Metabolic pathway

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Metabolic_pathway 

In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. In most cases of a metabolic pathway, the product of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell.

Different metabolic pathways function in the position within a eukaryotic cell and the significance of the pathway in the given compartment of the cell. For instance, the electron transport chain and oxidative phosphorylation all take place in the mitochondrial membrane. In contrast, glycolysis, pentose phosphate pathway, and fatty acid biosynthesis all occur in the cytosol of a cell.

There are two types of metabolic pathways that are characterized by their ability to either synthesize molecules with the utilization of energy (anabolic pathway), or break down complex molecules and release energy in the process (catabolic pathway).

The two pathways complement each other in that the energy released from one is used up by the other. The degradative process of a catabolic pathway provides the energy required to conduct the biosynthesis of an anabolic pathway. In addition to the two distinct metabolic pathways is the amphibolic pathway, which can be either catabolic or anabolic based on the need for or the availability of energy.

Pathways are required for the maintenance of homeostasis within an organism and the flux of metabolites through a pathway is regulated depending on the needs of the cell and the availability of the substrate. The end product of a pathway may be used immediately, initiate another metabolic pathway or be stored for later use. The metabolism of a cell consists of an elaborate network of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism).

Overview

Net reactions of common metabolic pathways

Each metabolic pathway consists of a series of biochemical reactions that are connected by their intermediates: the products of one reaction are the substrates for subsequent reactions, and so on. Metabolic pathways are often considered to flow in one direction. Although all chemical reactions are technically reversible, conditions in the cell are often such that it is thermodynamically more favorable for flux to proceed in one direction of a reaction. For example, one pathway may be responsible for the synthesis of a particular amino acid, but the breakdown of that amino acid may occur via a separate and distinct pathway. One example of an exception to this "rule" is the metabolism of glucose. Glycolysis results in the breakdown of glucose, but several reactions in the glycolysis pathway are reversible and participate in the re-synthesis of glucose (gluconeogenesis).

• Glycolysis was the first metabolic pathway discovered:

1. As glucose enters a cell, it is immediately phosphorylated by ATP to glucose 6-phosphate in the irreversible first step.
2. In times of excess lipid or protein energy sources, certain reactions in the glycolysis pathway may run in reverse to produce glucose 6-phosphate, which is then used for storage as glycogen or starch.

• Metabolic pathways are often regulated by feedback inhibition.
• Some metabolic pathways flow in a 'cycle' wherein each component of the cycle is a substrate for the subsequent reaction in the cycle, such as in the Krebs Cycle (see below).
• Anabolic and catabolic pathways in eukaryotes often occur independently of each other, separated either physically by compartmentalization within organelles or separated biochemically by the requirement of different enzymes and co-factors.

Major metabolic pathways

For additional infographics of major metabolic pathways, see § External links.

Carbon fixation Photo- respiration Pentose phosphate pathway Citric acid cycle Glyoxylate cycle Urea cycle Fatty acid synthesis Fatty acid elongation Beta oxidation Peroxisomal beta oxidation Glyco- genolysis Glyco- genesis Glyco- lysis Gluconeo- genesis Pyruvate decarb- oxylation Fermentation Keto- lysis Keto- genesis feeders to gluconeo- genesis Direct / C4 / CAM carbon intake Light reaction Oxidative phosphorylation Amino acid deamination Citrate shuttle Lipogenesis Lipolysis Steroidogenesis MVA pathway MEP pathway Shikimate pathway Transcription & replication Translation Proteolysis Glycosyl- ation Sugar acids Double/multiple sugars & glycans Simple sugars Inositol-P Amino sugars & sialic acids Nucleotide sugars Hexose-P Triose-P Glycerol P-glycerates Pentose-P Tetrose-P Propionyl -CoA Succinate Acetyl -CoA Pentose-P P-glycerates Glyoxylate Photosystems Pyruvate Lactate Acetyl -CoA Citrate Oxalo- acetate Malate Succinyl -CoA α-Keto- glutarate Ketone bodies Respiratory chain Serine group Alanine Branched-chain amino acids Aspartate group Homoserine group & lysine Glutamate group & proline Arginine Creatine & polyamines Ketogenic & glucogenic amino acids Amino acids Shikimate Aromatic amino acids & histidine Ascorbate (vitamin C) δ-ALA Bile pigments Hemes Cobalamins (vitamin B12) Various vitamin Bs Calciferols (vitamin D) Retinoids (vitamin A) Quinones (vitamin K) & tocopherols (vitamin E) Cofactors Vitamins & minerals Antioxidants PRPP Nucleotides Nucleic acids Proteins Glycoproteins & proteoglycans Chlorophylls MEP MVA Acetyl -CoA Polyketides Terpenoid backbones Terpenoids & carotenoids (vitamin A) Cholesterol Bile acids Glycero- phospholipids Glycerolipids Acyl-CoA Fatty acids Glyco- sphingolipids Sphingolipids Waxes Polyunsaturated fatty acids Neurotransmitters & thyroid hormones Steroids Endo- cannabinoids Eicosanoids Major metabolic pathways in metro-style map.   Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes). Orange nodes: carbohydrate metabolism. Violet nodes: photosynthesis. Red nodes: cellular respiration. Pink nodes: cell signaling. Blue nodes: amino acid metabolism. Grey nodes: vitamin and cofactor metabolism. Brown nodes: nucleotide and protein metabolism. Green nodes: lipid metabolism.

Catabolic pathway (catabolism)

A catabolic pathway is a series of reactions that bring about a net release of energy in the form of a high energy phosphate bond formed with the energy carriers adenosine diphosphate (ADP) and guanosine diphosphate (GDP) to produce adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively. The net reaction is, therefore, thermodynamically favorable, for it results in a lower free energy for the final products. A catabolic pathway is an exergonic system that produces chemical energy in the form of ATP, GTP, NADH, NADPH, FADH2, etc. from energy containing sources such as carbohydrates, fats, and proteins. The end products are often carbon dioxide, water, and ammonia. Coupled with an endergonic reaction of anabolism, the cell can synthesize new macromolecules using the original precursors of the anabolic pathway. An example of a coupled reaction is the phosphorylation of fructose-6-phosphate to form the intermediate fructose-1,6-bisphosphate by the enzyme phosphofructokinase accompanied by the hydrolysis of ATP in the pathway of glycolysis. The resulting chemical reaction within the metabolic pathway is highly thermodynamically favorable and, as a result, irreversible in the cell.

${\displaystyle \text{Fructose}-6-\text{Phosphate}+\text{ATP}⟶\text{Fructose}-1,6-\text{Bisphosphate}+\text{ADP}}$

Cellular respiration

Main article: Cellular respiration

A core set of energy-producing catabolic pathways occur within all living organisms in some form. These pathways transfer the energy released by breakdown of nutrients into ATP and other small molecules used for energy (e.g. GTP, NADPH, FADH₂). All cells can perform anaerobic respiration by glycolysis. Additionally, most organisms can perform more efficient aerobic respiration through the citric acid cycle and oxidative phosphorylation. Additionally plants, algae and cyanobacteria are able to use sunlight to anabolically synthesize compounds from non-living matter by photosynthesis.

Gluconeogenesis mechanism

Anabolic pathway (anabolism)

In contrast to catabolic pathways, anabolic pathways require an energy input to construct macromolecules such as polypeptides, nucleic acids, proteins, polysaccharides, and lipids. The isolated reaction of anabolism is unfavorable in a cell due to a positive Gibbs free energy (+ΔG). Thus, an input of chemical energy through a coupling with an exergonic reaction is necessary. The coupled reaction of the catabolic pathway affects the thermodynamics of the reaction by lowering the overall activation energy of an anabolic pathway and allowing the reaction to take place. Otherwise, an endergonic reaction is non-spontaneous.

An anabolic pathway is a biosynthetic pathway, meaning that it combines smaller molecules to form larger and more complex ones. An example is the reversed pathway of glycolysis, otherwise known as gluconeogenesis, which occurs in the liver and sometimes in the kidney to maintain proper glucose concentration in the blood and supply the brain and muscle tissues with adequate amount of glucose. Although gluconeogenesis is similar to the reverse pathway of glycolysis, it contains four distinct enzymes(pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose 6-phosphatase) from glycolysis that allow the pathway to occur spontaneously.

Amphibolic pathway (Amphibolism)

Amphibolic properties of the citric acid cycle

An amphibolic pathway is one that can be either catabolic or anabolic based on the availability of or the need for energy. The currency of energy in a biological cell is adenosine triphosphate (ATP), which stores its energy in the phosphoanhydride bonds. The energy is utilized to conduct biosynthesis, facilitate movement, and regulate active transport inside of the cell. Examples of amphibolic pathways are the citric acid cycle and the glyoxylate cycle. These sets of chemical reactions contain both energy producing and utilizing pathways. To the right is an illustration of the amphibolic properties of the TCA cycle.

The glyoxylate shunt pathway is an alternative to the tricarboxylic acid (TCA) cycle, for it redirects the pathway of TCA to prevent full oxidation of carbon compounds, and to preserve high energy carbon sources as future energy sources. This pathway occurs only in plants and bacteria and transpires in the absence of glucose molecules.

Regulation

The flux of the entire pathway is regulated by the rate-determining steps. These are the slowest steps in a network of reactions. The rate-limiting step occurs near the beginning of the pathway and is regulated by feedback inhibition, which ultimately controls the overall rate of the pathway. The metabolic pathway in the cell is regulated by covalent or non-covalent modifications. A covalent modification involves an addition or removal of a chemical bond, whereas a non-covalent modification (also known as allosteric regulation) is the binding of the regulator to the enzyme via hydrogen bonds, electrostatic interactions, and Van der Waals forces.

The rate of turnover in a metabolic pathway, also known as the metabolic flux, is regulated based on the stoichiometric reaction model, the utilization rate of metabolites, and the translocation pace of molecules across the lipid bilayer. The regulation methods are based on experiments involving 13C-labeling, which is then analyzed by nuclear magnetic resonance (NMR) or gas chromatography–mass spectrometry (GC–MS)–derived mass compositions. The aforementioned techniques synthesize a statistical interpretation of mass distribution in proteinogenic amino acids to the catalytic activities of enzymes in a cell.

Clinical applications in targeting metabolic pathways

Targeting oxidative phosphorylation

Metabolic pathways can be targeted for clinically therapeutic uses. Within the mitochondrial metabolic network, for instance, there are various pathways that can be targeted by compounds to prevent cancer cell proliferation. One such pathway is oxidative phosphorylation (OXPHOS) within the electron transport chain (ETC). Various inhibitors can downregulate the electrochemical reactions that take place at Complex I, II, III, and IV, thereby preventing the formation of an electrochemical gradient and downregulating the movement of electrons through the ETC. The substrate-level phosphorylation that occurs at ATP synthase can also be directly inhibited, preventing the formation of ATP that is necessary to supply energy for cancer cell proliferation. Some of these inhibitors, such as lonidamine and atovaquone, which inhibit Complex II and Complex III, respectively, are currently undergoing clinical trials for FDA approval. Other non-FDA-approved inhibitors have still shown experimental success in vitro.

Targeting Heme

Heme, an important prosthetic group present in Complexes I, II, and IV can also be targeted, since heme biosynthesis and uptake have been correlated with increased cancer progression. Various molecules can inhibit heme via different mechanisms. For instance, succinylacetone has been shown to decrease heme concentrations by inhibiting δ-aminolevulinic acid in murine erythroleukemia cells. The primary structure of heme-sequestering peptides, such as HSP1 and HSP2, can be modified to downregulate heme concentrations and reduce proliferation of non-small lung cancer cells.

Targeting the tricarboxylic acid cycle and glutaminolysis

The tricarboxylic acid cycle (TCA) and glutaminolysis can also be targeted for cancer treatment, since they are essential for the survival and proliferation of cancer cells. Ivosidenib and enasidenib, two FDA-approved cancer treatments, can arrest the TCA cycle of cancer cells by inhibiting isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2), respectively. Ivosidenib is specific to acute myeloid leukemia (AML) and cholangiocarcinoma, whereas enasidenib is specific to just acute myeloid leukemia (AML).

In a clinical trial consisting of 185 adult patients with cholangiocarcinoma and an IDH-1 mutation, there was a statistically significant improvement (p<0.0001; HR: 0.37) in patients randomized to ivosidenib. Still, some of the adverse side effects in these patients included fatigue, nausea, diarrhea, decreased appetite, ascites, and anemia. In a clinical trial consisting of 199 adult patients with AML and an IDH2 mutation, 23% of patients experienced complete response (CR) or complete response with partial hematologic recovery (CRh) lasting a median of 8.2 months while on enasidenib. Of the 157 patients who required transfusion at the beginning of the trial, 34% no longer required transfusions during the 56-day time period on enasidenib. Of the 42% of patients who did not require transfusions at the beginning of the trial, 76% still did not require a transfusion by the end of the trial. Side effects of enasidenib included nausea, diarrhea, elevated bilirubin and, most notably, differentiation syndrome.

Glutaminase (GLS), the enzyme responsible for converting glutamine to glutamate via hydrolytic deamidation during the first reaction of glutaminolysis, can also be targeted. In recent years, many small molecules, such as azaserine, acivicin, and CB-839 have been shown to inhibit glutaminase, thus reducing cancer cell viability and inducing apoptosis in cancer cells. Due to its effective antitumor ability in several cancer types such as ovarian, breast and lung cancers, CB-839 is the only GLS inhibitor currently undergoing clinical studies for FDA-approval.

Genetic engineering of metabolic pathways

Many metabolic pathways are of commercial interest. For instance, the production of many antibiotics or other drugs requires complex pathways. The pathways to produce such compounds can be transplanted into microbes or other more suitable organism for production purposes. For example, the world's supply of the anti-cancer drug vinblastine is produced by relatively ineffient extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which are then chemically converted into vinblastine. The biosynthetic pathway to produce vinblastine, including 30 enzymatic steps, has been transferred into yeast cells which is a convenient system to grow in large amounts. With these genetic modifications yeast can use its own metabolites geranyl pyrophosphate and tryptophan to produce the precursors of catharanthine and vindoline. This process required 56 genetic edits, including expression of 34 heterologous genes from plants in yeast cells.

Dysthymia

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Dysthymia

 

Dysthymia
Other names	Persistent depressive disorder, dysthymic disorder, chronic depression
Specialty	Psychiatry, clinical psychology
Symptoms	Low mood, low self-esteem, loss of interest in normally enjoyable activities, low energy, pain without a clear cause
Complications	Self-harm, suicide
Usual onset	Early adulthood
Causes	Genetic, environmental, and psychological factors
Risk factors	Family history, major life changes, certain medications, chronic health problems, substance use disorders
Treatment	Counseling, antidepressant medication, electroconvulsive therapy
Frequency	104 million (2015)

Dysthymia (/dɪsˈθaɪmiə/ dihs-THIY-mee-uh), known as persistent depressive disorder (PDD) in the DSM-5-TR and dysthymic disorder in ICD-11, is a psychiatric condition marked by symptoms that are similar to those of major depressive disorder, but which persist for at least two years in adults and one year among pediatric populations. The term was introduced by Robert Spitzer in the late 1970s as a replacement for the concept of "depressive personality."

With the DSM-5's publication in 2013, the condition assumed its current name (i.e., PDD), having been called dysthymic disorder in the DSM's previous edition (DSM-IV), and remaining so in ICD-11. PDD is defined by a 2-year history of symptoms of major depression not better explained by another health condition, as well as significant distress or functional impairment.

Individuals with PDD, defined in part by its chronicity, may experience symptoms for years before receiving a diagnosis, if one is received at all. Consequently, they might perceive their dysphoria as a character or personality trait rather than a distinct medical condition and never discuss their symptoms with healthcare providers. PDD subsumed prior DSM editions' diagnoses of chronic major depressive disorder and dysthymic disorder. The change arose from a continuing lack of evidence of a clinically meaningful distinction between chronic major depression and dysthymic disorder.

Signs and symptoms

Dysthymia is characterized by 2-year history of depressed mood, as well as at least two of the following symptoms: poor appetite or overeating, hypersomnia or insomnia, fatigue or low energy, low self-esteem, poor concentration or difficulty making decisions, and hopelessness. Irritability, rather than sadness, may predominate in the pediatric setting.

Mild degrees of dysthymia may result in withdrawal from stress-inducing activities and avoidance of opportunities for failure. In more severe cases of dysthymia, the patient may withdraw from daily activities. They will usually find little pleasure in usual activities and pastimes, a symptom of depression known as anhedonia.

Diagnosis of dysthymia can be difficult because of the subtle nature of the symptoms and patients can often hide them in social situations, making it challenging for others to detect symptoms. Additionally, dysthymia is often comorbid with other psychological conditions, adding complexity to dysthmia recognition due to overlapping symptoms. Dysthymia is frequently comorbid with anxiety disorders, substance use disorders, and personality disorders, and suicidal ideation is common.

Causes

There are no known biological causes that apply consistently to all cases of dysthymia, which suggests diverse origin of the disorder. However, there are some indications that there is a genetic predisposition to dysthymia: "The rate of depression in the families of people with dysthymia is as high as fifty percent for the early-onset form of the disorder." More recent studies have indicated that the frequency of dysthymia is likely influenced more heavily by "family environmental and non-shared environmental factors," rather than genetic or neurobiological factors. Part of the reason for the uncertainty with regard to understanding the biological basis of dysthymia is due to the lack of genetic and neurobiological research, genome wide studies, and "grossly underpowered sample sizes." Other factors linked with dysthymia include stress, social isolation, and lack of social support.

In a 1998 study using identical and fraternal twins, results indicated that there was not a stronger likelihood of identical twins both having dysthymia than fraternal twins. This provides support for the idea that dysthymia does not have a consistent genetic basis.

Co-occurring conditions

Dysthymia often co-occurs with other mental disorders. A "double depression" is the occurrence of episodes of major depression in addition to dysthymia. Switching between periods of dysthymic moods and periods of hypomanic moods is indicative of cyclothymia, which is a mild variant of bipolar disorder.

"At least three-quarters of patients with dysthymia also have a chronic physical illness or another psychiatric disorder such as one of the anxiety disorders, cyclothymia, drug addiction, or alcoholism". Common co-occurring conditions include major depression (up to 75%), anxiety disorders (up to 50%), personality disorders (up to 40%), somatoform disorders (up to 45%) and substance use disorders (up to 50%). People with dysthymia have a higher-than-average chance of developing major depression. A 10-year follow-up study found that 95% of dysthymia patients had an episode of major depression. When an intense episode of depression occurs on top of dysthymia, the state is called "double depression."

Double depression

Main article: Double depression

Double depression occurs when a person experiences a major depressive episode on top of the already-existing condition of dysthymia. It is difficult to treat, as patients accept these major depressive symptoms as a natural part of their personality or as a part of their life that is outside of their control. The fact that people with dysthymia may accept these worsening symptoms as inevitable can delay treatment. When and if such people seek out treatment, the treatment may not be very effective if only the symptoms of the major depression are addressed, but not the dysthymic symptoms.

Patients with double depression tend to report significantly higher levels of hopelessness than is normal. This can be a useful symptom for mental health services providers to focus on when working with patients to treat the condition. Additionally, cognitive therapies can be effective for working with people with double depression in order to help change negative thinking patterns and give individuals a new way of seeing themselves and their environment.

It has been suggested that the best way to prevent double depression is by treating the dysthymia. A combination of antidepressants and cognitive therapies can be helpful in preventing major depressive symptoms from occurring. Additionally, exercise and good sleep hygiene (e.g., improving sleep patterns) are thought to have an additive effect on treating dysthymic symptoms and preventing them from worsening.

Pathophysiology

There is evidence that there may be neurological indicators of early onset dysthymia. There are several brain structures (corpus callosum and frontal lobe) that are different in women with dysthymia than in those without dysthymia. This may indicate that there is a developmental difference between these two groups.

Another study, which used fMRI techniques to assess the differences between individuals with dysthymia and other people, found additional support for neurological indicators of the disorder. This study found several areas of the brain that function differently. The amygdala (associated with processing emotions such as fear) was more activated in dysthymia patients. The study also observed increased activity in the insula (which is associated with sad emotions). Finally, there was increased activity in the cingulate gyrus (which serves as the bridge between attention and emotion).

A study comparing healthy individuals to people with dysthymia indicates there are other biological indicators of the disorder. An anticipated result appeared as healthy individuals expected fewer negative adjectives to apply to them, whereas people with dysthymia expected fewer positive adjectives to apply to them in the future. Biologically these groups are also differentiated in that healthy individuals showed greater neurological anticipation for all types of events (positive, neutral, or negative) than those with dysthymia. This provides neurological evidence of the dulling of emotion that individuals with dysthymia have learned to use to protect themselves from overly strong negative feelings, compared to healthy people.

There is some evidence of a genetic basis for all types of depression, including dysthymia. A study using identical and fraternal twins indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is caused in part by heredity.

A new model has recently surfaced in the literature regarding the HPA axis (structures in the brain that get activated in response to stress) and its involvement with dysthymia (e.g. phenotypic variations of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), and down-regulation of adrenal functioning) as well as forebrain serotonergic mechanisms. Since this model is highly provisional, further research is still needed.

Diagnosis

The Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), published by the American Psychiatric Association, characterizes dysthymic disorder. The essential symptom involves the individual feeling depressed for the majority of days, and parts of the day, for at least two years. Low energy, disturbances in sleep or in appetite, and low self-esteem typically contribute to the clinical picture as well. Those with the condition have often experienced dysthymia for many years before it is diagnosed. People around them often describe them in words similar to "just a moody person". The following are the diagnostic criteria:

• During a majority of days for two years or more, the adult patient reports depressed mood, or appears depressed to others for most of the day.
• When depressed, the patient has two or more of:
  • decreased or increased appetite;
  • decreased or increased sleep (insomnia or hypersomnia);
  • fatigue or low energy;
  • reduced self-esteem;
  • decreased concentration or problems making decisions;
  • feelings of hopelessness or pessimism.
• During this two-year period, the above symptoms are never absent longer than two consecutive months.
• During the duration of the two-year period, the patient may have had a perpetual major depressive episode.
• The patient has not had any manic, hypomanic, or mixed episodes.
• The patient has never fulfilled criteria for cyclothymic disorder.
• The depression does not exist only as part of a chronic psychosis (such as schizophrenia or delusional disorder).
• The symptoms are often not directly caused by a medical illness or by substances, including substance use or other medications.
• The symptoms may cause significant problems or distress in social, work, academic, or other major areas of life functioning.

In children and adolescents, mood can be irritable, and duration must be at least one year, in contrast to two years needed for diagnosis in adults.

Early onset (diagnosis before age 21) is associated with more frequent relapses, psychiatric hospitalizations, and more co-occurring conditions. For younger adults with dysthymia, there is a higher co-occurrence in personality abnormalities and the symptoms are likely chronic. However, in older adults with dysthymia, the psychological symptoms are associated with medical conditions and/or stressful life events and losses.

Dysthymia can be contrasted with major depressive disorder by assessing the acute nature of the symptoms. Dysthymia is far more chronic (long lasting) than major depressive disorder, in which symptoms may be present for as little as two weeks. Also dysthymia often presents itself at an earlier age than major depressive disorder.

Prevention

Though there is no clear-cut way to prevent dysthymia from occurring, there are some suggestions to help reduce its effects. Since dysthymia often appears first in childhood, it is important to identify children who may be at risk. It may be beneficial to work with children in helping to control their stress, increase resilience, boost self-esteem, and provide strong social support networks. These tactics may be helpful in warding off or delaying dysthymic symptoms.

Treatments

Main article: Management of depression

Persistent depressive disorder can be treated with psychotherapy and pharmacotherapy. The overall rate and degree of treatment success is somewhat lower than for non-chronic depression, and a combination of psychotherapy and pharmacotherapy shows best results.

Therapy

Psychotherapy can be effective in treating dysthymia. In a meta-analytic study from 2010, psychotherapy had a small but significant effect when compared to control groups. However, psychotherapy is significantly less effective than pharmacotherapy in direct comparisons.

There are many different types of therapy, and some are more effective than others.

• The empirically most studied type of treatment is cognitive-behavioral therapy. This type of therapy is very effective for non-chronic depression, and it appears to be also effective for chronic depression.
• Cognitive behavioral analysis system of psychotherapy (CBASP) has been designed specifically to treat PDD. Empirical results on this form of therapy are inconclusive: While one study showed remarkably high treatment success rates, a later, even larger study showed no significant benefit of adding CBASP to treatment with antidepressants.
• Schema therapy and psychodynamic psychotherapy have been used for PDD, though good empirical results are lacking.
• Interpersonal psychotherapy has also been said to be effective in treating the disorder, though it only shows marginal benefit when added to treatment with antidepressants.

Medications

In a 2010 meta-analysis, the benefit of pharmacotherapy was limited to selective serotonin reuptake inhibitors (SSRIs) rather than tricyclic antidepressants (TCA).

According to a 2014 meta-analysis, antidepressants are at least as effective for persistent depressive disorder as for major depressive disorder. The first line of pharmacotherapy is usually SSRIs due to their purported more tolerable nature and reduced side effects compared to the irreversible monoamine oxidase inhibitors or tricyclic antidepressants. Studies have found that the mean response to antidepressant medications for people with dysthymia is 55%, compared with a 31% response rate to a placebo. The most commonly prescribed antidepressants/SSRIs for dysthymia are escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine. It often takes an average of 6–8 weeks before the patient begins to feel these medications' therapeutic effects. Additionally, STAR*D, a multi-clinic governmental study, found that people with overall depression will generally need to try different brands of medication before finding one that works specifically for them. Research shows that 1 in 4 of those who switch medications get better results regardless of whether the second medication is an SSRI or some other type of antidepressant.

In a meta-analytic study from 2005, it was found that SSRIs and TCAs are equally effective in treating dysthymia. They also found that MAOIs have a slight advantage over the use of other medication in treating this disorder. However, the author of this study cautions that MAOIs should not necessarily be the first line of defense in the treatment of dysthymia, as they are often less tolerable than their counterparts, such as SSRIs.

Tentative evidence supports the use of amisulpride to treat dysthymia but with increased side effects.

Combination treatment

When pharmacotherapy alone is compared with combined treatment with pharmacotherapy plus psychotherapy, there is a strong trend in favour of combined treatment. Working with a psychotherapist to address the causes and effects of the disorder, in addition to taking antidepressants to help eliminate the symptoms, can be extremely beneficial. This combination is often the preferred method of treatment for those who have dysthymia. Looking at various studies involving treatment for dysthymia, 75% of people responded positively to a combination of cognitive behavioral therapy (CBT) and pharmacotherapy, whereas only 48% of people responded positively to just CBT or medication alone.

A 2019 Cochrane review of 10 studies involving 840 participants could not conclude with certainty that continued pharmacotherapy with antidepressants (those used in the studies) was effective in preventing relapse or recurrence of persistent depressive disorder. The body of evidence was too small for any greater certainty although the study acknowledges that continued psychotherapy may be beneficial when compared to no treatment.

Treatment resistance

Because of dysthymia's chronic nature, treatment resistance is somewhat common. In such a case, augmentation is often recommended. Such treatment augmentations can include lithium pharmacology, thyroid hormone augmentation, amisulpride, buspirone, bupropion, guanfacine, stimulants, and mirtazapine. Additionally, if the person also has seasonal affective disorder, light therapy can be useful in helping augment therapeutic effects.

Epidemiology

Globally, the one-year incidence is about 105 million people (1.53% of the global population). As of 2012, research suggests incidence rates of 1.8% for women and 1.3% for men. In the U.S. general population, research suggests a lifetime prevalence rate of 3 to 6 percent. In primary care settings the lifetime prevalence rate is 5 to 15 percent.