Types of postpartum affective illness are divided into three categories such as postpartum blues, postpartum psychosis and postpartum depression [15, 16] as mentioned in Table 1. About 300-750 per 1000 mothers globally, suffer from postpartum blues which is resolved from a few days to a week and has some negative impacts whereas postpartum psychosis begins from four weeks postpartum and it can also lead to hospitalization; and this can have prevalence rates ranging from 0.89-2.6 per 1000 childbirths.And in postpartum depression, this can start soon after the childbirth and needs to be treated through various therapies otherwise can lead to disruption of mother-infant relationship, child development and its growth. About 5-7 children of mothers who are suffering from PPD can have the highest cognitive behavioural and related problems as compared with the children of the non-depressed mothers as this can have high prevalence rates as 100-150 per 1000 births [17, 18].

It remains unpredictable as sometimes it was thought that PPD is caused due to lack of nutrients, such as vitamins, as there are no causative agents that can trigger the PPD or they have not been documented, whereas there are some other studies which tend to depict that the more significant causes of PPD are the changes in a woman’s hormonal level during gestation period (pregnancy) [19]. The levels of hormones that is oestrogen, progesterone, and cortisol (stress hormone) can drop drastically and dramatically within 48 hours after parturition (delivery). Therefore, most of the women are sensitive towards these hormonal changes during the reproductive cycles, especially in menses, pregnancy and menopause [20]. Women who suffered from postpartum depression are sensitive towards these hormonal changes which are dropped dramatically after the delivery of a child [21, 22]. According to some research reports it was depicted that there is a link between the cortisol and the depressive and related disorder symptoms during pregnancy and postpartum stage, while some show that there is no relation between the hormones and the postpartum depression so all mothers can experience these changes, but only 10-15% can suffer from PPD [23].

Changes in hormones during pregnancy and postpartum as mentioned in Table 2 can manifest the postpartum depression because the dramatic changes in the level of hormones lead to the development of anxiety, fear, sadness during puerperium [24]. Several endocrinal changes can lead to neuropsychoendocrinology which can follow a systematic pattern because of a continuous increase in the hormonal plasma concentration throughout the 40 weeks of pregnancy, followed by a dramatic drop in the levels at parturition. Various gonadal steroidal hormones like oestrogen, progesterone, testosterone, Corticotropin-releasing Hormone (CRH), cortisol, oxytocin and many more can adhere to this temporal plasma profile [25-29]. Estradiol increases about 50-folds [30], progesterone 10-fold [31], and prolactin about 7-folds [32]; testosterone can show the moderate increases as compared with the pregnancy periods, and oxytocin levels are increased just before the stage of delivery (parturition). Most of the hormones are suppressed in breastfeeding mothers or women, while prolactin levels change or elevate, and because of this the breastfeeding bouts can trigger the acute increment in both prolactin and oxytocin, while estradiol and progesterone levels are suppressed during lactation amenorrhea [33-35]. The continuous increase of steroid hormones can fluctuate in the negative feedback systems and this is achieved by the feto-placental unit, which ultimately produces large amounts of oestrogen, progesterone and CRH. Apart from this effect on hypothalamic CRH production, cortisol can also have positive feedback on placental CRH production, in the last weeks of pregnancy cortisol produced by the foetal adrenal gland which is the signal derived for the maturation and development of organs of the foetus as well as denoted the time of parturition [36].

Various risk factors which can cause the postpartum depression (PPD) in new mothers as mentioned in Fig. (1) . Is it a crucial time which is followed by the birth of a baby during which one of the most intense physiologic and psychological changes are taking place in the new mothers?

Most of the women can experience an episode of the onset of depression during the process of pregnancy and the childbirth as it can be depicted as a stressful event of life. There are many psychological stressors identified which are responsible for or act as a risk factor for the initiation of the postpartum affective illness and related disorders [37, 38]. The factors such as marital disharmony, lack of mutual understanding between partners, lack of relationships and life events, have the potential to develop PPD as mentioned in Table 3. As there are more factors like neurobiological interest and a family chart to predict the history of depression [39-41]. According to the clinical evidences stress can act as a risk factor for the development of depression, by using various animal models for screening for the study of PPD by utilizing an exogenous corticosterone or stress-based models. They are used during pregnancy and lactation by which they can easily and sufficiently increase the depression and fear, anxiety-like behaviours and disorders and induce a disruptive and deficient maternal care in rodents [42, 43].

Besides these factors, the impact parenting role of father involvement towards the child was also a risk factor for the emergence of postpartum depression in women. It was found that lower rates of PPD found in women/mothers when the proper high range of satisfaction levels were determined with father/husband involvement. The insecure attachment towards infant was linked with the profound depression in the adolescent's mothers is associated with the negative vibes, thoughts, stress, relationship issues, financial stress problems [44].

Fig. (1). shows the types of factors and life events which are relevant in manifestations of postpartum depression in women.

Today women who experienced the occurrence of the multiple adverse life events, including sexual abuse, childhood sexual abuses and adult sexual abuse, were found to be more prone to have increased risk of postpartum depression. These conditions or factors can cause changes in the physiological behaviour of the women and cause disruption of the mental level. Nowadays women who are suffered from the postpartum depression, had 3-5 times higher Everyday Stressor Index (ESI) ranges as compared with the healthy women who are not suffered from PPD and relevant psychiatric mental disorders [45].

These all kinds of numerous environmental risk factors conclude the identification of the postpartum depression and include various depressions like prenatal depression, prenatal anxiety, disruption or impaired infant-mother relationship, lack of confidence and social supports, financial and marital status stress and many other adverse life events [46-48]. The risk factors can act as triggering agents for depression and it is more prevalent in women than men because of internalizing and externalizing of each symptom [49]. In a research study of dizygotic twins, women can show more sensitivity to the interpersonal relationships whereas men show more sensitivity towards factors like external career, goal and future perspectives orientation [50]. Due to the changes in the ovarian hormones, it could also contribute to a high prevalence rate of depressive illness and associated disorders including, premenstrual dysphoric disorder, postpartum depression and postmenopausal depression and anxiety in women. However the mechanisms remain uncleared and it treatments specific to women have not been developed. And the society derived risk factors for depression in women are more likely to have biological aspects, such as the differences in the physical strength and personality traits and energy levels, which can also lead to a higher prevalence of depression in women [51].

The symptoms differ from the non-postpartum depression, as most of the women who are suffering from postpartum depression (PPD) have no psychiatric or mental illness history and they are resistant to symptoms [52]. The clinical manifestations or emerging symptoms of the postpartum depression include sleep cycle disturbances, excessive thoughts, crying, mood swings, change in mental and behavioural patterns, difficulty in thinking, remembering and concentrating, feeling of sadness, doubt, guilt, fear, change in appetite, suicidal thoughts, melancholia, and excessive care of baby and many more as mentioned in Table 4 [53-55].

Many researchers and experts in the field of science consider that postpartum depression shows symptoms and extend to 12 months after delivery [56]. About 60% of women with PPD are diagnosed with obsessive thoughts, focussing, and aggression to their infant as they do not show a desire to hurt the infant most of the time or overcaring leading to avoidance of the baby to minimize these thoughts [57]. Most of the genetic studies determine that depressive episodes begin within the first four weeks of parturition (delivery of the child) [58].

There are various types of predictors which can predict the pathogenesis or pathophysiological conditions and mechanisms of the Postpartum Depression (PPD) as shown in Fig. (2). There are various biological and physiological changes which characterize normal human pregnancy because these biological changes are designed to maintain the pregnancy, trigger labour, support the foetal development and maturation, parturition, and lactation. The female body physiology can have the potential adaptive capacity. After the delivery of the baby and, the placenta maintains the maternal-placental-foetal unit throughout the gestation period which was sustained by intricate balance. Due to this, the maternal system undergoes various types of biological changes drastically within the first postnatal days and these adjustments and fluctuations lead to an impact also on maternal health. And the biological predictors can emphasise on the endocrine systems, immune/inflammatory factors, and genetic factors which ultimately cause postpartum depression [59]. On the other hand, psychosocial predictors lead research towards the PPD as it will have a longer period history as compared with biological research factors. They depend on two factors that are stress and interpersonal facts. During pregnancy and delivery, there is an abrupt change occurring in the physiology of the mother and thousands of sudden changes in a woman’s roles for responsibilities and caring and demands towards the new baby. In the past few decades, there has been stress on showing perspective for PPD development because it is paired with other social, psychological, biological, and interpersonal vulnerabilities [60, 61] as mentioned in Table 5.

This stress can lead to the destruction of the mother-infant relationship and caring [62] and harms pregnancy [63]. These psychological and psychosocial predictors act as biomarkers for postpartum depression which was documented only in cases of poor mental health conditions in developed countries, worst life conditions [64], history of premenstrual dysphoric disorders, and stress [65]. These factors associated with PPD and psychological abuse were reported in developed countries [66].

Circadian rhythm has played a vital role because of any dysregulation or alteration in mood changes due to the dramatical variations in the sleep patterns, lack of sleep in the first months of postpartum, and struggling with the issues of life which have been associated with both new-onset and recurrence of PPD [67, 68]. By using these Postpartum Depression Predictors Inventory-Revised (PDPI-R) shows the distribution of risk factors for PPD at different times. Depression and antenatal depression are associated with PPD at six months postpartum. Antenatal anxiety occurs during the first trimester of pregnancy and it is not a predicted postpartum depression but is determined during the last phase of pregnancy. And during this period, the lack of social and socio-economic support and status can predict the occurrence of postpartum depression [69, 70].

Fig. (2). Shows different types of predictors which have the potential for the occurrence of the postpartum depression in women and leading to worsening conditions.

Before giving treatment, therapies or medications, there has been increasing focus on the early detection of depression after or during pregnancy. Screening of PPD was performed in a 4-6-week postpartum period or the 2-month well-child visit [89, 90]. The most common method for the screening of PPD is the Edinburgh Postnatal Depression Scale (EPDS) as this screening tool is based on a simple 10-item questionnaire which gives the information on suicidal ideation initially proposed by Cox et al. in 1987. Another screening tools are the Postpartum Depression Screening Scale (PDSS) and Physicians' Health Questionnaire (PHQ-9) used to detect PPD [91-93]. Edinburg Postpartum Depression Scale was the most widely used tool for estimating PPD in studies for research purposes. It was found that low birth weight and congenital abnormalities in babies have an effect on depression after the delivery. It is recommended that health care providers and physicians should be provided with information regarding factors contributing PPD and postmenopausal depression.

Most researchers, scientist and scholarly journal articles support that postpartum depression is treatable by knowing the root cause of problem and treatment can be both pharmacological and non-pharmacological. There are two therapies, first-line therapy and second-line therapy. First-line therapy is considered with Psychotherapy in which mothers prefer psychological treatment. The most commonly used therapies under psychotherapy and found to be beneficial are interpersonal therapy (IPT) and cognitive behavioural therapy (CBT) [94]. In IPT, the patient and physician select one of four interpersonal problems like dispute, grief, lack of understanding) etc. as an ailment focus. During therapy which lasts for about 12-20 weeks, patients are assisted in problematic approaches and conditions to build up the relationship with better social support. IP addresses the relevant areas of PPD conditions such as bonding between mother-infant relationship, mother and partner mutual relationship, etc. [95]. Cognitive Behaviour Therapy (CBT) is based on perceptions and behaviours which are ultimately linked with the mood. CBT focusses on caring the patients who are depressed and modifies the negative impacts or thoughts and enhances to makes behavioural changes which lead to generating capability and potential to reduce distress and coping with the social factors. There were many trials held to assess the CBT or other interventions for the treatment of PPD [96]. A clinical trial conducted on 120 women who recently gave birth to a baby, showed that interpersonal psychotherapy was effective towards the ailment of depressive episodes and treated the symptoms and also used for improving the psychosocial functions in the PPD treated women as compared with the control groups who were on the list of such therapies [97]. Whereas the second-line therapy is pharmacotherapy in which a Selective Serotonin Reuptake Inhibitor (SSRI) acts as the first agent because it is associated with low toxicity if patients are taking an overdose, and there is ease of administration. Randomized controlled trials are held and conducted over 87 women who are suffered from PPD compared with fluoxetine, placebo and counselling (cognitive behavioural therapy). These subjects were divided and randomized into one of four groups who received either fluoxetine drug or placebo plus the addition of one or six CBT sessions [98]. Fluoxetine has shown better efficacy as compared with placebo and reduced the symptoms of depression and also showed improvement. Women who breastfeed are excluded from this trial because all the antidepressant medications are excreted in breast-milk and have potential to transfer the effects to the child due to breastfeeding [99]. There was a pooled analysis of Selective Serotonin Reuptake Inhibitors (SSRI) which found that sertraline, paroxetine, and nortriptyline are the least detected in infants and with rare side effects. Also detectable levels of fluoxetine and citalopram are found in infant serum [100-102]. Most of the physicians prescribe the antidepressant medication as mentioned in Table 6 before prescribing any new treatment because if the patient has positive responses towards certain and specific drugs, then that agent will be considered as the first choice for the ailment of the disorder [103].

As there is no evidence which can suggest that one antidepressant drug has the potential for treating women who are suffered from postpartum depression who are not breastfeeding, the choice of medication should be based on patient's history and tolerability profile [ 104 ] .

Other non-pharmacological treatments are used for the treatment of postpartum depression (PPD) are Electroconvulsive Therapy (ECT), Bright Light Therapy, Omega-3 fatty acids, Acupuncture, Massage and Physical exercise.

Psychotherapy, useful interventional therapies, general well-being which includes yoga mindfulness-based therapies, change lifestyle factors such as less alcohol intake.

Synthetic steroid such as Tibolone with a hormone makeup induces minor intermenstrual bleeding and treats perimenopausal depression. Bioidentical hormones are those compounds /drugs which resemble the ovarian hormones (oestrogen/ progesterone), but they are used in a limited manner and not recommended by the International Menopause Society. Antidepressant drugs were used such as SSRI (first-line drugs), SNRI (second-line drugs). However, these two classes of drugs have adverse drug reaction like agitating, irritation, sedation, with perimenopausal insomnia, anxiety, leading to worsening the symptoms with drugs such as fluoxetine. Combining hormone therapy with antidepressant drugs is used for the treatment of perimenopausal depression followed by a decrease in the depressive symptoms. As a single therapy is not responding to either treatment alone,so this combined treatment needs to be monitored carefully [115-117].

The rising high levels of the Follicular Stimulating Hormone (FSH) is the very first hormonal change which is caused by reduced levels of gonadotropin hormones which are secreted from ovarian follicles as menopause reaches. Oestrogen levels increase at the time of follicular growth and pituitary gland of brain stimulate the secretion of FSH (to inhibit the growth and maturation of other follicles cells) and Luteinizing Hormone (LH); as these two hormones have negative feedback mechanism towards the ovarian gonadal sexual hormones such as oestrogens and progesterone in females. During the menopausal transition period, these gonadal sex steroids are circulating and fluctuating and later produce granular cells of the ovaries due to reduced levels of oestrogens and inhibin. However, the serum levels of FSH and estradiol, oestrone (oestrogens) are high in the perimenopausal stage and vary from woman to woman and cycle to cycle. But the confirmation diagnosis is done by laboratory testing and depends upon woman who reports about her past and early period. And about after 1 year of perimenopause, the women reach to postmenopause in which woman experience permanent cessation of menstrual periods (amenorrhoea condition) due to low oestrogen and progesterone hormone level and with a high level of gonadotropins [118].

Causal Mechanisms of perimenopausal depression is related to a different hypothesis which suggests why most of the women would be prone to experience depression during perimenopause. Al these symptoms are experienced by 45-85% of women, hot flushes (perspiration during sleep) mechanisms are not completely determined but there is a hypothesis regarding their mechanism of action which suggests that change in the thermoregulatory system in the hypothalamus region of the brain may lead to elevate the levels of sex steroids (gonadal) and the opioid peptides. So, most researchers /clinicians suggest that oestrogen administration decreases the occurrences of hot flushes depend upon dose-dependent fashion [119].

Women are particularly susceptible to mood and behaviour disorders during stages of hormone changes and this is explained by the interactions among the neuro-modulating effects of oestrogen on the serotonergic system [131]. These changes in the reproductive events lead to dysregulation of the serotonergic and noradrenergic systems which are involved in mood and behaviour. There is a hypothesis that a reduced capacity to adapt fluctuations and alterations of estradiol or progesterone are predisposed in certain women and lead to depression [132, 133]. In addition to these factors, lifestyle factors also played a vital role in postmenopausal depression such as smoking, other medical conditions, ethnicity, age factors, and employment status. All these factors are associated with increased risk of depression and depressive episodes during menopause [134-136]. Many studies conducted show various factors which are responsible for disturbing and deteriorating the quality of life in the menopausal women [137]. The factors which are responsible for postmenopausal depression, are shown in Table 7, and other depressive disorders that are associated with the early and late menopause in females interact with age factors and increase the risk of the onset of several various chronic disorders and diseases such as cardiovascular diseases, breast and endometrial cancers and osteoporosis [138].

The aetiology of the perimenopausal depression, oestrogen alteration, fluctuation and loss act as: a predisposing factor, when they increase its limbic vulnerability to environmental stressors; act as a precipitating factor when they trigger the gene expression and cause manipulation in genetic field and produce major depression; act as a maintenance factor, when there is a lack of hormonal therapy; thus these factors can worsen the conditions either it is neuronal or genetic.

There are various independent predictors of menopausal depression which are frequent episodes of depression in reproductive age, premenstrual syndrome, postpartum depression, and comorbid symptoms like hot flashes, insomnia; elevation in the BMI (Body Mass Index); social and cultural status [139]. Moreover, women who are experiencing bilateral oophorectomy without oestrogen replacement are more affected from major depression [140, 141]. The chronic deficiency of oestrogen hormone can produce a negative impact on the brain major systems: the neurovegetative [142, 143], the emotional/effective [144], and the cognitive and motor [145-147]. The symptoms which were noticed in women who are suffering from menopausal depression after postpartum according to the type of neuronal damage, can produce are shown in Table 8.

As menopause is the influential period during which women undergo a new biological transition, so women with postmenopausal depression have lower levels of estradiol and serotonin concentrations, in spite of high levels of Follicle Stimulating Hormone (FSH). These hormones are having trophic effect on brain, disrupting the nervous system and producing various depressive affective disorders in the mid-aged pregnant women [148].

There are various therapies and treatments for postmenopausal depression such as Hormonal treatment, antidepressant treatment, physical activities treatment, mindfulness-based therapies, cognitive behavioural therapies, and mind-body therapies.

Most of the females complain about difficulties initiating and or maintaining proper sleep during the menopausal transition. However, it is difficult to determine whether this is a primary disorder or it may be related to vasomotor symptoms of depression. It may also cause medical conditions and lifestyle. Sleep quality can be worsening if obstructive sleep apnoea and leg syndrome problems arise which is common in this age group [180]. The possible interactions between menopausal changes and sleep disturbances are investigated and are associated with the onset of sleep disturbances [181]. Vasomotor symptoms are the primary predictor of sleep problems in menopausal women while sleep disturbances were shown and associated with depression in midlife women when compared with non-depressed females, and those with VMS have even worse sleep quality and a high number of depressed groups [182, 183]. These were improved by using sleep aids such as zolpidem, with no improvement in flush number during the day time, suggesting that women were sleeping all night with no changes in nocturnal VMS.

It was studied that sexually dimorphic behaviours may be suggestive of sex differences in brain neuroanatomy and neurophysiology [184]. The preoptic is the area which is responsible for reproduction, thermoregulation, and sleep with the help of a complex network of regulatory signals which include several neurotransmitters, neuropeptides and hormones.

Serotonin (5-HT) is one of the neurotransmitters which is involved in thermoregulation as well as sleep and release of Gonadotropin-Releasing Hormone (GnRH). Any type of changes occurred in 5-HT receptors and transporters are reported in ageing, and in animal studies in which preoptic neurons are affected during reproductive ageing [185]. The animal studies also demonstrated some behaviour associated with kisspeptin and its related receptors which include anxiety and depression. The alterations are shown by kisspeptin in the postmenopause period that may play a role in mood regulation in women during their midlife years [186].

The oestrogen receptors are found throughout the brain, and the effects of oestrogen are observed in the hypothalamus, prefrontal cortex, and hippocampus and brainstem regions. As in animal models, oestrogens withdrawal has been proposed to play a key role in the onset of postpartum anxiety and depression which occurs mainly within 4 to 6 weeks after the birth of a child. However, circulating oestrogen levels are dramatically and drastically reduced during the early postpartum periods and then return to dioestrus levels at 3 weeks postpartum, raising the possibility that changes in oestrogen levels and its sensitivity are involved in postpartum depression [187].

Genetic association studies identified the individual candidate genes as well as potential pathways involved in postpartum depression.

Numerous findings implicate that the HPA axis is involved in postpartum depression. Variations in both the MAOA and COMT genes are implicated in postpartum depression and are also linked with sex-specific differences in cortisol responses to a social stressor. Protein Kinase C Beta Type (PRKCB) is a regulator of the HPA axis indirectly through Glucocorticoid Receptors (GR) and Corticotropin-Releasing Hormone (CRH) signalling and mutations in this gene are also associated with postpartum depression [188, 189].

The Hemicentin 1 gene had the strongest association with postpartum depression. Though its function is unclear, HMNC1 is highly shown in the hippocampus region, which was shown to be altered in rats followed by a postpartum drop in oestrogen levels. Further studies were held which showed a relationship between HMNC1 and the postpartum depression, for which candidate gene approach was taken which confirmed that the HMCN1 polymorphism was associated with postpartum depression in a small number of Brazilian women. Further research required to find about the role of HMNC1 gene in underlying pathogenesis of postpartum depression [190-192].

Postpartum depression is a major international human health problem which affects at least one in eight mothers and their children in the year after parturition (childbirth) worldwide affecting the mother-infant relationship. It has been associated with negative effects and related symptoms not only on women who were depressed but also on their children affecting their physical, cognitive and emotional development and state of mind. Most and numerous studies show the effectiveness of the medication and various therapies.

A study was conducted showing the effect of oxytocin and HPA on PPD in women. Lactation has shown shielding action towards stress reactivity due to the release of oxytocin. In women suffering from postpartum depression, the Dysregulation of the HPA axis has been reported. On the other hand, the presence of PPD and failure to lactate has shown a strong correlation in the OT signaling thus leading to PPD. A research was performed on fifty pregnant women who anticipated breastfeeding. 47 out of them underwent Trier Social Stress Test (TSST) after eight weeks of postpartum whereas thirty nine women were breastfeeding at the time of conduction of TSST. The symptoms were noted and blood was withdrawn to check the hormone levels. It was found that in breastfeeding women the OT surge leads to shielding of the stress-induced secretions of CORT. A strong correlation was noted in symptomatic women who were breastfeeding and showed a correlation between OT, AUC and CORT. The results showed that in symptomatic breastfeeding women low OT levels were noted and high CORT levels were seen during breastfeeding during the TSST in comparison to the asymptomatic breastfeeding women [193].

Trials are held for medication specifically evaluating the effectiveness and potential capability of antidepressant medication, hormonal therapy or Electroconvulsive Therapy (ECT) for postpartum depression They also provided evidence that those treatments which show potential in treating major depression in the general population are equally effective in treating postpartum depression. Selective Serotonin Reuptake Inhibitor (SSRI) is mostly used in treating PPD in women. [194].

It is suggestive from all the cases reported that women of midlife age experience major episodes of depression especially during perimenopausal, postmenopause and postpartum phases. Depression of midlife is a classic case of depression commonly noted with symptoms like sleep disturbance, vasomotor symptoms etc. and even major psychological disorders. Symptoms of menopause co-occur thus making it a complicated case of depression [ 195 ].

Various diagnosis involves the prior detection of menopausal stage by assessment of the concurrently occurring symptoms of psychiatric and psychological conditions.