Depression

Depression is a common problem in healthcare. Despite its prevalence, it is underdiagnosed and undertreated, which is unfortunate because many treatments are available to relieve this disabling disease. Many reasons explain why it is underdiagnosed, but it is often not discussed enough in the medical office. Depression comes with a negative social stigma, and people are often ashamed to discuss it with their providers. In addition to doctors being reluctant to bring it up, they often lack time to dive into a discussion about depression with their patients.

Depression is more than feeling sad. Everyone has days when they are sad, but depression is a persistent feeling of sadness that disrupts life for the person afflicted and their loved ones.

This article will focus on major depressive disorder (MDD), but depression can have other forms. Major depressive disorder is associated with a reduction in pleasure and feelings of sadness that affect the individual's ability to work, interact, eat, sleep, and derive pleasure from life (American Psychiatric Association [APA], 2013).

Another common type of depressive disorder is persistent depressive disorder, previously known as dysthymic disorder. This depression is associated with more than two years of impaired function, but symptoms are not as severe as major depressive disorder (APA, 2013).

Bipolar depression is another type of depression where the individual cycles between depression and mania. Mania is characterized by an elevated mood, increased energy, and irritability and is associated with euphoria, reduced sleep times, excessive talking, and a lack of inhibitions (APA, 2013).

Postpartum depression is associated with depression within four weeks of delivering a child (APA, 2013).

The seasonal affective disorder is depression that starts in the fall, continues into the winter months, and is associated with less natural light. This type of depression improves in the spring and summer (APA, 2013).

In 2015, among adults in the United States, an estimated 16.1 million had at least one major depressive episode in the past year. This number represented 6.7% of all adults (Halverson, 2020). Depression is more common in those between 40 to 59 years old. Females are seventy percent more likely to be depressed than males over their lifetime (Halverson, 2020). Eventually, depression can be successfully managed in most patients, but 40 percent do not respond to the first treatment (Blackburn, 2019).

Most patients with depression receive treatment. Approximately 66 percent of American adults with MDD received treatment over the last 12 months. About 71 percent of those with severe disease received treatment over the previous 12 months (National Institute of Mental Health, 2022).

Antidepressant use is increasing. Between 1999-2002 there was a 7.7 percent use rate, and between 2011-2014 the use rate was 12.7 percent (the female use rate was 16.5 percent) (Blackburn et al., 2019). Depression rates in children are high, with up to eight percent of teenagers meeting depression criteria in the last year; by age 21, almost 15 percent have had a mood disorder (Blackburn, 2019).

Suicide is a serious problem that often complicates depression. It is estimated that 45,979 people died by suicide in the United States in 2020 (Centers for Disease Control and Prevention [CDC], 2022). It is the second leading cause of death for individuals aged 10 to 14 and 25 to 34 (CDC, 2022). Groups more commonly afflicted by suicide are veterans, rural residents, non-Hispanic Whites, non-Hispanic American Indian/Alaskan Natives, and younger people who identify as gay, lesbian, or bisexual (CDC, 2022).

Depression is laced with many complications. The most severe complication is suicide. Along with substance abuse, depression is the most common mental disease that afflicts those who commit suicide (CDC, 2020).

While depression is more common in women, successful suicide is more common in men. Women more commonly attempt suicide (2-3 times more often) but are not as successful. Older white men have the highest rate of completed suicide (CDC, 2022; Halverston, 2020). Specific factors increase the risk of suicide, including chronic medical illness, access to firearms, depression, family history of suicide, social isolation, and delusions.

Depression is associated with many other problems in addition to suicide. Those with depression suffer more medical illness and have worse medical illness outcomes than those without depression (Thom et al., 2019). Depression significantly impacts work life. Those with depression are more likely to miss work and be inefficient at work. Depression can profoundly affect the quality of life (Malhi & Mann, 2018). It significantly disrupts family, friends, and work relationships. Some with depression are socially isolated, do not interact with other people, and may not leave home.

Depression is associated with higher rates of substance abuse. It is unclear if depression causes substance abuse or if substance abuse causes depression. There is likely a complex interaction between the two conditions (National Institute of Mental Health, n.d.).

Depression may lead to significant complications in a patient's physical health. Depression may lower compliance with medical treatment and occurs for many reasons, including depression leading to patients making poor lifestyle choices.

Those with depression have reduced survival rates when compared to those without depression. Depression is a risk factor for heart disease and subsequent myocardial infarction. In addition, those who have depression are more likely to have more severe cardiac symptoms, reduced quality of life, and a worse prognosis for heart disease (Zhang, 2018). Depression has also been noted to increase the risk of dementia. In addition, depression is a risk factor for cognitive decline in those diagnosed with dementia (Sáiz-Vázquez et al., 2021).

Those who are depressed are more likely to make poor lifestyle choices. Obesity rates are higher in those with depression than in those without depression. A study confirmed that those who are obese are more likely to become depressed, and those who are depressed are more likely to become obese. In addition, management of depression helps with obesity, and management of obesity helps depression (Jantaratnotai et al., 2017).

The following case studies are descriptions of the patient's presentation. The conclusion of the case study is presented later in this course after the discussion of treatment options.

The exact pathophysiology of depression is unknown, but there are many theories. It is likely caused by biochemical, genetic, psychological, and environmental factors. Major theories revolve around disturbances in neurotransmitters and chemicals in the central nervous system, particularly serotonin, norepinephrine, and dopamine.

It is clear that depression runs in families, but it is unknown exactly how it is transmitted. Likely, multiple genes interact together to increase the risk of depression. Individuals with a family history of depression or alcohol dependence have a higher risk of depression (McHugh & Weiss, 2019).

Life can contribute to depression. Stressors and interpersonal loss are often associated with depression. While some depressive episodes occur without an apparent cause, a direct reason is usually responsible. Trauma, loss of a loved one, a complicated relationship, or any stressful situation may trigger a depressive episode. Stress increases cortisol levels and may affect mood. An early life loss increases the risk of depression over a lifetime (Halverson, 2020; McCarron, 2021).

Depression presents differently in different individuals. A common pneumonic to help nurses remember the classical signs and symptoms of major depressive disorder is SIG-E-CAPS.

Other symptoms that can present with depression include irritability, restlessness, pessimism, a variety of pain complaints, headaches, or gastrointestinal problems.

According to the DSM-V criteria (APA, 2013), to meet the diagnostic criteria for major depression, an individual must have five signs/symptoms that change from the previous function over two weeks. Depressed mood or reduced interest/pleasure must be present, and at least four other criteria described above.

In addition, the individual must not have manic episodes. The symptoms must cause impairment in function or significant distress. Other medical problems (such as hyperthyroidism, drug abuse, or alcohol abuse) must be ruled out, and the symptoms must not be related to bereavement/grief.

It is often more challenging to diagnose depression in those who have dementia. Those with dementia may demonstrate increased agitation, irritability, fatigue, hallucinations, or delusions. Those with dementia may be less likely to have feelings of hopelessness/helplessness or guilt.

Children who are depressed have a higher risk of developing severe depression when they become adults. Children may present differently with depression when compared to adults. Children with depression may practice avoidance behaviors, including refusing to go to school, pretending to be sick, or not wanting to leave the parent's side. They may also demonstrate behavioral problems, get into trouble, be irritable or have mood swings. Many of these behaviors are common among teenagers without depression, and it is often difficult to determine if depression is present in children.

A physical exam is typically unremarkable in the depressed patient. Certain features may be noticed on the exam, including flat affect, poor personal hygiene, psychomotor agitation or retardation, or slow speech. Many patients with depression will have none of these features. Mental status should be checked, particularly in the older patient, to assess for cognitive declines. The exam should reveal any key features of depression noted above and any mood swings, delusions, and hallucinations.

Depression is a diagnosis of exclusion. No diagnostic test is available to diagnose the disease. When it is suspected, other conditions must be ruled out with a history, physical exam, selected blood tests, and occasionally radiographic tests to rule out conditions that mimic depression.

For the condition to be managed appropriately, it needs to be diagnosed. Adults should be screened for depression when there is a place to ensure a correct diagnosis, appropriate treatment, and follow-up (AHRQ, 2016). A similar statement has been made for adolescents with depression. Those between the ages of 12-18 years old should be screened for major depression if a system is in place to diagnose, provide psychotherapy and follow up accurately. For those between 7-11 years old, there is not enough evidence to evaluate if screening is appropriate (Forman-Hoffman et al., 2016).

Depression often co-exists with other mental health conditions. Healthcare professionals need to be on the lookout for different conditions. Identifying other disorders is important because it can significantly impact treatment options. For example, certain antidepressant medications are indicated for both anxiety and depression. Other antidepressant medications, while treating depression, will worsen anxiety.

One of the most common co-existent conditions is anxiety disorder. Anxiety disorders may include generalized anxiety disorder, social phobia, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder.

Other mental health conditions co-existing with depression include substance and alcohol abuse, personality disorders, bipolar disease, eating disorders, adjustment disorder, and schizophrenia.

In addition to mental illness, depression often co-exists with many medical diseases. Depression may result from a medical disease, or depression may exacerbate the medical disease. Common medical conditions that are seen in combination with depression include heart disease, cancer, stroke, Parkinson's disease, dementia, and diabetes.

When evaluating someone with depression, identifying these medical conditions is critical concerning the medication selection. For example, individuals with high blood pressure and heart disease may want to avoid certain antidepressants that increase blood pressure, such as venlafaxine.

Depression adversely affects chronic disease. Those with depression typically have more severe underlying medical illnesses and more costs associated with their medical condition. When faced with a person with probable depression, it is essential to consider other diagnoses. Some of them include:

• Anxiety disorders and other mental health conditions, as discussed above
• Dementia
• Cancer of the central nervous system; mood changes are often noted before other neurological signs and symptoms
• Substance abuse: alcoholism, cocaine use, marijuana use, or opioid abuse
• Inflammatory conditions such as systemic lupus erythematosus
• Sleep problems such as obstructive sleep apnea or insomnia
• Infectious diseases such as Lyme Disease, syphilis, or HIV
• Chronic fatigue syndrome
• Endocrine diseases such as hypothyroidism/hyperthyroidism, Cushing disease, prolactinoma, and hyperparathyroidism
• Anemia
• Female hormonal disorders such as menopause or premenstrual dysphoric disorder

Some medications can cause depression. Common medications to consider as causes of depression include beta-blockers, calcium channel blockers, corticosteroids, H2 blockers, sedatives, chemotherapy agents, or hormones.

A variety of treatments are available to manage depression. Common treatments include lifestyle changes, psychotherapy, medications, electroconvulsive therapy, and light therapy.

The goal of treatment is to alleviate symptoms and restore the patient's function. Treatment with both pharmacotherapy and psychotherapy for mild to moderate unipolar depression is preferred (Halverson, 2020). Studies have shown that those treated with psychotherapy will have benefits that will persist, and those treated with antidepressants are more likely to relapse (Halverson, 2020).

Initial medication treatment for depression is typically done with SSRIs. Still, consideration may be given to a serotonin-norepinephrine reuptake inhibitor, an atypical antidepressant (e.g., bupropion®, mirtazapine®), or a serotonin modulator (e.g., vilazodone®). Tricyclic antidepressants and monoamine oxidase inhibitors are not typically used as initial treatment.

A recent systematic review and meta-analysis looked at the most effective antidepressant medications. The review showed that all medications were more effective than placebo in managing depression (Cipriani et al., 2018).  The most effective medications noted were escitalopram, paroxetine, venlafaxine, amitriptyline, mirtazapine, and vortioxetine.  The most tolerable medications include fluoxetine, sertraline, citalopram, escitalopram, and vortioxetine. The least effective medications were fluvoxamine, trazodone, and fluoxetine, and the highest dropout rates were noted with duloxetine, amitriptyline, fluvoxamine, venlafaxine, and trazodone (Cipriani et al., 2018).

Research has not clearly defined a superior antidepressant, so the agent selected is dependent on multiple factors, including drug-to-drug interactions, comorbid conditions, safety, side effects, cost, personal response, or response of family members to medications in the past. Sometimes, specific medications are helpful based on other symptoms or comorbidities the patient suffers. For example, those with insomnia may be prescribed trazodone or mirtazapine because of their sedating properties. Those who wish to stop smoking may consider the use of bupropion. Escitalopram and citalopram are least likely to lead to drug-to-drug interactions.

Treatment is typically started at a low dose and slowly titrated upwards to the therapeutic range. Some response is generally seen within one to two weeks. Individuals who respond early to treatment with antidepressants are more likely to go into remission (Kang et al., 2020). Up to three months of treatment is generally recommended to determine if the treatment was effective. The treatment regime should be reevaluated in those with minimal effect after 4-6 weeks (Gautman et al., 2017).

Medications must be continued for at least 4-9 months (Halverson, 2020; informedhealth.org, 2020). If treatment is discontinued early, there is a high risk of relapse. Most antidepressants need to be weaned gradually. Abrupt discontinuation of antidepressants can result in serious side effects known as the discontinuation syndrome. Medications should be discontinued over two months for those on treatment for 6-12 months and up to 6 months for long-term treatment. Gradually tapering the medication is more critical if the patient is on a high dose.

Some individuals benefit from long-term treatment. Individuals who would benefit from long-term treatment have had multiple relapses, suffer from chronic depression, and want to avoid relapse (National Institute of Health [NIH], 2020). Long-term treatment with an antidepressant over an extended period reduces the risk of relapse in about 27 out of 100 people (NIH, 2020).

Many medications are available for the treatment of depression. Not all medications are equally effective in all individuals. Switching to another medication may be more effective when one medication is ineffective. Those with more severe depression are more likely to benefit from treatment. Research suggests that antidepressants improve symptoms in up to 60 percent of patients, but symptoms improve in only about 20 out of 100 patients above expected with a placebo (NIH, 2020).

Resistant depression is when treatment does not fully improve the condition. In resistant depression, standard treatments usually do not help. Thirty-three to sixty-seven percent of people fail to respond to first-line therapy (Halverson, 2020). It is often not a failure of the medication but a failure in the use of the medication. Failure can stem from the patient not taking the medication appropriately, the dose being incorrect, the patient not tolerating the medication, or not using the medication for the correct amount of time.

A few steps must be taken when faced with treatment-resistant depression (Halverson, 2020). First, the clinician must reevaluate the diagnosis to ensure it is correct. Determine if there is a comorbid factor that is contributing to the depression. Is there any anxiety, substance abuse, or psychosis? Review the differential diagnosis list and determine if depression is still the diagnosis. Next, determine if the medication is being used correctly. Has an adequate trial been used, has the duration been long enough, and has the patient taken the medication as prescribed?

A few strategies can be implemented if all of this checks out.

• The clinician can increase the dose of the medication if the drug allows.
• Different medications can be tried. For example, going from an SSRI to an SNRI.
• Augmentation - adds a different medication to the current treatment.
• The addition of talk therapy.
• Electroconvulsive therapy.

For those with resistant depression, many medications are available to add to typical antidepressants to see if a response can be elicited. Augmentation is beneficial if a comorbid condition is responsive to a specific medication. For example, those with psychotic depression may respond to an antipsychotic added to their antidepressant.

A meta-analysis found that adding an atypical antipsychotic is more effective than a placebo (Zhou et al., 2015). Side effects are significantly more pronounced with antipsychotics. Typical antipsychotics used in augmentation for depression include aripiprazole and quetiapine. Other augmentation strategies include combining an SSRI and TCA, adding triiodothyronine, buspirone, lithium, methylphenidate (Ritalin®), esketamine nasal spray, or dextroamphetamine (Dexedrine®) to an antidepressant (Halverson, 2020).

The majority of cases of depression are managed in primary care. Some situations require the help of a psychiatrist. Primary care doctors and psychiatrists should ensure adequate patient treatment, especially medically complex ones. The psychiatrist should be consulted when there are:

• Suicidal ideation
• Mania
• Severe depression
• Resistant depression
• Psychosis
• ECT is being considered

A psychologist is a valuable part of the team to help maximize depression therapy. Consultation with a psychologist is helpful when:

• Psychotherapy is being considered
• Specialized testing is desired

Depression is a prevalent, disabling disease. Healthcare professionals need to evaluate for depression using some of the many screening tools. In addition, treatment options should be understood and discussed with patients. A significant role is to encourage patients to discuss depression with their primary healthcare provider.

• AHRQ. US Preventive Services Task Force. Agency for Healthcare Research and Quality. (2016, January 26) Screening for depression in adults. Final Recommendation Statement: Depression in Adults: Screening | United States Preventive Services Taskforce (uspreventiveservicestaskforce.org).
• American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Visit Source.
• Bais, B., Hoogendijk, W., & Lambregtse-van den Berg, M. P. (2021). Light therapy for mood disorders. Handbook of Clinical Neurology, 182, 49–61. Visit Source.
• Blackburn T. P. (2019). Depressive disorders: Treatment failures and poor prognosis over the last 50 years. Pharmacology Research & Perspectives, 7(3), e00472. Visit Source.
• CDC National Center for Health Statistics. (March 25, 2022). Center for Disease Control. Depression. FastStats - Depression (cdc.gov).
• Center for Disease Control and Prevention. (2022, April 6). Suicide Prevention. Visit Source.
• Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Leucht, S., Ruhe, H. G., Turner, E. H., Higgins, J., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J., & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet (London, England), 391(10128), 1357–1366. Visit Source.
• Fischer Fumeaux, C. J., Morisod Harari, M., Weisskopf, E., Eap, C. B., Epiney, M., Vial, Y., Csajka, C., Bickle Graz, M., & Panchaud, A. (2019). Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence - an update. Expert Opinion on Drug Safety, 18(10), 949–963. Visit Source.
• Forman-Hoffman, V., McClure, E., McKeeman, J., Wood, C. T., Middleton, J. C., Skinner, A. C., Perrin, E. M., & Viswanathan, M. (2016). Screening for Major Depressive Disorder in Children and Adolescents: A Systematic Review for the US Preventive Services Task Force. Annals of Internal Medicine, 164(5), 342–349. Visit Source.
• Forsdike, K., & Pirotta, M. (2019). St John's wort for depression: scoping review about perceptions and use by general practitioners in clinical practice. The Journal of Pharmacy and Pharmacology, 71(1), 117–128. Visit Source.
• Gautam, S., Jain, A., Gautam, M., Vahia, V. N., & Grover, S. (2017). Clinical Practice Guidelines for the management of depression. Indian Journal of Psychiatry, 59(Suppl 1), S34–S50. Visit Source.
• Geng, C., Shaikh, A. S., Han, W., Chen, D., Guo, Y., & Jiang, P. (2019). Vitamin D and depression: mechanisms, determination and application. Asia Pacific Journal of Clinical Nutrition, 28(4), 689–694. Visit Source.
• Halverson, J. L.  (2020, August 5). Depression. Visit Source.
• Hazell P. (2021). Updates in treatment of depression in children and adolescents. Current Opinion in Psychiatry, 34(6), 593–599. Visit Source.
• Hermida, A. P., Glass, O. M., Shafi, H., & McDonald, W. M. (2018). Electroconvulsive Therapy in Depression: Current Practice and Future Direction. The Psychiatric Clinics of North America, 41(3), 341–353. Visit Source.
• Jantaratnotai, N., Mosikanon, K., Lee, Y., & McIntyre, R. S. (2017). The interface of depression and obesity. Obesity Research & Clinical Practice, 11(1), 1–10. Visit Source.
• Jia, Y., Wang, X., & Cheng, Y. (2020). Relaxation Therapy for Depression: An Updated Meta-analysis. The Journal of Nervous and Mental Disease, 208(4), 319–328. Visit Source.
• Kang, H. J., Kim, K. T., Yoo, K. H., Park, Y., Kim, J. W., Kim, S. W., Shin, I. S., Kim, J. H., & Kim, J. M. (2020). Genetic Markers for Later Remission in Response to Early Improvement of Antidepressants. International Journal of Molecular Sciences, 21(14), 4884. Visit Source.
• Karyotaki, E., Efthimiou, O., Miguel, C., Bermpohl, F., Furukawa, T. A., Cuijpers, P., Individual Patient Data Meta-Analyses for Depression (IPDMA-DE) Collaboration, Riper, H., Patel, V., Mira, A., Gemmil, A. W., Yeung, A. S., Lange, A., Williams, A. D., Mackinnon, A., Geraedts, A., van Straten, A., Meyer, B., Björkelund, C., Knaevelsrud, C., … Forsell, Y. (2021). Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis. JAMA Psychiatry, 78(4), 361–371. Visit Source.
• Kellner, C., 2022. Overview of electroconvulsive therapy (ECT) for adults. Uptodate.com. Visit Source.
• Long J. D. (2019). Vortioxetine for Depression in Adults. Issues in Mental Health Nursing, 40(9), 819–820. Visit Source.
• Malhi, G. S., & Mann, J. J. (2018). Depression. Lancet (London, England), 392(10161), 2299–2312. Visit Source.
• McCarron, R. M., Shapiro, B., Rawles, J., & Luo, J. (2021). Depression. Annals of Internal Medicine, 174(5), ITC65–ITC80. Visit Source.
• McHugh, R. K., & Weiss, R. D. (2019). Alcohol Use Disorder and Depressive Disorders. Alcohol Research: Current Reviews, 40(1), arcr.v40.1.01. Visit Source.
• Mikkelsen, K., Stojanovska, L., & Apostolopoulos, V. (2016). The Effects of Vitamin B in Depression. Current Medicinal Chemistry, 23(38), 4317–4337. Visit Source.
• National Institute of Health. (June 18, 2020). Depression: How effective are antidepressants?Visit Source.
• National Institute of Mental Health. (n.d.). Substance Use and Co-Occurring Mental Disorders. Visit Source.
• National Institute of Mental Health. (2022). Major Depression. Visit Source.
• Ng, Q. X., Venkatanarayanan, N., & Ho, C. Y. (2017). Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis. Journal of Affective Disorders, 210, 211–221. Visit Source.
• Ng, Q. X., Venkatanarayanan, N., Ho, C., Sim, W. S., Lim, D. Y., & Yeo, W. S. (2019). Selective Serotonin Reuptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn: An Updated Meta-Analysis. Journal of Women's Health (2002), 28(3), 331–338. Visit Source.
• Rush, A.J, 2022. Unipolar major depression in adults: Choosing initial treatment. [online] Uptodate.com. Visit Source.
• Sáiz-Vázquez, O., Gracia-García, P., Ubillos-Landa, S., Puente-Martínez, A., Casado-Yusta, S., Olaya, B., & Santabárbara, J. (2021). Depression as a Risk Factor for Alzheimer's Disease: A Systematic Review of Longitudinal Meta-Analyses. Journal of Clinical Medicine, 10(9), 1809. Visit Source.
• Schwasinger-Schmidt, T. E., & Macaluso, M. (2019). Other Antidepressants. Handbook of Experimental Pharmacology, 250, 325–355. Visit Source.
• Thom, R., Silbersweig, D. A., & Boland, R. J. (2019). Major Depressive Disorder in Medical Illness: A Review of Assessment, Prevalence, and Treatment Options. Psychosomatic Medicine, 81(3), 246–255. Visit Source.
• Viguera, A., 2021. Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis. [online] Uptodate.com. Visit Source.
• Wang, J., Um, P., Dickerman, B. A., & Liu, J. (2018). Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications. Nutrients, 10(5), 584. Visit Source.
• Wani, A. L., Bhat, S. A., & Ara, A. (2015). Omega-3 fatty acids and the treatment of depression: a review of scientific evidence. Integrative Medicine Research, 4(3), 132–141. Visit Source.
• Williams, J. and Nieuwsma, J., 2022. Screening for depression in adults. [online] Uptodate.com. Visit Source.
• Yonkers, K. A., Wisner, K. L., Stewart, D. E., Oberlander, T. F., Dell, D. L., Stotland, N., Ramin, S., Chaudron, L., & Lockwood, C. (2009). The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstetrics and Gynecology, 114(3), 703–713. Visit Source.
• Zhang, Y., Chen, Y., & Ma, L. (2018). Depression and cardiovascular disease in elderly: Current understanding. Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia, 47, 1–5. Visit Source.
• Zhou, X., Keitner, G. I., Qin, B., Ravindran, A. V., Bauer, M., Del Giovane, C., Zhao, J., Liu, Y., Fang, Y., Zhang, Y., & Xie, P. (2015). Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis. The International Journal of Neuropsychopharmacology, 18(11), pyv060. Visit Source.