender differences in depression: an elaborated cognitive vulnerability-transactional stress theory. Psychol Bull. 2001;127:773-796.
7.     Petersen AC, Sarigiani PA, Kennedy RE. Adolescent depression: why more girls? J Youth Adol. 1991;20:247-271.
8.     Ge X, Lorenz FO, Conger RD, Elder GH, Simons RL. Trajectories of stressful life events and depressive symptoms during adolescence. Dev Psychol. 1994;30:467-483.
9. Wade TJ, Cairney J, Pevalin DJ. Emergence of gender differences in depression during adolescence: national panel results from three countries. J Am Acad Child Adolesc Psychiatry. 2002;41:190-198.
10. Petersen AC, Compas BE, Brooks-Gunn J, Stemmler M, Ey S, Grant KE. Depression in adolescence. Am Psychol. 1993;48:155-168.
11. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29:85-96.
12. Lewinsohn PM, Hops H, Roberts RE, Seeley JR, Andrews JA. Adolescent psychopathology: I. prevalence and incidence of depression and other DSM-III-R disorders in high school students. J Abnorm Psychol. 1993;102:133-144.
13. Silberg J, Pickles A, Rutter M, et al. The influence of genetic factors and life stress on depression among adolescent girls. Arch Gen Psychiatry. 1999;56:225-232.
14. Angold A, Costello EJ, Worthman CM. Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychol Med. 1998;28:51-61.
15. Weissman MM, Warner V, Wickramaratne P, Moreau D, Olfson M. Offspring of depressed parents. 10 Years later. Arch Gen Psychiatry. 1997;54:932-942.
16. Hayward C, Gotlib IH, Schraedley PK, Litt IF. Ethnic differences in the association between pubertal status and symptoms of depression in adolescent girls. J Adolesc Health. 1999;25:143-149.
17. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in chronic major and double depression. J Affect Disord. 2000;60:1-11.
18. Silverstein BP. Gender difference in the prevalence of clinical depression: the role played by depression associated with somatic symptoms. Am J Psychiatry. 1999;156:480-482.
19. Loeber R, Keenan K. Interaction between conduct disorder and its comorbid conditions: effects of age and gender. Clin Psychol Rev. 1994;14:497-523.
20. Kendler KS, Davis CG, Kessler RC. The familial aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: a family history study. Br J Psychiatry. 1997;170:541-548.
21. Rutter M, Silberg J, O’Connor T, Simonoff E. Genetics and child psychiatry: II. Empirical research findings. J Child Psychol Psychiatry. 1999;40:19-55.
22. Kendler KS, Prescott CA. A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry. 1999;56:39-44.
23. Eaves LJ, Silberg JL, Meyer JM, et al. Genetics and developmental psychopathology: 2. The main effects of genes and environment on behavioral problems in the Virginia Twin Study of Adolescent Behavioral Development. J Child Psychol Psychiatry. 1997;38:965-980.
24. Jacobson KC, Rowe DC. Genetic and environmental influences on the relationships between family connectedness, school connectedness, and adolescent depressed mood: sex differences. Dev Psychol. 1999;35:926-939.
25. Silberg JL, Pickles A, Rutter M, et al. The influence of genetic factors and life stress on depression among adolescent girls. Arch Gen Psychiatry. 1999;56:225-232.
26. Steiner M, Yonkers KA, Eriksson E. Mood Disorders in Women. London, UK: M. Dunitz; 2000.
27. Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry. 1997;154:1641-1647.
28. Susman EJ, Dorn LD, Inoff-Germain G, Nottelman ED, Chrousos GP. Cortisol reactivity, distress behavior, and behavioral and psychological problems in young adolescents: a longitudinal perspective. J Res Adolesc. 1997;7:81-105.
29. Mokrani MC, Duval F, Crocq A, Bailey P, Macher JP. HPA axis dysfunction in depression: correlation with monoamine system abnormalities. Psychoneuroendocrinology. 1997;22(suppl 1):S63-S68.
30. Brooks-Gunn J, Graber JA, Paikoff RL. Studying links between hormones and negative affect: models and measures. J Res Adolesc. 1994;4:469-486.
31. Dorn LD, Chrousos GP. The neurobiology of stress: understanding regulation of affect during female biological transitions. Sem Reprod Endocrinol. 1997;15:19-35.
32. Cutler SE, Nolen-Hoeksema S. Accounting for sex differences in depression through female victimization: childhood sexual abuse. Sex Roles. 1991;24:425-438.
33. Whiffen VE, Clark SE. Does victimization account for sex differences in depressive symptoms? Br J Clin Psychol. 1997;36:185-193.
34. Nolen-Hoeksema S, Larson J, Grayson C. Explaining the gender difference in depressive symptoms. J Pers Soc Psychol. 1999;77:1061-1072.
35. Rudolph KD, Hammen C. Age and gender as determinants of stress exposure, generation, and reactions in youngsters: a transactional perspective. Child Dev. 1999;70:660-677.
36. Davies PT, Windle M. Gender-specific pathways between maternal depressive symptoms, family discord, and adjacent adjustment. Dev Psychol. 1997;33:657-668.
37. Wichstrom L. The emergence of gender difference in depressed mood during adolescence: the role of intensified gender socialization.
Dev Psychol. 1999;35:232-245.
38. Allgood-Merten B, Lewinsohn PM, Hops H. Sex differences and adolescent depression.
J Abnorm Psychol. 1990;99:55-63.
39. Cole DA, Martin JM, Peeke LJ, Seroczynski AD, Hoffman K. Are cognitive errors of underestimation predictive or reflective of depressive symptoms in children: a longitudinal study.
J Abnorm Psychol. 1998;107:481-497.
40. Hankin BL, Roberts J, Gotlib IH. Elevated self standards and emotional distress during adolescence: emotional specificity and gender differences. Cognit Ther Res. 1997;21:663-680.
41. Strazdins LM, Galligan RF, Galligan ED. Gender and depressive symptoms: parents’ sharing of instrumental and expressive tasks when their children are young. J Fam Psychol. 1997;11:222-233.
42. Nolen-Hoeksema S, Larson J, Grayson C. Explaining the gender difference in depressive symptoms. J Pers Soc Psychol. 1999;77:1061-1072.
43. Parker S, Nichter M, Nichter M, Vuckovic N. Body image and weight concerns among African American and White adolescent females: differences that make a difference. Hum Organ. 1995;54:103-114.
44. Abramson LY, Alloy LB, Hankin BL, Haeffel GJ, MacCoon D, Gibb BE. Cognitive vulnerability-stress models of depression in a self-regulatory and psychobiological context. In: Gotlib IH, Hammen C, eds. Handbook of Depression. New York, NY: Guilford Press; 2002:268-294.
45. Lewinsohn PM, Gotlib IH, Lewinsohn M, Seeley JR, Allen NB. Gender differences in anxiety disorders and anxiety symptoms in adolescents. J Abnorm Psychol. 1998;107:109-117.
46. Cole DA, Martin JM, Peeke LA, Seroczynski AD, Fier J. Children’s over- and underestimation of academic competence: a longitudinal study of gender differences, depression, and anxiety. Child Dev. 1999;70:459-473.
47. Kling KC, Hyde JS, Showers CJ, Buswell BN. Gender differences in self-esteem: a meta-analysis. Psychol Bull. 1999;125:470-500.
48. Hankin BL, Abramson LY. Measuring cognitive vulnerability to depression in adolescence: reliability, validity, and gender differences. J Child Adolesc Clin Psychology. 2002;31(4):491-504.
49. Schwartz JAJ, Koenig LJ. Response styles and negative affect among adolescents. Cognit Ther Res. 1996;20:13-36.
50. Cyranowski JM, Frank E, Young E, Shear K. Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry. 2000;57:21-27.
51. Olfson M, Zarin DA, Mittman BS, McIntyre JS. Is gender a factor in psychiatrists’ evaluation and treatment of patients with major depression? J Affect Disord. 2001;63:149-157.
52. Gater R, Tansella M, Korten A, Tiemens BG, Maureas G, Olatawura MO. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings: report from the World Health Organization Collaborative Study on Psychological Problems in General Health Care. Arch Gen Psychiatry. 1998;55:405-414.
53. Garfield SL. Research on client variables in psychotherapy. In: Garfield SL, Bergin AE, eds. Handbook of Psychotherapy and Behavior Change. 3rd ed. New York, NY: Wiley; 1994.
54.   Zlotnick C, Elkin I, Shea MT. Does the gender of a patient or the gender of a therapist affect the treatment of patients with major depression? J Consul Clin Psychol. 1998;66:655-659.