Current research suggests that depression is the product of the interaction of multiple predisposition genes and environmental factors. Depression is not only a chronic, relapsing disorder, but may also be a progressive disorder in which sustained functional changes within the brain prompt corresponding structural changes as well. Depression is associated not only with altered neural circuits in the brain, but also with changes in endocrine, immune, and autonomic functions. Depression may not be a simple syndrome, but a complex group of disorders involving alterations at different levels of the brain and the soma, thus increasing the difficulty of treatment. We will take a holistic and integrated view of depression in terms of both what prevents depressed patients from getting better treatment, and how to treat it successfully. I. Reasons preventing depressed patients from getting better treatment outcomes 1. Residual symptoms: The ideal treatment goal for depressed patients is to achieve clinical cure and functional recovery, but the current treatment outcomes for depression are not ideal. The Sequential Treatment of Depression (STAR*D) study showed that after 12 weeks of antidepressant treatment, only 1/3 of patients achieved clinical cure using the Rapid Inventory of Self-Rated Depressive Symptoms assessment, and 2/3 of patients still had mild, moderate, or severe residual symptoms of depression. Residual symptoms include sleep disturbances, sad mood, problems with appetite or body mass, difficulty concentrating, low energy, fatigue, and suicidal ideation. the STAR*D study showed that residual symptoms are one of the reasons for the suboptimal treatment outcome of depressed patients. Other studies have shown that the higher the number of residual symptoms, the greater the cumulative probability of relapse. 2. Number of previous episodes: Treatment outcome is not only related to residual symptoms, but also to the number of previous depressive episodes. The higher the number of residual symptoms and previous depressive episodes, the worse the final treatment outcome. Usually, people think that clinical cure is equal to recovery. However, clinical cure is not the same as complete absence of symptoms. A 3-year prospective study of 267 patients in primary care settings showed that common symptoms during depressive episodes included cognitive problems (94%), lack of energy (90%), and sleep problems (85%); during depressive episodes, symptoms did not completely disappear for some clinically cured patients, and the most common symptoms were still cognitive problems (44%), lack of energy (35%), and sleep problems (5%). percent) and sleep problems (39 percent). Such cognitive problems can be improved by antidepressant treatment. Another study showed that even in patients who achieved a complete clinical cure, an average of 2 residual symptoms remained. It can be seen that the complete elimination of depressive symptoms should be the goal for which doctors strive. 3. somatic symptoms and individual differences: antidepressants are not equally effective in treating somatic symptoms of depression. a clinical trial of SSRIs by Greco et al. showed that the efficacy of different drugs in treating patients’ somatic symptoms varied during the first 4 weeks of treatment, while the efficacy was similar after 4 weeks. This suggests that physicians should actively treat patients’ somatic symptoms during the initial 4 weeks of treatment to prevent the persistence of somatic symptoms from affecting patients’ confidence in treatment. In addition, individual differences in patient response to antidepressants are significant. power et al. treated depressed patients with antidepressants for 12 weeks and classified the homogeneity of the patients using a mixed model of growth. The results showed that it was transiently effective in 1%, ineffective in 16%, effective in 73% and significantly effective in 10%. It is evident that individual differences in the treatment of depressed patients are significant, suggesting that depression has complex pathophysiological mechanisms. Second, how to define the successful treatment of depression After effective treatment, depressed patients may have a series of pathophysiological changes from microscopic to macroscopic. 1. Changes at the cellular and subcellular levels: The major monoamine neurotransmitter pathways in the brain include the norepinephrine (NE), 5-HT and dopamine pathways, which are distributed in cortical and subcortical brain regions. The neurotransmitters work together to assist in the physiological functions of the monoamine transmitter system. 2. Changes in neuroendocrine, autonomic and immune system dysregulation: Several Meta-analyses have shown that depression is associated with increased inflammatory responses, such as increased interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α in depressed patients. After effective treatment with depressants, the inflammatory response can be reduced. o’Brien et al. showed that when normal mood was achieved with antidepressant treatment, TNF-α and IL-6 levels decreased in depressed patients and were comparable to the levels in controls. In addition, antidepressant treatment has an effect on sympathetic nerve activity in depressed patients. For example, Barton et al. showed that in the resting state, norepinephrine release was low in some depressed patients (below the median of 352 ng/min) and high in others (above the median of 325 ng/min). After 12 weeks of treatment with SSRIs, NE release decreased in the high-release group, while the low-release group showed no statistically significant pre- and post-treatment differences, suggesting that antidepressant treatment can reduce sympathetic activity in patients with high levels of NE. 3. structural changes in the associated affected brain regions: delayed treatment may lead to a decrease in hippocampal volume. arnone et al. showed that the duration of untreated depressive symptoms was associated with a decrease in gray matter volume in the hippocampus bilaterally. And changes in hippocampal volume were predictive of subsequent treatment effects. a 3-year follow-up study of hospitalized depressed patients by Frodl et al. showed that patients with reduced hippocampal volume at admission had poorer efficacy of antidepressant treatment; whereas patients with normal hippocampal volume at admission had better efficacy of antidepressants. Third, factors affecting the successful treatment of depression 1. Delayed treatment can affect the treatment outcome of depression: Altamura et al. conducted a 4-year follow-up of patients with depression. They divided the patients into 2 groups, one with untreated time ≤ 12 months and the other with DUI > 12 months. the DUI is the time interval from the first depressive episode to the 1st treatment with appropriate antidepressants. The results of the study showed that during the 4-year follow-up observation period, the number of relapses was significantly higher in patients with DUI > 12 months than in those with DUI ≤ 12 months. It is evident that the longer the duration of untreated depression, the more likely the depressed patients are to relapse. It suggests that depressed patients should be given appropriate treatment as soon as they are identified. 2. Patient treatment preference can predict treatment outcome: A large multicenter study by Kocsis et al. on nefazodone pharmacotherapy, cognitive behavioral psychotherapy, and a combination of 2 treatment modalities in 429 depressed patients showed that patient preference strongly predicted outcome after 12 weeks of treatment. Patients have better outcomes if they are randomly assigned to their preferred treatment modality group. If patients preferred medication and were randomly assigned to the medication group, they had a clinical cure rate of 45,5% after 12 weeks. Conversely, if patients preferred medication but were assigned to the psychotherapy group, the clinical cure rate was only 7.7%. If patients preferred psychotherapy and were assigned to the psychotherapy group, the clinical cure rate was as high as 50%. Conversely, if patients preferred psychotherapy but were assigned to the medication group, the clinical cure rate was only 22.2%. This suggests that the successful treatment of depressed patients depends not only on the physician but also on the patient’s treatment preference. 3. risk of not obtaining clinical cure: studies have shown that depressed patients who do not obtain clinical cure will result in increased co-morbidity, decreased quality of life, increased residual symptoms, increased risk of relapse, decreased gray matter volume, and impaired social functioning. thase et al. observed 12 months of follow-up after the end of cognitive-behavioral therapy for depressed patients and showed that the risk of relapse in patients who achieved clinical cure was significantly Romera et al. studied the importance of achieving clinical cure in depressed patients using the Social and Occupational Functioning Rating Scale and showed that the functional status of partially clinically cured patients was lower than that of fully clinically cured patients, whether at baseline, 3 months, or 6 months. In summary, understanding the factors associated with success or failure in the treatment of depression may contribute to early and effective improvement of clinical symptoms of depression eliminating residual symptoms, achieving clinical cure, minimizing the risk of future structural changes in the brain, and correcting impaired neuroendocrine, neuroimmune, and autonomic functions involved. Thus, it may facilitate the functional recovery of depressed patients and reduce the risk of relapse.