The Diagnostic and Statistical Manual of Mental Disease-Fifth Edition (DSM-5) definition of major depressive disorder (MDD) includes postpartum depression (PPD) as 1 of 6 MDD subtypes.¹ Referring to PPD as a “depressive disorder with peripartum onset,” the DSM-5 distinguishes PPD from MDD primarily in terms of time of onset being within 4 weeks of delivery. Beyond the time parameter, a diagnosis of PPD requires the presence of at least 5 of same 9 criteria.  

However, while MDD and PPD share important similarities with respect to their causes, symptoms, and treatment, key differences other than time of onset do exist and are important considerations for diagnosis and treatment.

Prevalence and Risk Factors

MDD during the peripartum period occurs in about 10% to 15% of women, which is similar or greater than the rates reported in women experiencing MDD outside the peripartum period.² Stress, chronic psychosocial stress, prior trauma, and low social support increase the risk of both conditions; and a history of MDD increases the risk of PPD.³ Risk factors such as having a difficult pregnancy/delivery or low birthweight baby are, of course, unique to motherhood.⁴ Approximately two-thirds of susceptibility genes overlap, but PPD is believed to have a higher heritability than does MDD.⁵ Both conditions are triggered by chronic stress and exacerbated by a lack of social support and low socioeconomic status.³ 

Diagnosis

MDD and PPD each present challenges with respect to differential diagnosis. MDD must be distinguished from bipolar depression⁶ and PPD from the normal “baby blues” that typically occur during the early days postpartum.⁷ In the absence of reliable disease markers, diagnosis may require longitudinal observation to see if a depressed patients cycles into mania, or a new mother has persistent depressive symptoms. 
Identifying PPD presents unique challenges. Symptoms may resemble normal events expected in a new mother.^8,9 For example, sleep disturbances may be a sign of PPD, or they may be the natural disturbances of sleep expected for a new mother. Emotional challenges, changes in partner relationship, and disruptions in routine may resemble normal adjustments expected for a new mother rather than being pathological. As a result, new mothers and their partners and families may be reluctant to consult a physician if they find it difficult to distinguish between the normal aspects of transitioning to motherhood and mental illness.^8,9 

Pathophysiology and Symptoms

In both MDD and PPD, disruptions in the serotonergic and gamma-aminobutyric acid (GABA) neurotransmitter systems have been identified; and in both conditions, early increases in hormones during acute stress serve a protective function, while decreased levels postpartum or during chronic stress contribute to the development of depression.³ Both conditions are associated with disruptions in the reward circuitry of the brain; however, amygdala response to negative stimuli is increased in MDD but reduced in PPD, which may blunt a mother’s response to her infant’s crying or other needs.³ Disruption of the mother-infant interaction can greatly impair infant cognitive, emotional, and social development, so that the public health implications of PPD extend far beyond the patient’s well-being.³

MDD and PPD are both heterogenous conditions with overlapping symptom clusters that include various combinations of the 9 DSM-5 criteria for depression.³ However, there are differences. In particular, women with early onset of PPD (≤8 weeks postpartum) are more likely to have severe disease and the anxious, anhedonic subtype of depression.³ PPD may be more closely associated with anxiety, aggressive obsessional thoughts, restlessness and agitation, and impaired concentration and decision making.³ MDD may be more associated with psychomotor disturbances.³ 

Treatment

Psychotherapy is a key component of care for patients with MDD or PPD, particularly in patients with mild or moderate cases, but with important differences. Cognitive-behavioral therapy and interpersonal therapy are both helpful in MDD¹⁰; but interpersonal therapy may be the more effective option in women with PPD because their condition takes place in the context of a new role as a mother and changes in partner interactions, priorities, and roles.¹¹ Women with PPD may also benefit from mother-infant psychotherapy, which seeks to improve mother-infant relationships that might be impaired to the detriment of infant development.¹²

Treatment of MDD and PPD have relied on drugs targeting the monoamines, including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors,² with similar response and remission rates between the two indications.¹³ However, women with PPD show a slower response to antidepressants and are more likely to need multiple agents.¹⁴ Women with PPD need to consider whether an antidepressant is safe for use during breastfeeding.² In this regard, sertraline is often considered the first-line SSRI because it does not  produce detectable drug levels in breast milk,¹⁵ and in fact, produces very low levels of fetal exposure.¹⁶   

Deficits of GABAergic function have also been of great interest in the management of both MDD and PPD. An intravenous neuro-steroid targeting the GABA-A receptors is approved for the treatment of PPD,¹⁷ which provides rapid response within hours of administration.¹⁸ However, this agent must be administered in a continuous 60-hour infusion and carries black box warnings for neurotoxic effects, especially excessive sedation with potential loss of consciousness.¹⁷ The intravenous neurosteroid is available only through a restricted Risk Evaluation and Mitigation (REM) program. 

An oral neuro-steroid targeting the GABA-A receptors is being studied in patients with MDD and PPD.¹⁹ In both indications, this compound produced statistically significant reduction in depression measured by the Hamilton Depression Rating Scale (HAMD-17) at day 15, with onset of efficacy during the first 3 days of treatment reported.^20,21 The drug has been well tolerated, with no reports of loss of consciousness reported,^20,21 which hopefully eliminates the need for an REM program. 

Seeking and Receiving Help 

A relatively low proportion of patients with MDD and PPD actually seek and receive care. It has been estimated that only 28% to 60% of patients with MDD and 6% to 40% with symptoms of PPD seek and receive treatment.^22-24 Commonly held barriers to receiving treatment include a lack of understanding about the condition and institutional barriers within the healthcare system.^22,24 Central to the lack of help-seeking is perceived stigma about needing it.^24,25

Universal screening for both MDD and PPD is recommended by the United States Preventive Services Task Force,²⁶ suggesting prompt recognition and diagnosis of depressive conditions is a priority. Recent data also suggest stigma associated with depression is decreasing in the US general population. In a longitudinal study,²⁷ samples of the US general population were surveyed in 1996 (n=1444), 2006 (n=1522), and 2018 (n=1173) to identify trends in attitudes about mental health conditions. Survey results indicated that over two decades, decreasing percentages of respondents attributed depression to bad character or upbringing, and more attributed it to chemical imbalances, genetic problems, or mental illness. Fewer respondents expressed reluctance to have a depressed individual as a coworker, neighbor, friend, or in-law. The researchers attributed these shifts to a greater belief in science and trends among younger US residents. It is hoped that an evolving understanding of mental health, coupled with a lowering of financial and institutional barriers to care, will continue to promote the acceptance of, and care for individuals, with MDD or PPD.²⁷ 

References
1.    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.
2.    Work Group on Major Depressive Disorder. Practice guideline for the treatment of patients with major depressive disorder. American Psychiatric Association; 2010. Accessed August 14, 2022.
3.    Batt MM, Duffy KA, Novick AM, Metcalf CA, Epperson CN. Is postpartum depression different from depression occurring outside of the perinatal period? A review of the evidence. Focus (Am Psychiatr Publ). 2021;18:106-119. doi:10.1176/appi.focus.20190045
4.    Ghaedrahmati M, Kazemi A, Kheirabadi G, Ebrahimi A, Bahrami M. Postpartum depression risk factors: a narrative review. J Educ Health Promot. 2017;6:60. doi:10.4103/jehp.jehp_9_16.eCollection 2017
5.    Viktorin A, Meltzer-Brody S, Kuja-Halkola R, et al. Heritability of perinatal depression and genetic overlap with nonperinatal depression. Am J Psychiatry. 2016;173(2):158–165. doi:10.1176/appi.ajp.2015.15010085
6.    Wu X, Niu Z, Zhu Y, et al. Peripheral biomarkers to predict the diagnosis of bipolar disorder from major depressive disorder in adolescents. Eur Arch Psychiatry Clin Neurosci. 2022;272(5):817-826. doi:10.1007/s00406-021-01321-4
7.    Berglund J. Treating postpartum depression: beyond the baby blues. IEEE Pulse. 2020;11(1):17-20. doi:10.1109/MPULS.2020.2972723
8.    Fonseca A, Gorayeb R, Canavarro MC. Women's help-seeking behaviours for depressive symptoms during the perinatal period: Socio-demographic and clinical correlates and perceived barriers to seeking professional help. Midwifery. 2015;31:1177-1185. doi:10.1016/j.midw.2015.09.002
9.    Henshaw EJ, Durkin KM, Snell RJ. First-time parents’ shared representation of postpartum depressive symptoms: a qualitative analysis. Social Sci Med. 2016;160:102-110. doi:10.1016/j.socscimed.2016.05.025
10.    van Zoonen K, Buntrock C, Ebert DD, et al: Preventing the onset of major depressive disorder: a meta-analytic review of psychological interventions. Int J Epidemiol. 2014;43(2):318-329. doi:10.1093/ije/dyt175
11.    Sockol LE, Epperson CN, Barber JP. A meta-analysis of treatments for perinatal depression. Clin Psychol Rev. 2011;31(5):839-849. doi:10.1016/j.cpr.2011.03.009
12.    Clark R, Tluczek A, Brown R. A mother-infant therapy group model for postpartum depression. Infant Ment Health J. 2008;29(5):514-536. doi:10.1002/imhj.20189
13.    De Crescenzo F, Perelli F, Armando M, Vicari S. Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials. J Affect Disorder. 2014;152-154:39-44. doi:10.1016/j.jad.2013.09.019
14.    Hendrick V, Altshuler L, Strouse T, et al. Postpartum and nonpostpartum depression: differences in presentation and response to pharmacologic treatment. Depress Anxiety. 2000;11(2):66-72. doi:10.1002/(sici)1520-6394(2000)11:2<66::aid-da3>3.0.co;2-d
15.    Pinheiro E, Bogen DL, Hoxha D, et al. Sertraline and breastfeeding: review and meta-analysis. Arch Women Ment Health. 2015;18(2):139–146. doi:10.1007/s00737-015-0499-y
16.    Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry. 2003;160(5):993-996. doi:10.1176/appi.ajp.160.5.993
17.    Zulresso. Prescribing information. Sage Therapeutics, Inc; 2022.
18.    Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070. doi:10.1016/S0140-6736(18)31551-4
19.    Walkery A, Leader LD, Cooke E, VandenBerg A. Review of allopregnanolone agonist therapy for the treatment of depressive disorders. Drug Design Dev Ther. 2021;15:3017-3026. doi:10.2147/DDDT.S240856
20.    Sage Therapeutics and Biogen announce that the Phase 3 SKYLARK study of zuronalone in postpartum depression met its primary and all key secondary endpoints. News release. Biogen; June 1, 2022. Accessed November 6, 2022. https://investors.biogen.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-phase-3-skylark-study 
21.    Sage Therapeutics announces positive interim, topline zuranolone safety and tolerability data from open-label SHORELINE study in patients with MDD. News release. Sage Therapeutic®; October 15, 2020. Accessed November 6, 2022. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-positive-interim-topline-zuranolone 
22.    Boerma AM, Kleiboer A, Beekman ATF, van Zoonen K, Kifkshoorn H, Cuijpers P. Determinants of help-seeking behavior in depression: a cross-sectional study. BMC Psychiatry. 2016;16:78. doi:10.1186/s12888-016-0790-0
23.    Grissette BG, Spratlin R, Aycock DM. Barriers to help-seeking behavior among women with postpartum depression. J Obstet Gynecol Neonatal Nurs. 2018;47(6):812-819. doi:10.1016/j.jogn.2018.09.006
24.    Manso-Córdoba S, Pickering S, Ortega MA, Asúnsolo Á, Romero D. Factors related to seeking help for postpartum depression: a secondary analysis of New York City PRAMS data. Int J Environ Res Pub Health. 2020;17(24):9328. doi:10.3390/ijerph17249328
25.    Chekroud AM, Foster D, Zheutlin AB, et al. Predicting barriers to treatment for depression in a U.S. national sample: a cross-sectional, proof-of-concept study. Psychiatr Serv. 2018;69(8):927-934. doi:10.1176/appi.ps.201800094
26.    Siu AL; US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, et al. Screening for depression in adults US Preventive Services Task Force recommendation statement. JAMA. 2016;315(4):380-387. doi:10.1001/jama.2015.18392
27.    Pescosolido BA, Halpern-Manners A, Luo L, Perry B. Trends in public stigma of mental illness in the US, 1996-2018. JAMA Network Open. 2021;4(12):e2140202. doi:10.1001/jamanetworkopen.2021.40202