Oral Contraceptives and Depressive Symptomatology: Biologic Mechanisms Barbara

L. Parry and A. John

Rush

D

EPRESSION is an important but often overlooked side effect of oral contraceptives (OC). Depressive symptoms have been reported in up to 50% of women using contraceptive steroids. l Although oral contraceptives exert their primary mode of action in the central nervous system, psychological sequelae have received less attention than other systemic side effects (e.g., hypertension, thromboembolic phenomena hepatomas, etc.). This paper elucidates some potential biologic mechanisms by which the oral contraceptives act on the central nervous system (CNS) to cause depression. The effect of these agents on biogenic amines (serotonin, dopamine, and norepinephrine), and on vitamin (folic acid, B6, B12), and endocrine metabolism are described. A better understanding of how oral contraceptives might cause depressive side effects should improve both our treatment for these problems and our understanding of brain biology. DEPRESSIVE SIDE EFFECTS The symptoms of oral contraceptive-induced depression are characterized by pessimism, dissatisfaction, lethargy, loss of libido, crying, irritability, and emotional lability.’ These symptoms differ from those of endogenous or reactive depressive illness in that sleep and appetite disturbances are less common.3 However, decreased sexual drive and capacity for orgasm is a frequent occurrence.4 Although uncommon, psychotic episodes coincident with the use of oral contraceptives have also been reported.5 A number of studies document the increased likelihood of psychiatric problems with oral contraceptives. Nilsson found birth control pill users had an increase in depressive symptoms (depression, inferiority, difficulty starting work), neurasthenic symptoms (increased fatigue, emotional lability, or irritability), and weight gain, compared to controls. Lewis and Hoghijhi,7 using psychiatric evaluations and a Hamilton Rating Scale for Depressive Symptoms, found significantly more clinical depression (two were suicidal) as compared to controls. Higher depression scores were associated with longer time periods of use, higher doses of progesterone, and a previous history of depression. Culberg,s in a well documented double-blind study of 229 women using interview

From the Department of Psychiatry, UCLA School of Medicine, Los Angeles, Calif., and Department of Psychiatry. Southwestern Medical School, Dallas, Tex. Barbara L. Parry, M.D.: Resident. Department of Psychiatry, UCLA School of Medicine, Los Angeles, Calif.; A. John Rush. M.D.: Associate Professor. Department of Psychiatry, Southwestern Medical School, Dallas, Tex. Address reprint requests to A. John Rush, M.D., Associate Professor. Department of Psychiatry, Southwestern Medicul School, Dallas, Tex. 75235 @ I979 by Grune & Stratton, Inc. 0010-440X/79/2004&006$02.00/0

Comprehensive

Psychiatry,

Vol. 20, No. 4 (July/August),

1979

347

PARRY AND RUSH

348

ratings, found significant increases in adverse mental symptoms of a depressive, dysphoric type. Huffer,g in a study using nonrandomized subjects, found that all of those who developed depressive reactions and loss of libido while on the oral contraceptives lost these symptoms after discontinuance (N = 39). However, Goldzieher,‘O (21) using a double blind crossover study, and Kuther,” using an MMPI Depression Scale, failed to find an increased incidence of psychiatric symptoms in association with oral contraceptive use. Certain factors appear to predispose toward the development of depressive symptoms with oral contraceptives. A history of previous emotional disturbance is more frequently associated with increased risk of psychiatric side effects with oral contraceptives. In one study, l2 75% of women with a psychiatric history (N = 64) reported adverse changes, particularly depression and irritability, with oral contraceptives; whereas only 52% of women without such a history (N = 139) reported such side effects. The authors concluded that oral contraceptives enhanced already present neurotic traits since those at highest risk were women with significant menstrual disability and lower frequency of sexual activity prior to contraceptive use. In a study by Nilsson.” women at most risk for developing psychiatric symptoms were those with previous psychiatric histories. those with psychiatric symptoms of severe nausea and vomiting during previous pregnancies, and/or overweight women. The majority of patients who developed psychotic episodes coincident with the use of OC had had a previous history of emotional disturbance.‘” Depressive symptoms are frequent and severe enough in some to warrant serious consideration. Importantly, depressive side effects are one of the most common reasons for discontinuation of steroidal contraceptives.‘” In one study, psychiatric symptoms were severe enough to warrant change to another form of contraception in up to 10% of the users.‘” Though suggestions have been published that these side effects could be a purely psychological phenomenon related to conflicts over accepting the contraceptive.1° fears about bodily damage, loss of control of sexual impulses, and future fertility.‘” as well as the biologic effects of these agents on brain function may also account for these unwanted side effects. DEPRESSION AND MONOAMINES Before discussing the potential mechanisms by which the contraceptive steroids affect the brain monamines, let us review how altered levels of these amines, particularly norepinephrine (NE) and serotonin, may be related to depression. According to the catecholamine hypothesis of affective disorders, “depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines.“” Evidence supporting this hypothesis comes from studies with drugs that alter these biogenic amines. Norepinephrine depleting agents (e.g., reserpine and alpha methyldopa) tend to produce depressive symptons in some patients. Drugs that increase the functional availability of brain catecholamines and am(e.g., monoamine oxidase inhibitors, tricyclic antidepressants, phetamines) tend to have an antidepressant effect. Furthermore. urinary

ORAL CONTRACEPTIVES

AND DEPRESSION

349

MHPG (3-methoxy-4-hydroxyphenyl glycol) excretion rates correlate in some patients with response to tricychc antidepressant therapy.‘? This metabolite is said to reflect central NE metabolism.18 It is becoming increasingly apparent that serotonin plays an important role in the biology of depression. Central nervous system serotonin and dompamine levels are likewise affected by pharmacologic manipulations with such drugs as reserpine, amphetamines, monoamine oxidase inhibitors (MAOI), and tricyclic antidepressants. Amitriptyline in particular increases central levels of serotonin, whereas amphetamines increase central levels of dopamine.18 A metabolite of serotonin found in the cerebrospinal fluid (CSF). 5-hydroxyindole-3-acetic acid (5HIAA), appears to correlate with central serotonin metabolism. The 5-HIAA is found in low concentrations in the CSF of some depressed patients. ls In fact, the CSF concentrations of 5-HIAA may correlate with the severity of depression. *OAutopsy studies of brains of suicide cases reveal a low concentration of brain serotonin.21 Recent evidence suggests that depression may exist in at least two biologic forms: a central norepinephrine deficiency and a central serotonin deficiency. The “serotonin-deficient” depression may be more effectively treated with amitriptyline, whereas the preferred treatment for the “norepinephrinedeficient depression” may be desipramine or imipramine.22*23 Tryptophan, the precursor of serotonin, has also been implicated in the biology of depression. 24Depressed patients may have low levels of tryptophan in the cerebrospinal fluid, which probably reflects low levels of unbound plasma tryptophan.25 Tryptophan potentiates the antidepressant effect of the MAO inhibitors in the treatment of depression. 26Tryptamine concentrations rise with antidepressant therapy, which also argues for the importance of the serotonin and its precursors on mood regulation.27 New evidence suggests that the ratio of central amines may be even more important than their absolute levels. There seems to be a balance between cholinergic and adrenergic activities. Depression is hypothesized to be associated with a relative cholinergic dominance. Thus, oral contraceptives may affect mood regulation by changing the turnover rates or ratios of central norepinephrine, serotinin, tryptophan, and/or tryptamine. ORAL CONTRACEPTIVES AND TRYPTOPHAN METABOLISM The oral contraceptives affect the metabolism of tryptophan, a precursor of serotonin, by several mechanisms. Tryptophan is metabolized by two pathways (Fig. 1). The first pathway occurs in the liver where tryptophan is converted to nicotinic acid. The second pathway occurs in the brain where tryptophan is converted to serotonin and tryptamine. In the liver, tryptophan is first converted to kynurenine by the enzyme tryptophan oxygenase, which is the rate limiting enzyme for the tryptophannicotinic acid pathway. This enzyme is induced by estrogen and cortisol. From kynurenine, the pathway continues on to 3-hydroxykyunrenine. The 3-hydroxykynurenine is converted to 3-hydroxyanthranilic acid by kynureninase and the coenzyme pyridoxal phosphate. After production of quinolinic acid, the final product is a nicotinic acid ribonucleotide. Note that pyridoxal phosphate is also

PARRY AND RUSH

late)

Kvnurenic

Quinolinic Acid

I

-4

Nicotinic

Acid

Ribonucleotide

Fig. 1.

Tryptophan

metabolism.‘”

Asterisk denotes rate-limiting

steps.

required as a coenzyme in the metabolism of kynurenine and of 3-hydroxykynurenine to kynurenic and xanthurenic acids, respectively. In the brain, tryptophan is first converted to 5hydroxytryptophan. which is then converted to serotonin (5hydroxytryptamine) by a decarboxylase enzyme. This enzyme is rate-limiting and requires the coenzyme, priodoxal phosphate. Serotonin is catabolized to 5-hydroxyindoleacetic acid (5HIAA) by a monoamine oxidase. Tryptophan is also metabolized to tryptamine, by a pyridoxal phosphate dependent decarboxylase. Subsequently, tryptamine is catabolized to indoleacetic acid by a monoamine oxidase. Oral contraceptives may increase the conversion of tryptophan to nicotinic acid in the liver, because estrogens induce increased activity of the rate limiting enzyme, tryptophan oxygenase. 28 Moreover, this enzyme induction is influenced by adrenal gland activity, since this enzyme induction following estrogen administration is reduced in adrenalectomized rats.2g The estrogenic components of the oral contraceptives increase plasma cortisol and its activity in the liver; this increased cortisol serves to increase the level of tryptophan oxygenase in the liver.30 Thus, both estrogen and cortisol, by increasing hepatic tryptophan oxygenase activity, enhance the metabolism of tryptophan to nicotinic acid in

ORAL CONTRACEPTIVES

AND DEPRESSION

351

the liver. This leaves less tryptophan available for conversion to serotonin and tryptamine in the brain. After 2-3 weeks of oral contraceptive use, there are increased levels of kynurenine and 3-hydroxykynurenine in the urine.14,31 Furthermore, increased kynurenine and 3-hydroxykynurenine inhibit the transport of tryptophan across the blood brain barrier.32 Consequently, an increased conversion of tryptophan to nicotinic acid in the liver may lead to a decreased transport of tryptophan across the blood brain barrier. Therefore, less tryptophan is available for conversion to serotonin and tryptamine in the brain. As has been previously mentioned, lowered levels of serotonin and tryptamine in the brain are associated with depressive symptoms. Also, the lowered tryptophan by itself may contribute to the depression. Indeed, administration of tryptophan to oral contraceptive users often alleviate some of the depressive side effects.33 It also has been suggested that the effects of increased cortisol and consequent weight gain may also play a role in the increased morbidity seen in these patients.34 Thus, oral contraceptives may lead to decreased central tryptophan, serotonin, and tryptamine by increasing liver metabolism of tryptophan down the nicotinic acid pathway with oral contraceptives, and secondarily, by inhibiting tryptophan transport across the blood brain barrier. Estrogenic oral contraceptives may interfere with the production of serotonin and other central indoleamines by their effects on pyridoxal phosphate. Estrogen conjugates are competitive inhibitors of pyridoxal phosphate, the coenzyme derived from vitamin B6. 35Estrogen competes with pyridoxal phosphate for binding sites on apoenzymes in several enzymatic reactions involved in tryptophan metabolism. The aminotransferase enzymes involved in the kynurenine to kynurenic acid and 3-hydroxykynurenine to xanthurenic acid are pyridoxal phosphate-dependent. Likewise, the kynureninase enzyme that converts 3-hydroxykynurenine to 3-hydroxyanthranilic acid also requires pyridoxal phosphate as a coenzyme. The rate-limiting decarboxylase enzyme involved in the conversion of 5hydroxytryptophan to serotonin in the brain is even more sensitive to pyridoxal phosphate depletion than the aminotransferase enzymes in the liver. Further, the conversion of tryptophan to tryptamine is also pyridoxal phosphate-dependent. Increased metabolism of tryptophan down the nicotinic acid pathway would require greater amounts of pyridoxal phosphate for the aminotransferase and kyneurininase reactions. These increased requirements for pyridoxal phosphate are further exacerbated because estrogens competitively inhibit pyridoxal phosphate. This would raise the requirements for pyridoxal phosphate to such a level that available pyridoxine is insufficient. This relative deficiency of pyridoxal phosphate may effectively reduce available central serotonin by impairing the conversion of tryptophan to serotonin and tryptamine. This constitutes a second mechanism by which oral contraceptives might reduce CNS indole levels and result in depressive symptomatology. Although most of the women on oral contraceptives are able to meet the increased demands for vitamin B6 or pyridoxine, they can be shown to have a functional deficiency of this vitamin as evidenced by impaired tryptophan me-

352

PARRY AND RUSH

tabolism. The alterations in tryptophan metabolism found in women using oral contraceptives is similar to that seen in vitamin B6 deficiency. There is an altered ratio of urinary hydroxykynurenine to 3-hydroxyanthranilic acid in response to a tryptophan load. According to this standard, 80% of women on oral contraceptives are functionally B6 deficient. About 20% of women on oral contraceptives, for some unknown reason, fail to compensate for increased vitamin B6 requirements and develop a true, as opposed to a functional, 86 deficiency. This is evidenced by decreased levels of urinary 4-pyridoxal phosphate levels, and by altered pyridoxal phosphate dependent erythrocyte enzyme metabolism. Wynn et al.“5 in a double-blind crossover trial. administered pyridoxine hydrochloride to depressed women whose symptoms were judged to be due to the effects of oral contraceptives. Pyridoxine resulted in significant clinical improvement in the depression as measured by a self-report symptom inventory in women with a true vitamin B6 deficiency. Other studies confirm these findings.35-37 It appears that 25 mg daily of pyridoxine is usually sufficient to correct the disordered tryptophan metabolism in women using oral contraceptives.“* The usual human dietary requirement is 2 mg daily. Thus. oral contraceptives do appear to increase significantly the need for pyridoxine. Other enzymes such as glutamic oxalolacetic transaminase. liver glutamic pyruvic transaminase. and tyrosine aminotransferase may require vitamin B6 as a cofactor.39 Since estrogen and cortisol also induce these enzymes by acceleration of these pathways, oral contraceptives may further impair a pyridoxine deficiency. Considering the many decarboxylase and aminotransferase enzymes that require pyridoxal phosphate, a functional pyridoxine deficiency could impair these pathways. possibly contributing to other side Indeed. an oral contraceptive manufactured in effects of oral contraceptives.’ Spain that contains 25 mg of pyridoxine is reported to have fewer side effects. ’ The potential risks associated with administering high doses of this vitamin. such as the possibility of increased breakdown of amino acids secondary to the catabolic effect of elevated aminotransferase activity,3” remain to be clarified. Thus, estrogenic oral contraceptives alter tryptophan metabolism by: (I) inducing the rate-limiting enzyme tryptophan oxygenase and thereby enhancing the metabolism of tryptophan to nicotinic acid: (2) by serving as a competitive inhibitor of pyridoxal phosphate, a coenzyme required in several enzymatic processes of tryptophan metabolism. As a consequence of tryptophan and pyridoxal phosphate being diverted to the nicotinic acid pathway in the liver. neither substance is as available for production of serotonin in the brain. This may result in lowered central serotonin and tryptamine levels and associated depressive symptomatology. Pyridoxine. 25 mg daily. may alleviate the depressive symptoms in those who have a true vitamin B6 deficiency. ORAL CONTRACEPTIVES

AND NOREPINEPHRINE

METABOLISM

In addition to affecting tryptophan and serotonin metabolism, oral contraceptives may induce depression by altering norepinephrine metabolism (Fig. 2). Tyrosine, the precursor of norepinephrine, is converted to dihyroxyphenyalanine (DOPA) by the rate-limiting enzyme. tyrosine hydroxylase.

ORAL CONTRACEPTIVES

Tyrosine

AND DEPRESSION

(A)

353

)

Tyrosine Hydroxylase (rate limiting) Dihydroxyphenylalanine

(B)

(DOPA)

>

DOBA Decarboxylase (pyridoxal phosphate dependent) )

Dopamine

Norepinephrine (NE)

Beta Hydroxylation

(C) ? MAO

Fig. 2.

Norepinephrine

metabolism.

DOPA is decarboxylated to dopamine by DOPA decarboxylase; this step requires pyridoxal phosphate as a coenzyme. Finally, dopamine is converted to norepinephrine by beta hydroxylation. Nerve stimulation may release either dopamine or norepinephrine from presynaptic terminals into synaptic clefts to serve as neurotransmitters. They attach to specific receptor sites on the postsynaptic neuron. Catecholamines are inactivated by monoamine oxidase within the nerve terminals, while they are inactivated by catechol-O-methyl transferase (COMT) in the synaptic cleft. The oral contraceptives may affect this pathway at three specific points (Fig. 2). (1) Lowered levels of plasma tyrosine (possibly secondary to increased levels of aminotransferase) are found in women using oral contraceptives.40-42 A lower plasma tyrosine may reduce the production of central catecholamines, specifically NE, which may result in depressive symptoms. (2) Estrogenic oral contraceptives may impair norepinephrine and dopamine synthesis, by competitively inhibiting pyridoxal phosphate, the coenzyme required for conversion of DOPA to dopamine; thereby effectively reducing norepinephrine and dopamine synthesis. Recall that lowered levels of norepinephrine and serotonin are associated with depressive disturbances. (3) Oral contraceptives may alter the levels of monoamine oxidase (MA0).43 Progesterone in particular appears to increase brain MAO levels.44 MAO is believed to regulate brain levels of catecholamines by affecting metabolism in the presynaptic terminal. MAO inhibitors appear to exert their antidepressant action by inhibiting catecholamine metabolism by MAO, thereby increasing the availability of catecholamines to serve as neurotransmitters in the synaptic cleft. Elevated progesterone levels are also associated with elevated plasma MAO activity as evidenced by studies of pre- and postovulatory phases of the menstrual cycle and from studies of amenorrheic women receiving cyclic

354

PARRY AND RUSH

treatment with estrogen and a progesterone.45 From this data, one might also infer that increased levels of progesterone may cause increased MAO levels in the brain, thereby lowering central catecholamine levels and contributing to depressive symptomatology.“” Thus, oral contraceptives affect norepinephrine metabolism by: (I) decreasing tyrosine, a precursor of NE synthesis; (2) altering the metabolism of vitamins that serve as important coenzymes in NE production: and (3) increasing MAO levels, thereby decreasing available NE. Suggestive evidence that oral contraceptives decrease the synthesis of NE is offered by the findings of decreased urinary excretion of catecholamine metabolites (VMA and normetanephrines), l3 and a decreased basal heart rate*7 in contraceptive users. More specific studies of MHPG excretion are needed to further assess these hypotheses. Although the evidence that oral contraceptives alter tryptophan metabolism seems well substantiated, studies of the effect of these agents on central norepinephrine metabolism are also suggestive of how contraceptives might lead to a biologic state contributory to depression. However. the catecholamine hypothesis of affective disorders has come under more careful scrutiny recently. To what degree contraceptives actually do influence norepinephrine and whether this accounts for depressive symptomatology needs further study. Changes in central norepinephrine and/or serotonin metabolism may be reflected in electronencephalographic (EEG) patterns and may account for abnormalities in psychological function. In fact, women taking oral contraceptives have been found to have a decreased alpha rhythm, fast component, on EEG studies. Further, these changes seem to be associated with decreased speed and accuracy on tests of reaction time. concentration. integration. and learning abilities.48 OTHER VITAMIN AND NEUROENDOCRINE

EFFECTS

OF CONTRACEPTIVES

Oral contraceptives may also alter folate and/or vitamin B-12 metabolism. which also constitute potential mechanisms leading to depressive reactions. Oral contraceptive use has been associated with decreased folic acid and vitamin B 12 levels. Lowered plasma folate levels have been found in up to 307~ of oral contraceptive users.4g~soWomen who develop folic acid deficiency and megaloblastic anemia will respond to either 250 mg of folic acid while on the oral contraceptive, or to discontinuance of the oral contraceptive without folic acid supplementation.’ Decreased folate levels have been associated with significantly higher depressive scores on Temperament Sca1es.j’ Significant reduction in serum vitamin BI2 levels have also been found in women using contraceptive steroids. 52 This may occur within 5 months of starting the oral contraceptive. Vitamin B12 deficiency may produce depression, confusion, and psychotic reactions.“’ Though alterations in vitamins A and C have been reported with oral contraceptive use. these studies are controversial.“” Depressive symptoms seen with use of the OC might also result from altered neuroendocrine function. It appears that the biogenic amines play an important

ORAL CONTRACEPTIVES

AND DEPRESSION

355

role in neuroendocrine control. Serotonin, dopamine, and norepinephrine, by serving as excitatory or inhibitory transmitters, are involved in the control of releasing factors from the hypothalamus. These neurotransmitters are thought to act in the hypophysiotropic region by stimulating or inhibiting neurons from which releasing factors are secreted.53 More specifically, norepinephrine has been found to stimulate the release of gonadotropin-releasing factor, particularly luteinizing hormone-releasing factor (LHRF), from the hypothalamus. 54-56Thus, decreased NE would be associated with a diminished gonadotropin-releasing factor response. Norepinephrine also appears to stimulate the release of thyrotropin-releasing factor (TRF) and growth hormone releasing factor. 54,56It appears to be inhibitory to the release of corticotropin releasing factor or CRF.54*56 Serotonergic neurons are thought to activate the release of prolactinreleasing factor and growth hormone-releasing factor.57 They also may inhibit the release of FSH- and LH-releasing factors. Serotonin injected into the ventricles of rats depresses FSH- and LH-releasing factors from the hypothalamus. 58Dopaminerg. IC p athways have been found to activate prolactin-inhibiting factor and growth hormone-inhibiting factor.54,56*5g It is becoming increasingly apparent that these hypothalamic polypeptide hormones, particularly TRF, somatostatin, CRF, and LHRF may have behavioral effects.60 These effects may be mediated by the catecholamines. Diminished activity of thyrotropin-releasing factor has been associated with depressive symptoms.“‘,‘j* Some depressions have responded transiently to treatment with thryotropin-releasing factor. l6 Interestingly, when rats are given TRH intraperitoneally, there is an associated increase in brain NE. Thus, the hormone may be mediating its effect through alteration of central catecholamines. T3 (triiodothyronine) appears to potentiate the efficacy of tricyclic and antidepressants, at least in women. This effect is thought to be mediated by catecholamines.63 There may be an excessive activity of somatotropin release-inhibiting factor (SRIF, somatostatin) in depression. 64 Somatostatin inhibits the release of growth hormone and has recently been shown to inhibit TRH.64 In depression, GH secretion is diminished in response to insulin-induced hypog1ycemia.62*64 The hypoglycemic growth hormone response presumably depends upon stimulation of endogenous brain catecholamine activity.63 Depressed patients also have been found to have hypersecretion of cortisol, unresponsive to dexamethasone suppression. It is speculated that this may be due to disinhibition of CRF by decreased norepinephrine.63 Finally, LHRF has been found to have behavioral effects in animals,“O though its effect in humans needs further elucidation. Postmenopausal depressed women, however, have been found to have reduced luteinizing hormone levels in plasma as compared to postmenopausal contro1s.“‘62 Reduced norepinephtine production may be implicated in these reduced levels of luteinizing hormone.63 The OC may act in the hypothalamus or higher in the CNS to achieve their antifertility effect. The biogenic amines may prove to play an important role in this process. By decreasing levels of NE and serotonin, the oral contraceptives

PARRY AND RUSH

356

may thereby depress the release of gonadotrophin-releasing factors. With long-term use of the OC, LH and FSH release is decreased, while prolactin release is increased.65*66 The effects of the OC on other hypothalamic and pituitary hormones, however, has not been clarified. Thus, the OC, by affecting biogenic amines, may alter levels of the hypothalamic releasing hormones. These hormones, apart from their endocrine function, appear to have behavioral effects as well. Therefore, the effect of the oral contraceptives on hypothalamic pituitary function may not only be responsible for fertility control, but also help to explain their depressive side effects. CLINICAL AND THEORETICAL IMPLICATIONS In summary, a number of potentially important biologic mechanisms are affected by oral contraceptives. Altered serotonin, norepinephrine. vitamin. and endocrine metanolism may contribute to depressive symptoms of oral contraceptives. Physicians prescribing these agents should be on the alert foisymptoms of crying spells, pessimism, self-deprecation, and changes in libido. If the patient is found to be vitamin B6 deficient, daily administration of 2.5 mg of pyridoxine may help to alleviate depressive symptoms. Before starting birth control pills. patients should be screened for previous psychiatric disorders and postpartum reactions, since these variables are associated with increased risks of developing psychiatric complications. There is sufficient evidence about the depressive side effects of these agents so that physicians should be alert to the fact that oral contraceptives may alter CNS function. potentially impairing the usual psychological coping mechanisms and defenses.“’ Further studies of the effect of contraceptive steroids on biogenic amines. vitamins, and hypothalamic-pituitary functions may improve our understanding of the mechanisms of the antifertility action, and of the neurobiology of depression. REFERENCES I.

Kane FJ: latrogenic

in Farm WE,

Karcan

Phenomenology New

York.

depression

I, Polorny

and Treatment

Spectrum

in women,

traceptives.

A. et al teds): 1977,

Am

p

symptoms

A. Jacobson

Side effects

of an oral contraceptive

ticular attention adaptation.

to mental symptoms

Acta

46:536-556.

A.

Med J 4:14?-145. 4. Grounds of

Psychiatry

with parand sexual

Gynecol AL,

Brown

tives.

Br

1970

double

116: 169-172.

5. Kane FJ: Psychiatric

placebo.

R: The con-

blind

trial.

ReBr

J

Huffer

traceptives: Ment

to oral con-

Psychiatric

with

different

Acta

of

of oral contracep-

changes

A double

as related 1968

ll5:697-701.

J: Mood

1969

and menstrual

gestageniestrogen

blind comparison

Psychiatr

Stand

with

[Suppll

1972 V.

Levin

L.

Depression

Dis 151:35-41.

IO. Goldzieher

1970 reactions

9.

PE: period

M: An evaluation

as a side effect

Br J Psychiatry

236: I-86, B. Mowby

Almgren

Hoghughi

combinations: a

ltl~:lO53-

Br Med J 2453-455.

A,

8. Culberg

S: De-

and oral contraceptives.

D, Davies

control

depression

Stand

pill. side effects and personality: a

7. Lewis

symptoms

BN, Johnson

symptoms

traceptive

Obstet

CA:

1967

3. Herzberg pressive

L, Ingemanson

Gynecol

of the postpartum

to use of OC.

2. Nilsson

J Obstet

1968

6. Nilsson

of Depression.

Publications,

69-80

port

1063.

al: Nervousness

Arson

H: Oral

and frigidity.

con-

J Nerv

1970

JW, Moses LE,

Averkin

and depression

attributed

E. et to

ORAL CONTRACEPTIVES

AND DEPRESSION

oral contraceptives: A double blind, placebo controlled study. Am J Obstet Gynecol 111: 1013-1020, 1971 11. Kuther JS, Brown WL: Types of oral contraceptives, depression and premenstrual symptoms. J Nerv Ment Dis 155: 153-162. 1972 12. Kane FJ, Treadway R, Ewing F: Emotional change associated with oral contraceptives in female psychiatric patients. Compr Psychiatry 10:16-30, 1969 13. Kane FG, Lipton MA, Krail AR: Psychoendocrine study of oral contraceptive agents. Am J Psychiatry 127:443-450, 1970 14. Rose DP, Adams PW: Oral contraceptives and tryptophan metabolism: Effects of oestrogen in low-dose combined with a progesterone and of low-dose progestagen (megestrol acetate) given alone. J Clin Pathol 25:252-258, 1972 15. Parviz MA, Behrmann PJ: Depressive syndrome induced by oral contraceptives. Dis Nerv Syst 37:406-408, 1976 16. Rupp JJ: Psychosomatic aspects of endocrine disease. Audio Dig Practice 24: 1976 17. Schildkraut JJ: The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am J Psychiatry 122:509-522, I965 18. Aldophe AB, Dorsey RE, Napoliells MJ: The neuropharmacology of depression. Dis Nerv Syst 38:841-846, 1977 19. Coppen A, Prange AF, Whybrow PC, et al: Abnormalities of indoleamines in affective disorders. Arch Gen Psychiatry 26:474-478, 1972 20. Asberg M, Thoren P, Traskman L: “Serotonin depression.” A biochemical subgroup within the affective disorders. Science 191:478-480, 1976 21. Shaw DM. Camps FE, Eccleston EG: 5-hydroxytryptamine in the hind brain of depressive suicides. Br J Psychiatry 113:14071411, 1967 22. Maas, JW: Biogenic amines and depression: Biochemical and pharmacological separation of two types of depression. Arch Gen Psychiatry 32: 1357-1361, I975 23. Maas JW: Clinical and biological heterogeneity of depressive disorders. Ann Intern Med 88:556-563, 1978 24. Aylward M, Maddock J, Plasma tryptophan levels in depression. Lancet I:936. 1973 25. Wynn V, Adams PW, Folkard J, et al: Tryptophan, depression and steroidal contraception. Steroid Biochem 6:965-970, I975

357

26. Coppen A, Shaw DM: Potentiation of the antidepressive effect of a monoamine oxidase inhibitor by tryptophan. Lancet 1:79-81, 1963 27. DeWurst WG: New theory of cerebral amine function and its clinical application. Nature 218:1131-1133, 1968 28. Greengard 0: Relationship between urinary excretion of kynurenine and liver tryptophan oxygenase activity. Am J Clin Nutr 24:709-711, 1971 29. Braidman IP, Rose DP: Effects of sex hormones on three glucocorticoid-inducible enzymes concerned with amino acid metabolism in rat liver. Endocrinology 89:1250-1255, 1971 30. Durber SM, Lawson F, Daly JR: The effect of oral contraceptives of plasma cortisol and cortisol binding capacity throughout the menstrual cycle in normal women. Br J Obstet Gynecol 83:814-818, 1976 31. Rose DP, Braidman IP: Excretion of tryptophan metabolites as affected by pregnancy, contraceptive steroids, and steroid hormones Am J Clin Nutr 24:673-683, 1971 32. Green AR. Cuezon G: The effect of tryptophan metabolites on brain 5hydroxytryptamine metabolism. Biochem Pharmacol 19:20612068, 1970 33. Larsson-Cohn U: Oral contraceptives and vitamins: A review. Am J Obstet Gynecol 121:84-90, 1975 34. Bucci L: Drug induced depression and tryptophan metabolism. Dis Nerv Syst 33: 105-108, 1972 35. Adams PW, Rose DP, Folkard J, et al: Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1:897-904, 1973 36. Baumblatt MJ, Winston F: Pyridoxine and the pill. Lancet 1:832-833, 1970 contraceptives, F: Oral 37. Winston pyridoxine. and depression. Am J Psychiatry 130:1217-1221, 1973 38. Luhby LA, Brin M, Gordon M, et al: Vitamin B6 metabolism in users of oral contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Am J Clin Nutr 24:684-693, 1971 39. Rose DP. Strong R, Adams PW, et al: Experimental vitamin B6 deficiency and the effect of oestrogen containing oral contraceptives on tryptophan metabolism and vitamin B6 requirements. Clin Sci 42:465-477, 1972 40. Brin M: Abnormal tryptophan metabolism in pregnancy and with the oral contraceptive pill. I. Specific effects of an oral estrogenic

PARRYANDRUSH

358

contraceptive steroid on the tryptophanoxygenase and two aminotransferase activities in

systems,

in

levels of ovariectomized-adrenalectomized

Medicine.

New

rats.

Am .J Clin Nutr 24:699-703, 1971 41. Doar JW: Metabolic side effects

of oral

contraceptives.

2:503-

526.

Clin

Endocrinol

DP.

tyrosine

trogens:

A

Cramp

-‘9:49-53,

DG:

consequence

induction.

of

and esof

Clin

EL,

et al:

Effects

of estrogen

MAO

activity

and

depressed

Broverman

Chim

on

driving

Bardwick

JM:

and

plasma

in Sachar

and Psychopathology.

PI-es\.

1976. pp 95-105 Klaiher

regularly rheic

and

Grant

cyclic

a progestin.

traceptives phatasr\.

Br Med

Marcotta

J 3:777-780

DM.

Psychophy\iologic contraceptive

Kane

use. BrJ

Psychiatry

oral

ll6:lh%lh7.

D: Variations

psychological in women

tests

with

Brain

the menstrual

contraceptives.

GJ.

Leichter and

Am

cycle

MS,

Prait

in women J Clin

Nutr

using

contraceptives

and

l:l376-1377.

al: Decreased 53.

LF. serum

in man.

El2

use. JAMA

Frohman

macologic

JM.

Baily

J, et al:

L.

control Metabolism

EN.

1978

Lipton

levels

with

211: 1371-1374. Stacheira

of

M:

AF,

oral

J

1975

et

con-

1972

Neurophar-

neuroendocrine 24:21 l-234.

MA,

function

MA,

in

Farm

WE,

PhenomenolNew

York.

CB. et

Ncmeroff

Med

Bruse

effects

of

I.ife

Sci

pathology.

New

change\ Clin

GR.

Prange

i\J.

et al:

in Sachar

and

Raven

.4m

polypep-

and man.

Behavior

York,

in

North

hypothalamic

in animals

Hormones,

al:

Mishell

The

DR.

effect

Kletzky

of

12X:60-74.

66. al:

Schally

Studies

traceptive Li Buglio

in

in depre\\ion.

Psycho-

PI-es\.

1976.

levels roids

Brenner

PF. et

tions

function.

steroids.

Il.

Plasma

administration

J Ohstet

Carter

WH.

of

of ordl PH

hormone

86:530-541.

1970

FJ: Evaluation

to oral

contraceptive

126:968-971.

1976

and

antifertility

releasing

Kane

Gqnecol

AF.

of action

LH

on

Am

1977 Parlor0 site

Endocrinology 67.

\teroidy

on the

after and

AV.

0.4.

contraceptive

hypothalamic-pituitary

1970

Metz

review.

p IS-31

I.ancet

Br

l-e-

hormone

Endocrine

6’:409-424.

hormones

PH: Oral

illness.

pituitary

of Depre\+n.

PH:

(edI:

level.

depressive

by

A. et al (edhI:

disease\.

Gynecol in

Psy-

18, 1977

ES

folate

Preece

117:287-292,

Wertalik

traceptive

serum

EH,

deficiency

Psychiatry

G. Barnes

Ji,ordera

1978

AJ. Lipton

tide

1968

Reynolds

Folate 52.

Prange

65. A, Hornady

A

psychiatric

I977 SO. Shojania

Brain

1977. p I-15

in

30:375-380.

in clin-

.Am 62:409-

dysfunction.

Pattern\

1, Pokorny

62.

GM:

I:1 17-136.

patients:

RF: oral

respon\e

North

thq roxiopin-releasing

Behavioral

concentration

Clin

Brown

AJ:

to

64.

1975

intake

and erythrocytes

in

on the in rats.

1975

al: The role of hormone\

oral contraceptives.

Res 42:3?-323.

folate

serum

during

and without

Pietarinen

Dietar!

51.

Prange

20: 1305-13

of performance

neurons

D. et seroto-

contraceptive\

endocrine

Am

63. Gruen

4X. Becker

49.

AG.

Clin

Karcan

P. et al:

containing

Med

with

depressed

I970

Prog

Ehigi

Spectrum.

accompanying

S, Ghezi of brain

PH: The prolactin

ugy and Treatment

1968

FJ. Obrest

changes

pho\-

288:13X4-

1978

61.

and on

of growth

J Med

lesioning

steroid

psychiatry.

chiatr

and

N Engl

l?:356-364,

Gruen

60.

Endncrinol

in

1974. p 774-8X

regulation

S, Garattini

of oral

treatment

oxidase

Neural

of selective

associated

mood changes

monoamine

JB:

Bernasconi

\ponse\

on depressive

secre16: 1 lO9-

of endocrinology.

W. B. Saunders.

Pharmacology

4’4.

of oral con-

J.

particularly

Neuroendocrinology.

secretion.

and in amenol--

JD: Effect

Martinovea

ofgonadotropin

Textbook

nin or catecholamine

in with

SR.

1973

59.

Boverman activity

J Clin

in

1977. pp

Psychopharmacol S:

Martin

1392.

Raven

1971

EG, Davies

endometrial 47.

women

receiving

33:631-638.

Y.

oxidase

Ogedo

RH (ed):

activity

Be-

York.

Kobayashi

monoamine

women

Metab

57.

ical

menstruating

estrogen\ 46.

EL.

Plasma

of

Hormones.

New

Brunner-Mazel.

catecholamines.

Reichlin

Williams

58.

contraceptive

ES (ed):

havior 45.

of

Biochem

hormone

of

correlate

oral

Psychiatry

1114, 1977

128:1492-

Psychological

cycle

York,

in endocrine

(ed):

in the control

Adv

al: Effect

menstrual

DM:

tion.

W.

responses

Am J Psychiatry

control

G

SM.

Role

56.

Acta

Vogel

therapy

EEG

women.

DM.

Central

Usdin

McCann

al:

tyrosinr

1972

medication.

KH:

Philadelphia.

Klaiber

44.

55. et

1970

43.

1498.

Reduction

by oral contraceptives

possible

aminotransferase

the

Metab

dopamine.

Rose

plasma

Brodie

73-94

1973

42.

54.

FSH ste-

(LH-RH).

of emotional use.

et

con-

Am

r-eac-

J Ohstet