Treatment of depression associated with the menstrual cycle: premenstrual dysphoria, postpartum depression, and the perimenopause

Several forms of depression are unique to women because of their apparent association with changes in gonadal hormones, which in turn modulate neuroregulatory systems associated with mood and behavior. This review examines the evaluation and treatment of depression that occurs premenstrually, postpartum, or in the perimenopause on the basis of current literature. The serotonergic antidepressants consistently show efficacy for severe premenstrual syndromes (PMSs) and premenstrual dysphoric disorder (PMDD), and are the first-line treatment for these disorders. The use of antidepressants for postpartum depression is compromised by concerns for effects in the infants of breast-feeding mothers, but increasing evidence suggests the relative safety of the antidepressant medications, and the risk calculation should be made on an individual basis. Estradiol may be effective for postpartum depression and for moderate-to-severe major depression in the perimenopause. In spite of its frequent use, progesterone is not effective for the mood and behavioral symptoms of PMS/PMDD, postpartum depression, or perimenopausal depressive symptoms.     

Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles

BACKGROUND: Few studies have determined the impact of a lifetime history of major depression on an early transition to menopause. METHODS: Reproductive and psychiatric interviews and early follicular-phase blood specimens were obtained at study enrollment and every 6 months during 36 months of follow-up from 332 women with and 644 women without a history of major depression, 36 to 45 years of age. We used menstrual cycle markers to determine inception of perimenopause, defined as time from study enrollment to a follow-up interview with: (1) 7-day or more change in menstrual cycle length; (2) a change in menstrual flow amount or duration; or (3) amenorrhea lasting at least 3 months. RESULTS: Women with a history of depression had 1.2 times the rate of perimenopause of women with no such history (95% confidence interval, 0.9-1.6). Compared with nondepressed women, depressed women with more pronounced depressive symptoms at study enrollment (Hamilton Rating Scale for Depression scores >8) had twice the risk of an earlier perimenopausal transition. Among the women with greater depressive symptoms (Hamilton scores >8), those who also reported use of antidepressants had nearly 3 times the risk of an earlier perimenopausal transition (hazard ratio, 2.7; 95% confidence interval, 1.5-4.8) of nondepressed women. Women with a lifetime history of depression also had higher follicle-stimulating hormone and luteinizing hormone levels and lower estradiol levels at study enrollment and during the follow-up period after adjustment for covariates. CONCLUSION: A lifetime history of major depression may be associated with an early decline in ovarian function.     

Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment.

This article reviews the rapidly accumulating literature on the relationship between mood disorders and diabetes mellitus. Recent studies have demonstrated that depression and its associated symptoms constitute a major risk factor in the development of type 2 diabetes and may accelerate the onset of diabetes complications. Since the mid-1980s, multiple longitudinal and cross-sectional studies have scrutinized the association of diabetes with depressive symptoms and major depression. Utilizing the search terms depressive disorders, psychiatry, diabetes, and pathophysiology in MEDLINE searches (1966-2003), this article reviews studies investigating pathophysiological alterations related to glucose intolerance and diabetes in depressed patients. The few randomized, controlled studies of treatment of depression in patients with diabetes are also described. Short-term treatment of depression in patients with diabetes improves their dysphoria and other signs and symptoms of depression. Future research will confirm whether response to psychotherapy and/or psychopharmacologic treatment improves glucose control, encourages compliance with diabetes treatment, and perhaps even increases longevity.     

Clinical and health services relationships between major depression, depressive symptoms, and general medical illness.

Patients with chronic medical illness have a high prevalence of major depressive illness. Major depression may decrease the ability to habituate to the aversive symptoms of chronic medical illness, such as pain. The progressive decrements in function associated with many chronic medical illnesses may cause depression, and depression is associated with additive functional impairment. Depression is also associated with an approximately 50% increase in medical costs of chronic medical illness, even after controlling for severity of physical illness. Increasing evidence suggests that both depressive symptoms and major depression may be associated with increased morbidity and mortality from such illnesses as diabetes and heart disease. The adverse effect of major depression on health habits, such as smoking, diet, over-eating, and sedentary lifestyle, its maladaptive effect on adherence to medical regimens, as well as direct adverse physiologic effects (i.e., decreased heart rate variability, increased adhesiveness of platelets) may explain this association with increased morbidity and mortality.     

Are mood disorders and obesity related? A review for the mental health professional

OBJECTIVE: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. METHOD: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. RESULTS: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. CONCLUSION: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.     

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder.Consequently,the norepinephrine transporter gene is an attractive candidate in major depressive disorder research.In the present study,we evaluated the depression symptoms of subjects with major depressive disorder,who were all from the North of China and of Han Chinese origin,using the Hamilton Depression Scale.We examined the rela-tionship between two single nucleotide polymorphisms in the norepinephrine transporter,rs2242446 and rs5569,and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program.rs5569 was associated with depressed mood,and the GG genotype may be a risk factor for this;rs2242446 was associated with work and interest,and the TT genotype may be a risk factor for loss of interest.Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.     

Dopamine agonists in the treatment of non-motor symptoms of Parkinson's disease: depression

Background:  Psychiatric symptoms such as depression are common non-motor comorbidities of Parkinson's disease (PD). Depressive symptoms in patients with PD are a major complication that impairs quality of life independent of motor symptoms. The relationship between PD and comorbid depression is not completely understood.
Methods and Results:  Evidence suggests that both PD and depression may be mediated by degeneration of the dopaminergic system. Recent and ongoing research is exploring the potential role of dopamine agonists in the treatment of depressive symptoms in patients with PD.
Conclusion:  Experimental studies suggest a primary relationship and the importance of dopaminergic mechanisms in PD and depression. Patients with PD and depression might benefit from a global approach. Thus, treatment with dopamine agonists promises to reduce motor complications as well as depressive symptoms, avoiding multiple drug interactions as well as possible antidepressant medication side effects.     

Major Depressive Disorder and HIV-1 Infection: A Review of Treatment Trials

Major depression is a common psychiatric presentation during the course of many chronic illnesses. Although estimates of its prevalence in people with human immunodeficiency virus (HIV) infection and acquired immunedeficiency syndrome have varied widely in the literature, it has become increasingly clear that people with HIV infection experience depression or depressive symptoms frequently, and that major depression may be the most common psychiatric disorder. This report reviewed the currently reported data and clinical trials for treatment of depression or depressive symptoms in the course of HIV infection. We have reviewed both psychopharmacologic and psychotherapy trials and although blinded efficacy studies are the gold standard, because there is often a lack of data, we have included noncontrolled (open) trials for comparison. Pharmacologic medication trials show that selective serotonin reuptake inhibitors (SSRIs), although not more efficacious, may be more tolerable and have greater overall effectiveness. Furthermore, when medications are used to treat depression, it may be essential to evaluate for tolerability and potential drug interactions to increase efficacy. Psychotherapy trials have investigated a variety of treatment modalities including group, individual, and stress reduction techniques. In treatment trials, all of these modalities have been associated with a reduction in distress and depressive symptoms. With the advances in therapy for HIV infection, treatment of a major depressive episode or depressive symptoms has become increasing important because untreated depression could both compromise medication adherence and potentiate the disabling effects of the illness.     

Rejection Sensitivity and Depression: Indirect Effects Through Problem Solving

Objective: Rejection sensitivity (RS) and deficits in social problem solving are risk factors for depression. Despite their relationship to depression and the potential connection between them, no studies have examined RS and social problem solving together in the context of depression. As such, we examined RS, five facets of social problem solving, and symptoms of depression in a young adult sample. Method: A total of 180 participants completed measures of RS, social problem solving, and depressive symptoms. We used bootstrapping to examine the indirect effect of RS on depressive symptoms through problem solving. Results: RS was positively associated with depressive symptoms. A negative problem orientation, impulsive/careless style, and avoidance style of social problem solving were positively associated with depressive symptoms, and a positive problem orientation was negatively associated with depressive symptoms. RS demonstrated an indirect effect on depressive symptoms through two social problem-solving facets: the tendency to view problems as threats to one’s well-being and an avoidance problem-solving style characterized by procrastination, passivity, or overdependence on others. Conclusions: These results are consistent with prior research that found a positive association between RS and depression symptoms, but this is the first study to implicate specific problem-solving deficits in the relationship between RS and depression. Our results suggest that depressive symptoms in high RS individuals may result from viewing problems as threats and taking an avoidant, rather than proactive, approach to dealing with problems. These findings may have implications for problem-solving interventions for rejection sensitive individuals.     

Phenomenology, psychosocial correlates, and treatment seeking in major depression and dysthymia of adolescence

OBJECTIVE: To compare phenomenology, psychosocial correlates, and treatment seeking in DSM-Itt-R major depression and dysthymia among adolescents diagnosed as cases in a community-based study. METHOD: A self-report questionnaire, including psychosocial data, life events, eating behaviors, depressive symptoms, substance use, pathological behaviors, and family and school functioning was administered to a nonselected sample (N = 3,287, 93.2% of targeted population) of adolescents aged 11 to 20 years from several Haute-Marne communities in France in 1988-1989. Subgroups of subjects (n = 205, 84.7% of eligible subjects) were interviewed with a structured diagnostic schedule, and adolescents with major depression (n = 49), dysthymia (n = 21) and controls (n = 135) were compared. RESULTS: Nearly 30% of controls had at least one current symptom of depression. Patterns of affective symptoms were similar in major depression and dysthymia, but significant differences emerged in comorbid conditions (more anxiety disorders, suicidal behaviors, and alcohol intoxications associated with major depression) and stressor at onset (more severe in major depression). Experiences of loss during the prior 12 months were associated with both forms of affective disorder, while poor family relationships were specific correlates of dysthymia. In contrast, peer relationships and pathological behaviors did not differ between depressed subjects and controls. Although psychosocial functioning was significantly impaired in both groups of depressed adolescents, treatment seeking was limited to 34.7% for major depressive subjects and 23.8% for dysthymic subjects. CONCLUSION: The results provide evidence that major depression and dysthymia in adolescence are equally severe but may have distinct patterns in associated factors. Despite free access to health care, the rate of treatment seeking for mood disorders in France is similar to that reported in U.S. studies.     

The cyclical nature of depressed mood and future risk: Depression,rumination, and deficits in emotional clarity in adolescent girls

Deficits in emotional clarity, the understanding and awareness of one's own emotions and the ability to label them appropriately, are associated with increased depressive symptoms. Surprisingly, few studies have examined factors associated with reduction in emotional clarity for adolescents, such as depressed mood and ruminative response styles. The present study examined rumination as a potential mediator of the relationship between depressive symptoms and changes in emotional clarity, focusing on sex differences. Participants included 223 adolescents (51.60% female, Mean age = 12.39). Controlling for baseline levels of emotional clarity, initial depressive symptoms predicted decreases in emotional clarity. Further, rumination prospectively mediated the relationship between baseline depressive symptoms and follow-up emotional clarity for girls, but not boys. Findings suggest that depressive symptoms may increase girls' tendencies to engage in repetitive, negative thinking, which may reduce the ability to understand and label emotions, a potentially cyclical process that confers vulnerability to future depression.     

Major depression and depressive symptomatology among the physically disabled. Assessing the role of chronic stress

Although it is generally agreed that life stress represents a risk factor for depressive symptomatology, there is less agreement on the significance of such stress for the occurrence of major depression. Indeed, it has been suggested that stress factors of importance for depressive symptoms may be irrelevant for major depression. We report results based on a large sample of physically disabled and nondisabled adults that contradict this suggestion. The physically disabled show seriously elevated rates of both depressive symptomatology and major depressive disorder. Subgroup analyses confirmed the finding on depressive symptomatology within all age-gender groupings and the finding on major depression for young and middle-aged men and women but not for the aged. It is argued that these findings can be attributed to differences in chronic stress associated with disability status. We conclude that chronic stress represents a significant risk factor with respect to both depressive symptomatology and major depressive disorder.     

Depression in old age

The discrepancy between the constancy or increase of the prevalence of depressive symptoms and dysphoria in old age on one hand, and the decrease in the prevalence of the DSM-III diagnoses of major depression and dysthymia on the other, is discussed in light of the most frequent explanatory hypotheses such as memory defects, interpretation of depressive as somatic symptoms, higher risk of institutionalization as well as higher mortality of depressives and a mitigated course of depression in old age. We conclude that higher mortality, mitigation and the rarity of true late-onset depression are arguments for a real decline in prevalence, which occurs in accordance with the decline in all psychiatric disorders that are connected with emotional upheavals and substance ingestion. On the other hand, the connection of depressive states with somatic illness is strengthened, and according to preliminary validation studies, clinically relevant depressive states not reaching the threshold of DSM-III diagnoses may be typical for the depressive psychopathology of old age.     

The role of estrogen and progesterone in depression after birth

Previous reports suggest that massive hormonal changes that accompany the peripartum period may trigger perinatal depression. We investigated the relationship between magnitude of change and total level of estrogen and progesterone and grade of peripartal depression and depressive symptoms. One hundred and ninety two women were assessed in the 38th week of pregnancy (SDS scores), peripartum period (DSM-III-R diagnosis (n=105); SDS scores) and 6 months postpartum (EPDS; n=89) regarding diagnosis of depression, self-ratings of depressive symptoms and levels of estrogen and progesterone. The comparison of three diagnostic groups (lifetime major depressive disorder MDD (N=7), MDD at birth (N=12), healthy controls (N=70) showed that there were no differences in the magnitude of decline of estrogen and progesterone from day 1 to day 3 after birth . With respect to total levels of estrogen and progesterone, estrogen on day 3 was significantly higher [F(2,92)=6.6, p<0.05] in women with current MDD than in those with lifetime MDD or normal controls. Depression scores were significantly higher at the end of pregnancy (12.6% self-identified as depressed) than in postpartum period (5.8% day 3 p<.0004; 9.2% day 5 p<.008), whereas 13.3% of women received a DSM-III -R diagnosis for MDD 5 days postpartum. The results were in contrast to the current hypotheses of estrogen withdrawal or hypogonadal levels as an etiological factor for peripartum depression. But a limitation of the actual study is the low number of subjects with depression; therefore the current non-significant findings should be interpreted with great caution.     

Second generation antipsychotics in bipolar depression: a new therapeutic option?

Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Lithium, anticonvulsants or antidepressants offer some clinical efficacy. However, efficacy can be limited and side effects are sometimes problematic. There is still a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The second-generation antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some second-generation antipsychotics may improve depressive symptoms in mixed episodes in patients with bipolar disorder. More recently, specific studies have been performed in patients with bipolar depressive episodes. Quetiapine or olanzapine, as monotherapy or associated with other compounds, demonstrate an interesting efficacy. The international guidelines for the treatment of bipolar depression have identified quetiapine as a first line treatment in monotherapy. Second generation antipsychotics may prove to be important future treatments for patients with bipolar depression.     

The SSRIs drug Fluoxetine,but not the noradrenergic tricyclic drug Desipramine,improves memory performance during acute major depression

Accumulating evidence suggests that noradrenergic and serotonergic drugs are equally effective in ameliorating the depressive symptoms of major depression. Major depression is associated also with memory impairments, but the comparative effects of the antidepressant drugs on memory are not clear. We previously found that serotonergic neurotransmission is of particular importance for some aspects of episodic memory. We set out to test whether treatment with the selective serotonergic drug Fluoxetine (Prozac) would be advantageous in this respect over treatment with the selective noradrenergic tricyclic antidepressant drug Desipramine (Deprexan). Seventeen patients with major depressive episode, randomly assigned for treatment with either Fluoxetine (n = 8) or Desipramine (n = 9), were assessed for their clinical situation and for memory performance at the beginning of treatment, after 3 weeks, and after 6 weeks of pharmacological treatment. We found that although clinically both drugs were equally effective, the improvement of memory performance in the Fluoxetine-treated patients was significantly greater compared with that of the Desipramine-treated patients. The results support the role of serotonin in memory. More studies in larger samples of patients are required, but it may be that in cases where memory impairment is a major symptom, it would be beneficial to consider serotonergic antidepressant drugs for treatment. Furthermore, in cases where, for various reasons, the treatment of choice is noradrenergic, it may be worthwhile to consider a supplementary serotonergic drug to improve memory deficits.     

Diagnosing major depressive disorder I: A psychometric evaluation of the DSM-IV symptom criteria

The diagnostic criteria for depression were developed on the basis of clinical experience rather than empirical study. Although they have been available and widely used for many years, few studies have examined the psychometric properties of the DSM criteria for major depression. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined whether criteria such as insomnia, fatigue, and impaired concentration that are also diagnostic criteria for other disorders are less specific than the other DSM-IV depression symptom criteria. We also conducted a regression analysis to determine whether all criteria are independently associated with the diagnosis of major depressive disorder. A total of 1538 psychiatric outpatients were administered a semistructured diagnostic interview. We inquired about all of the symptoms of depression for all patients. All of the DSM-IV symptom criteria for major depressive disorder were significantly associated with the diagnosis. Contrary to our prediction, symptoms such as insomnia, fatigue, and impaired concentration, which are also criteria of other disorders, generally performed as well as the criteria that are unique to depression such as suicidality, worthlessness, and guilt. The results of the regression analysis, which controlled for symptom covariation, indicated that five symptoms (increased weight, decreased weight, psychomotor retardation, indecisiveness, and suicidal thoughts) were not independently associated with the diagnosis of depression. The implications of these results for revising the diagnostic criteria for major depression are discussed.     

Sleep, rhythms and women's mood. Part II. Menopause

This review summarizes studies of sleep and other biological rhythms in menopausal women with major depression compared with healthy control subjects. Where feasible, we focused on studies in women who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for a major depressive episode (MDE) compared with matched normal control subjects and the Staging System for Reproductive Aging in Women (STRAW) criteria. The aim was to review supporting evidence for the hypothesis that a disruption of the normal temporal relationship between sleep and other biological rhythms, such as melatonin, cortisol, thyroid stimulating hormone (TSH) or prolactin, occur during the menopausal transition. As a result, depressive disorders occur in predisposed women. Treatment strategies, designed to correct these altered phase (timing) or amplitude abnormalities, thereby improve mood. Although there may be some common features to menopausal depression compared with other depressive disorders related to the reproductive cycle (e.g. premenstrual dysphoric disorder or postpartum major depression), such as increased morning melatonin secretion, a specific profile of sleep and biological rhythms may distinguish healthy from depressed women during menopause. Further work is needed to characterize more fully the particular abnormalities associated with well-defined menopausal depression in order to develop treatment strategies targeted more specifically to pathogenesis.     

Burden of illness in bipolar depression

Bipolar depression is the underrecognized and unappreciated phase of bipolar disorder. Nevertheless, bipolar depression is responsible for much of the morbidity and mortality associated with the disorder. Depressive symptoms are far more prevalent than hypomanic or manic symptoms in bipolar patients, and they are associated with a heavier burden of illness, including reduced functioning, increased risk of suicidal acts, and high economic costs. Because most patients with bipolar disorder present with depression, misdiagnoses of major depressive disorder are common, even typical. Comorbid psychiatric disorders are also prevalent and may obscure the diagnosis and complicate treatment strategies. Depressed patients should be carefully assessed for manic or hypomanic symptoms to help reveal possible bipolar disorder. In addition to evaluation of psychiatric symptoms, a close examination of family history, course of illness, and treatment response will aid the clinician in making an accurate diagnosis. Treatment of acute depression in bipolar patients may require therapy combining agents such as lithium, divalproex, lamotrigine, carbamazepine, and atypical antipsychotics or using such agents in combination with an anti-depressant. Olanzapine/fluoxetine combination is the only medication currently approved for the treatment of bipolar depression. Antidepressant monotherapy should not be used, because there is evidence that such treatment increases the risk of switching into mania/hypomania and could induce treatment-refractory conditions such as mixed or rapid-cycling states. Maintenance therapy will be required by most patients, since discontinuation of mood stabilizers or antidepressants frequently leads to relapses in depressive symptoms. Prompt diagnosis and the use of specific therapeutic agents with evidence of efficacy may help reduce the disease burden associated with bipolar depression.     

Acne, isotretinoin treatment and acute depression.

The association between isotretinoin therapy and depressive symptoms in acne patients has generated much recent interest but has not been systematically explored. A 17-year-old man with acne vulgaris developed symptoms of acute depression two weeks after beginning isotretinoin therapy. The depressive symptoms improved with reduction of isotretnoin dose and treatment with sertraline. Of note, however, is that when the isotretinoin dose was again increased, the depressive symptoms recurred despite clearing of the skin, leading to an unsuccessful suicide attempt. Isotretinoin was finally discontinued and the depression rapidly resolved. Although the effects of hypervitaminosis A may be involved aetiologically, the predictive factors of drug-related depression remain unclear. Significant depressive symptoms that develop during the course of treatment need close monitoring and may necessitate both antidepressant therapy and discontinuation of the drug. Given the uncertain causal relationship between isotretinoin and depression, versus the potential psychological benefits of effective acne treatment, systematic studies exploring the impact of isotretinoin on mood are needed.