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Wednesday, December 26, 2018

Management of depression

From Wikipedia, the free encyclopedia

Management of depression may involve a number of different therapies: medications, behavior therapy, and medical devices. Major depressive disorder, often referred to simply as "depression", is diagnosed more frequently in developed countries, where up to 20% of the population is affected at some stage of their lives. According to WHO (World Health Organization), depression is currently fourth among the top 10 leading causes of the global burden of disease; it is predicted that by the year 2020, depression will be ranked second.
 
Though psychiatric medication is the most frequently prescribed therapy for major depression, psychotherapy may be effective, either alone or in combination with medication. Combining psychotherapy and antidepressants may provide a "slight advantage", but antidepressants alone or psychotherapy alone are not significantly different from other treatments, or "active intervention controls". Given an accurate diagnosis of major depressive disorder, in general the type of treatment (psychotherapy and/or antidepressants, alternate or other treatments, or active intervention) is "less important than getting depressed patients involved in an active therapeutic program."

Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. The possibility of depression, substance misuse or other mental health problems in the parents should be considered and, if present and if it may help the child, the parent should be treated in parallel with the child.

Psychotherapy

There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, clinical social workers, counselors or psychiatric nurses. With more chronic forms of depression, the most effective treatment is often considered to be a combination of medication and psychotherapy. Psychotherapy is the treatment of choice in people under 18.

As the most studied form of psychotherapy for depression, cognitive behavioral therapy (CBT) is thought to work by teaching clients to learn a set of cognitive and behavioral skills, which they can employ on their own. Earlier research suggested that cognitive behavioral therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression.

The effect of psychotherapy on patient and clinician rated improvement as well as on revision rates have declined steadily from the 1970s.

A systematic review of data comparing low-intensity CBT (such as guided self-help by means of written materials and limited professional support, and website-based interventions) with usual care found that patients who initially had more severe depression benefited from low-intensity interventions at least as much as less-depressed patients.

For the treatment of adolescent depression, one published study found that CBT without medication performed no better than a placebo, and significantly worse than the antidepressant fluoxetine. However, the same article reported that CBT and fluoxetine outperformed treatment with only fluoxetine. Combining fluoxetine with CBT appeared to bring no additional benefit in two different studies or, at the most, only marginal benefit, in a fourth study.

Behavior therapy for depression is sometimes referred to as behavioral activation. Studies exist showing behavioral activation to be superior to CBT. In addition, behavioral activation appears to take less time and lead to longer lasting change.

Acceptance and commitment therapy (ACT), a mindfulness form of CBT, which has its roots in behavior analysis, also demonstrates that it is effective in treating depression, and can be more helpful than traditional CBT, especially where depression is accompanied by anxiety and where it is resistant to traditional CBT.

A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects.

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT; however, the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.

Medication

Isoniazid, the first compound called antidepressant

To find the most effective pharmaceutical drug treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed. Response rates to the first agent administered may be as low as 50%. It may take anywhere from three to eight weeks after the start of medication before its therapeutic effects can be fully discovered. Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four months to prevent the chance of recurrence. 

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram, are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety, as well as reduced risk in overdose, compared to their older tricyclic alternatives. Those who do not respond to the first SSRI tried can be switched to another. If sexual dysfunction is present prior to the onset of depression, SSRIs should be avoided. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating noradrenergic and specific serotonergic antidepressant (NaSSA) antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. Cognitive Behavioral Therapy for Insomnia can also help to alleviate the insomnia without additional medication. Venlafaxine (Effexor) may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered. Evidence of effectiveness of SSRIs in those with depression complicated by dementia is lacking.

Tricyclic antidepressants have more side effects than SSRIs (but less sexual dysfunctions) and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective. A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy (although early studies used dosages now considered too low) and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.

There is evidence a prominent side-effect of antidepressants, emotional blunting, is confused with a symptom of depression itself. The cited study, according to Professor Linda Gask was: ‘funded by a pharmaceutical company (Servier) and two of its authors are employees of that company’, which may bias the results. The study authors’ note: "emotional blunting is reported by nearly half of depressed patients on antidepressants and that it appears to be common to all monoaminergic antidepressants not only SSRIs". Additionally, they note: "The OQuESA scores are highly correlated with the HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressant, but also as a symptom of depression...More emotional blunting is associated with a poorer quality of remission..."

Augmentation

Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant. Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent and potentially serious side effects. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function. Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the "classical augmentation strategy for treatment-refractory depression". However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.

Efficacy of medication and psychotherapy

Antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence criteria for a "clinically significant" effect. In particular, the effect size was very small for moderate depression but increased with severity, reaching "clinical significance" for very severe depression. These results were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment. Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there "seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit." The other author agreed that "antidepressant 'glass' is far from full" but disagreed "that it is completely empty". He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.

Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD. In contrast, medication gives better results for dysthymia. The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional "booster" sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.

Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents) showed very similar results. TADS resulted in 71% of their teen subjects having "much" or "very much" improvement in mood over the 60.6% with medication alone and the 43.2% with CBT alone. Similarly, TORDIA showed a 54.8% improvement with CBT and drugs versus a 40.5% with drug therapy alone.

Treatment resistance

The risk factors for treatment resistant depression are: the duration of the episode of depression, severity of the episode, if bipolar, lack of improvement in symptoms within the first couple of treatment weeks, anxious or avoidant and borderline comorbidity and old age. Treatment resistant depression is best handled with a combination of conventional antidepressant together with atypical antipsychotics. Another approach is to try different antidepressants. It's inconclusive which approach is superior. Treatment resistant depression can be misdiagnosed if subtherapeutic doses of antidepressants is the case, patient nonadherence, intolerable adverse effects or their thyroid disease or other conditions is misdiagnosed as depression.

Experimental treatments

Ketamine

Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success.

Creatine

The amino acid creatine, commonly used as a supplement to improve the performance of bodybuilders, has been studied for its potential antidepressant properties. A double-blinded, placebo-controlled trial focusing on women with major depressive disorder found that daily creatine supplementation adjunctive to escitalopram was more effective than escitalopram alone. Studies on mice have found that the antidepressant effects of creatine can be blocked by drugs that act against dopamine receptors, suggesting that the drug acts on dopamine pathways.

Dopamine receptor agonist

Some research suggests dopamine receptor agonist may be effective in treating depression, however studies are few and results are preliminary

SAMe

S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Evidence from 16 clinical trials with a small number of subjects, reviewed in 1994 and 1996 suggested it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.

Tryptophan and 5-HTP

The amino acid tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin. Since serotonin deficiency has been recognized as a possible cause of depression, it has been suggested that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. 5-HTP and tryptophan are sold over the counter in North America, but requires a prescription in Europe. Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticized for having methodological flaws, and a more recent study did not find sustained benefit from their use. The safety of these medications has not been well studied. Due to the lack of high quality studies, preliminary nature of studies showing effectiveness, the lack of adequate study on their safety, and reports of Eosinophilia–myalgia syndrome associated with tryptophan use, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.

Inositol

Inositol, an alcohol sugar found in fruits, beans grains and nuts may have antidepressant effects in high doses. Inositol may exert its effects by altering intracellular signaling.

Medical devices

A variety of medical devices are in use or under consideration for treatment of depression including devices which offer electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and cranial electrotherapy stimulation. Use of such devices in the United States requires approval by the U.S. Food and Drug Administration (FDA) after field trials. In 2010 a FDA advisory panel considered the question of how such field trials should be managed. Factors considered were whether drugs had been effective, how many different drugs had been tried, and what tolerance for suicides should be in field trials.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder.

A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond, relapse with twelve months.

Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anesthesia. Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.

A usual course of ECT involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms ECT is administered under anesthetic with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.

ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.

Deep brain stimulation

The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage. In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated. A March 2010 systematic review found that "about half the patients did show dramatic improvement" and that adverse events were "generally trivial" given the younger psychiatric patient population than with movements disorders. Deep brain stimulation is available on an experimental basis only in the United States; no systems are approved by the FDA for this use. It is available in Australia.

Repetitive transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a noninvasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or "coil" is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.

TMS was approved by the FDA for treatment-resistant major depressive disorder in 2008 and as of 2014 clinical evidence supports this use. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.

Vagus nerve stimulation

Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression in the EU and US and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit. The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favorable for one of the secondary outcomes. The authors concluded "This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression."

Cranial electrotherapy stimulation

A 2014 Cochrane review found insufficient evidence to determine whether or not Cranial electrotherapy stimulation with alternating current is safe and effective for treating depression.

Other treatments

Bright light therapy

Bright light therapy is sometimes used to treat depression, especially in its seasonal form.
 
A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found a significant reduction in depression symptom severity associated with bright light treatment. Benefit was found for both seasonal affective disorder and for nonseasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly in combination with antidepressants or wake therapy. A moderate statistically significant effect of light therapy was found, with response significantly better than control treatment in high-quality studies, in studies that applied morning light treatment, and with patients who respond to total or partial sleep deprivation. Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1–2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

Exercise

The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is moderately more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Smaller effects were seen in more methologically rigorous studies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression and mental illness in general. These studies also found smaller effect sizes in more methodologically rigorous studies. All four systematic reviews called for more research in order to determine the efficacy or optimal exercise intensity, duration, and modality. The evidence for brain-derived neurotrophic factor (BDNF) in mediating some of the neurobiological effects of physical exercise was noted in one review which hypothesized that increased BDNF signaling is responsible for the antidepressant effect.

A review of clinical evidence and guidelines for the management of depression with exercise therapy was published in June 2015. It noted that the available evidence on the effectiveness of exercise therapy for depression suffers from some limitations; nonetheless, it stated that there is clear evidence of efficacy in the reduction of depressive symptoms. The review also noted that patient characteristics, the type of depressive disorders, and the nature of the exercise program all affect the antidepressant properties of exercise therapy.

Meditation

Mindfulness meditation programs may help improve symptoms of depression, but they are no better than active treatments such as medication, exercise, and other behavioral therapies.

Music therapy

A 2009 review found that 3 to 10 sessions of music therapy resulted in a noticeable improvement in depressive symptoms, with still greater improvement after 16 to 51 sessions.

St John's wort

A 2008 Cochrane Collaboration meta-analysis concluded that "The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation." The United States National Center for Complementary and Integrative Health advice is that "St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive." and warns that "Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines."

Sleep

Depression is sometimes associated with insomnia - (difficulty in falling asleep, early waking, or waking in the middle of the night). The combination of these two results, depression and insomnia, will only worsen the situation. Hence, good sleep hygiene is important to help break this vicious circle. It would include measures such as regular sleep routines, avoidance of stimulants such as caffeine and management of sleeping disorders such as sleep apnea.

Smoking cessation

Quitting smoking cigarettes is associated with reduced depression and anxiety, with the effect "equal or larger than" those of antidepressant treatments.

Total/partial sleep deprivation

Sleep deprivation (skipping a night's sleep) has been found to improve symptoms of depression in 40% - 60% of patients. Partial sleep deprivation in the second half of the night may be as effective as an all night sleep deprivation session. Improvement may last for weeks, though the majority (50%-80%) relapse after recovery sleep. Shifting or reduction of sleep time, light therapy, antidepressant drugs, and lithium have been found to potentially stabilize sleep deprivation treatment effects.

Essential Fatty Acids

A 2015 Cochrane Collaboration review found insufficient evidence with which to determine if omega-3 fatty acid has any effect on depression. A 2016 review found that if trials with formulations containing mostly eicosapentaenoic acid (EPA) are separated from trials using formulations containing docosahexaenoic acid (DHA), it appeared that EPA may have an effect while DHA may not, but there was insufficient evidence to be sure.

Shared Care

Shared care, when primary and specialty physicians have joint management of an individual's health care, has been shown to alleviate depression outcomes.

Treatment-resistant depression

From Wikipedia, the free encyclopedia

Treatment-resistant depression
Classification and external resources
MeSHD061218

Treatment-resistant depression (TRD) or treatment-refractory depression is a term used in clinical psychiatry to describe a condition that affects people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Typical definitions of TRD vary, and they do not include a resistance to psychological therapies. Inadequate response has traditionally been defined as no clinical response whatsoever (e.g. no improvement in depressive symptoms). However, many clinicians consider a response inadequate if the person does not achieve full remission of symptoms. People with treatment-resistant depression who do not adequately respond to antidepressant treatment are sometimes referred to as pseudoresistant. Some factors that contribute to inadequate treatment are: early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, and concurrent psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people with TRD are resistant to (e.g.: SSRI-resistant).

Prevalence

Treatment-resistance is relatively common in people with MDD. Rates of total remission following antidepressant treatment are only 50.4%. In cases of depression treated by a primary care physician, 32% of people partially responded to treatment and 45% did not respond at all.

Predictors

Comorbid psychiatric disorders

Comorbid psychiatric disorders commonly go undetected in the treatment of depression. If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both MDD and panic disorder are the most likely to be nonresponsive to treatment. Substance abuse may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. Other psychiatric disorders that may predict treatment-resistant depression include personality disorders, obsessive compulsive disorder, and eating disorders.

Comorbid medical disorders

Some people who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing's disease, and Addison's disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson's disease. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.

Features of depression

People with depression who also display psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes. Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

Drug treatment

There are three basic categories of drug treatment that can be used when a medication course is found to be ineffective. One option is to switch the patient to a different medication. Another option is to add a medication to the patient’s current treatment. This can include combination therapy: the combination of two different types of antidepressants, or augmentation therapy: the addition of a non-antidepressant medication that may increase the effectiveness of the antidepressant.

Dose increase

Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration. Practitioners who use this strategy will usually increase the dose until the person reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.

Switching antidepressants

Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25-70% of people responding to a different antidepressant. There is support for the effectiveness of switching people to a different SSRI; 50% of people that were nonresponsive after taking one SSRI were responsive after taking a second type. Switching people with TRD to a different class of antidepressants may also be effective. People who are nonresponsive after taking an SSRI may respond to a Tricyclic antidepressant, bupropion or a MAOI.

Adding medication

Medications that have been shown to be effective in people with treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for people taking some types of antidepressants, it does not appear to be effective in patients taking SSRI’s. Triiodothyroxine (T3) is a type of thyroid hormone and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance. Since the entry of olanzapine into psychopharmacology, many psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine. Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combo formulation which contains olanzapine and fluoxetine in a single capsule. 

These have shown promise in treating refractory depression but come with serious side effects. Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have potential for abuse. However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.

Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder.

Other treatment options

Electroconvulsive therapy

Electroconvulsive therapy is generally only considered as a treatment option in severe cases of treatment-resistant depression. It is used when medication has repeatedly failed to improve symptoms, and usually when the patient’s symptoms are so severe that they have been hospitalized. Electroconvulsive therapy has been found to reduce thoughts of suicide and relieve depressive symptoms. It is associated with an increase in glial cell line derived neurotrophic factor.

Vagus nerve stimulation

Vagus nerve stimulation is a more invasive procedure than electroconvulsive therapy, but it has been shown to be well tolerated. During the procedure a stimulating electrode is surgically attached to the vagus nerve; this allows for continuous stimulation after implantation. Like electroconvulsive therapy, it is usually only used in severe cases of treatment-resistant depression that have been non-responsive to medication.

Psychological therapies

There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression. However, a review of the literature suggests that it may be an effective treatment option. Psychotherapy may be effective in people with TRD because it can help relieve stress that may contribute to depressive symptoms.

A Cochrane systematic review has shown that psychological therapies (including cognitive behavioural therapy, dialectal behavioural therapy, interpersonal therapy and intensive short term dynamic psychotherapy) added to usual care (with antidepressants) can be beneficial for depressive symptoms and for response and remission rates over the short term (up to 6 months) for patients with TRD. Medium‐ (7-12 months) and long‐term (longer than 12 months) effects seem similarly beneficial. Psychological therapies added to usual care (antidepressants) seem as acceptable as usual care alone.

rTMS

rTMS (Repetitive Transcranial Magnetic Stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. A number of randomised placebo-controlled trials have compared real versus sham rTMS. These trials have consistently demonstrated the efficacy of this treatment against major depression. There have also been a number of meta-analyses of RCTs  confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings. 

dTMS

dTMS (Deep Transcranial Magnetic Stimulation) is a continuation of the same idea as rTMS, but with the hope that deeper stimulation of subcortical areas of the brain leads to increased effect. A 2015 systematic review and health technology assessment found lacking evidence in order to recommend the method over either ECT or rTMS because so few studies had been published.

Outcomes

Treatment-resistant depression is associated with more instances of relapse than depression that is responsive to treatment. One study showed that as many as 80% of people with TRD who needed more than one course of treatment relapsed within a year. Treatment-resistant depression has also been associated with lower long term quality of life.

Reticular formation

From Wikipedia, the free encyclopedia

Reticular formation
Gray701.png
Axial section of the pons, at its upper part. (Formatio reticularis labeled at left.)
Gray694.png
Section of the medulla oblongata at about the middle of the olive. (Formatio reticularis grisea and formatio reticularis alba labeled at left.)
Details
Identifiers
Latinformatio reticularis
MeSHD012154
NeuroNames1223
NeuroLex IDnlx_143558
TAA14.1.00.021 A14.1.05.403 A14.1.06.327
FMA77719

The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. The reticular formation is not anatomically well defined because it includes neurons located in diverse parts of the brain. The neurons of the reticular formation make up a complex set of networks in the core of the brainstem that stretch from the upper part of the midbrain to the lower part of the medulla oblongata. The reticular formation includes ascending pathways to the cortex in the ascending reticular activating system (ARAS) and descending pathways to the spinal cord via the reticulospinal tracts of the descending reticular formation.

Neurons of the reticular formation, particularly those of the ascending reticular activating system, play a crucial role in maintaining behavioral arousal and consciousness. The functions of the reticular formation are modulatory and premotor. The modulatory functions are primarily found in the rostral sector of the reticular formation and the premotor functions are localized in the neurons in more caudal regions.

The reticular formation is divided into three columns: raphe nuclei (median), gigantocellular reticular nuclei (medial zone), and parvocellular reticular nuclei (lateral zone). The raphe nuclei are the place of synthesis of the neurotransmitter serotonin, which plays an important role in mood regulation. The gigantocellular nuclei are involved in motor coordination. The parvocellular nuclei regulate exhalation.

The reticular formation is essential for governing some of the basic functions of higher organisms and is one of the phylogenetically oldest portions of the brain.

General structure

A cross section of the lower part of the pons showing the pontine reticular formation labeled as #9
 
The human reticular formation is composed of almost 100 brain nuclei and contains many projections into the forebrain, brainstem, and cerebellum, among other regions. It includes the reticular nuclei, reticulothalamic projection fibers, diffuse thalamo-cortical projections, ascending cholinergic projections, descending non-cholinergic projections, and descending reticulospinal projections. The reticular formation also contains two major neural subsystems, the ascending reticular activating system and descending reticulospinal tracts, which mediate distinct cognitive and physiological processes. It has been functionally cleaved both sagittally and coronally

Traditionally the reticular nuclei are divided into three columns:
  • In the median column – the raphe nuclei
  • In the medial column – gigantocellular nuclei (because of larger size of the cells)
  • In the lateral column – parvocellular nuclei (because of smaller size of the cells)
The original functional differentiation was a division of caudal and rostral. This was based upon the observation that the lesioning of the rostral reticular formation induces a hypersomnia in the cat brain. In contrast, lesioning of the more caudal portion of the reticular formation produces insomnia in cats. This study has led to the idea that the caudal portion inhibits the rostral portion of the reticular formation. 

Sagittal division reveals more morphological distinctions. The raphe nuclei form a ridge in the middle of the reticular formation, and, directly to its periphery, there is a division called the medial reticular formation. The medial RF is large and has long ascending and descending fibers, and is surrounded by the lateral reticular formation. The lateral RF is close to the motor nuclei of the cranial nerves, and mostly mediates their function.

Medial and lateral reticular formation

The medial reticular formation and lateral reticular formation are two columns of neuronal nuclei with ill-defined boundaries that send projections through the medulla and into the mesencephalon (midbrain). The nuclei can be differentiated by function, cell type, and projections of efferent or afferent nerves. Moving caudally from the rostral midbrain, at the site of the rostral pons and the midbrain, the medial RF becomes less prominent, and the lateral RF becomes more prominent.

Existing on the sides of the medial reticular formation is its lateral cousin, which is particularly pronounced in the rostral medulla and caudal pons. Out from this area spring the cranial nerves, including the very important vagus nerve. The Lateral RF is known for its ganglions and areas of interneurons around the cranial nerves, which serve to mediate their characteristic reflexes and functions.

General functions

The reticular formation consists of more than 100 small neural networks, with varied functions including the following:
  • Somatic motor control – Some motor neurons send their axons to the reticular formation nuclei, giving rise to the reticulospinal tracts of the spinal cord. These tracts function in maintaining tone, balance, and posture—especially during body movements. The reticular formation also relays eye and ear signals to the cerebellum so that the cerebellum can integrate visual, auditory, and vestibular stimuli in motor coordination. Other motor nuclei include gaze centers, which enable the eyes to track and fixate objects, and central pattern generators, which produce rhythmic signals of breathing with swallowing, and with defecation and urination.
  • Cardiovascular control – The reticular formation includes the cardiac and vasomotor centers of the medulla oblongata.
  • Pain modulation – The reticular formation is one means by which pain signals from the lower body reach the cerebral cortex. It is also the origin of the descending analgesic pathways. The nerve fibers in these pathways act in the spinal cord to block the transmission of some pain signals to the brain.
  • Sleep and consciousness – The reticular formation has projections to the thalamus and cerebral cortex that allow it to exert some control over which sensory signals reach the cerebrum and come to our conscious attention. It plays a central role in states of consciousness like alertness and sleep. Injury to the reticular formation can result in irreversible coma.
  • Habituation – This is a process in which the brain learns to ignore repetitive, meaningless stimuli while remaining sensitive to others. A good example of this is a person who can sleep through loud traffic in a large city, but is awakened promptly due to the sound of an alarm or crying baby. Reticular formation nuclei that modulate activity of the cerebral cortex are part of the ascending reticular activating system.

Major subsystems

Ascending reticular activating system

Ascending reticular activating system. Reticular formation labeled near center.

The ascending reticular activating system (ARAS), also known as the extrathalamic control modulatory system or simply the reticular activating system (RAS), is a set of connected nuclei in the brains of vertebrates that is responsible for regulating wakefulness and sleep-wake transitions. The ARAS is a part of the reticular formation and is mostly composed of various nuclei in the thalamus and a number of dopaminergic, noradrenergic, serotonergic, histaminergic, cholinergic, and glutamatergic brain nuclei.

Structure of the ARAS

The ARAS is composed of several neuronal circuits connecting the dorsal part of the posterior midbrain and anterior pons to the cerebral cortex via distinct pathways that project through the thalamus and hypothalamus. The ARAS is a collection of different nuclei – more than 20 on each side in the upper brainstem, the pons, medulla, and posterior hypothalamus. The neurotransmitters that these neurons release include dopamine, norepinephrine, serotonin, histamine, acetylcholine, and glutamate. They exert cortical influence through direct axonal projections and indirect projections through thalamic relays.

The thalamic pathway consists primarily of cholinergic neurons in the pontine tegmentum, whereas the hypothalamic pathway is composed primarily of neurons that release monoamine neurotransmitters, namely dopamine, norepinephrine, serotonin, and histamine. The glutamate-releasing neurons in the ARAS were identified much more recently relative to the monoaminergic and cholinergic nuclei; the glutamatergic component of the ARAS includes one glutamatergic nucleus in the hypothalamus and various glutamatergic brainstem nuclei. The orexin neurons of the lateral hypothalamus innervate every component of the ascending reticular activating system and coordinate activity within the entire system.

The key components of the ARAS are listed in the table below. 

Key components of the ascending reticular activating system
Nucleus type Corresponding nuclei that mediate arousal
Dopaminergic nuclei
Noradrenergic nuclei
Serotonergic nuclei
Histaminergic nuclei
Cholinergic nuclei
Glutamatergic nuclei
Thalamic nuclei

The ARAS consists of evolutionarily ancient areas of the brain, which are crucial to survival and protected during adverse periods. As a result, the ARAS still functions during inhibitory periods of hypnosis.
 
The ascending reticular activating system which sends neuromodulatory projections to the cortex - mainly connects to the prefrontal cortex. There is seen to be low connectivity to the motor areas of the cortex.

Functions of the ARAS

Consciousness
The ascending reticular activating system is an important enabling factor for the state of consciousness. The ascending system is seen to contribute to wakefulness as characterised by cortical and behavioural arousal.
Regulating sleep-wake transitions
The main function of the ARAS is to modify and potentiate thalamic and cortical function such that electroencephalogram (EEG) desynchronization ensues. There are distinct differences in the brain's electrical activity during periods of wakefulness and sleep: Low voltage fast burst brain waves (EEG desynchronization) are associated with wakefulness and REM sleep (which are electrophysiologically similar); high voltage slow waves are found during non-REM sleep. Generally speaking, when thalamic relay neurons are in burst mode the EEG is synchronized and when they are in tonic mode it is desynchronized. Stimulation of the ARAS produces EEG desynchronization by suppressing slow cortical waves (0.3–1 Hz), delta waves (1–4 Hz), and spindle wave oscillations (11–14 Hz) and by promoting gamma band (20 – 40 Hz) oscillations.

The physiological change from a state of deep sleep to wakefulness is reversible and mediated by the ARAS. Inhibitory influence from the brain is active at sleep onset, likely coming from the preoptic area (POA) of the hypothalamus. During sleep, neurons in the ARAS will have a much lower firing rate; conversely, they will have a higher activity level during the waking state. Therefore, low frequency inputs (during sleep) from the ARAS to the POA neurons result in an excitatory influence and higher activity levels (awake) will have inhibitory influence. In order that the brain may sleep, there must be a reduction in ascending afferent activity reaching the cortex by suppression of the ARAS.
Attention
The ARAS also helps mediate transitions from relaxed wakefulness to periods of high attention. There is increased regional blood flow (presumably indicating an increased measure of neuronal activity) in the midbrain reticular formation (MRF) and thalamic intralaminar nuclei during tasks requiring increased alertness and attention.

Clinical significance of the ARAS

Mass lesions in brainstem ARAS nuclei can cause severe alterations in level of consciousness (e.g., coma). Bilateral damage to the reticular formation of the midbrain may lead to coma or death.

Direct electrical stimulation of the ARAS produces pain responses in cats and educes verbal reports of pain in humans. Additionally, ascending reticular activation in cats can produce mydriasis, which can result from prolonged pain. These results suggest some relationship between ARAS circuits and physiological pain pathways.
Pathologies
Given the importance of the ARAS for modulating cortical changes, disorders of the ARAS should result in alterations of sleep-wake cycles and disturbances in arousal. Some pathologies of the ARAS may be attributed to age, as there appears to be a general decline in reactivity of the ARAS with advancing years. Changes in electrical coupling have been suggested to account for some changes in ARAS activity: If coupling were down-regulated, there would be a corresponding decrease in higher-frequency synchronization (gamma band). Conversely, up-regulated electrical coupling would increase synchronization of fast rhythms that could lead to increased arousal and REM sleep drive. Specifically, disruption of the ARAS has been implicated in the following disorders:
  • Narcolepsy: Lesions along the PPT/LDT nuclei are associated with narcolepsy. There is a significant down-regulation of PPN output and a loss of orexin peptides, promoting the excessive daytime sleepiness that is characteristic of this disorder.
  • Schizophrenia: Intractable schizophrenic patients have a significant increase (> 60%) in the number of PPN neurons and dysfunction of NO signaling involved in modulating cholinergic output of the ARAS.
  • Post-traumatic stress disorder, Parkinson's disease, REM behavior disorder: Patients with these syndromes exhibit a significant (>50%) decrease in the number of locus coeruleus (LC) neurons, resulting is increased disinhibition of the PPN.
  • Progressive supranuclear palsy (PSP): Dysfunction of NO signaling has been implicated in the development of PSP.
  • Depression, autism, Alzheimer's disease, attention deficit disorder: The exact role of the ARAS in each of these disorders has not yet been identified. However, it is expected that in any neurological or psychiatric disease that manifests disturbances in arousal and sleep-wake cycle regulation, there will be a corresponding dysregulation of some elements of the ARAS.
  • Parkinson's disease: REM sleep disturbances are common in Parkinson's. It is mainly a dopaminergic disease, but cholinergic nuclei are depleted as well. Degeneration in the ARAS begins early in the disease process.
Developmental influences
There are several potential factors that may adversely influence the development of the ascending reticular activating system:
  • Preterm birth: Regardless of birth weight or weeks of gestation, premature birth induces persistent deleterious effects on pre-attentional (arousal and sleep-wake abnormalities), attentional (reaction time and sensory gating), and cortical mechanisms throughout development.
  • Smoking during pregnancy: Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. This exposure can induce up-regulation of nicotinic receptors on α4b2 subunit on Pedunculopontine nucleus (PPN) cells, resulting in increased tonic activity, resting membrane potential, and hyperpolarization-activated cation current. These major disturbances of the intrinsic membrane properties of PPN neurons result in increased levels of arousal and sensory gating deficits (demonstrated by a diminished amount of habituation to repeated auditory stimuli). It is hypothesized that these physiological changes may intensify attentional dysregulation later in life.

Descending reticulospinal tracts

Spinal cord tracts - reticulospinal tract labeled in red, near-center at left in figure.

The reticulospinal tracts, also known as the descending or anterior reticulospinal tracts, are extrapyramidal motor tracts that descend from the reticular formation in two tracts to act on the motor neurons supplying the trunk and proximal limb flexors and extensors. The reticulospinal tracts are involved mainly in locomotion and postural control, although they do have other functions as well. The descending reticulospinal tracts are one of four major cortical pathways to the spinal cord for musculoskeletal activity. The reticulospinal tracts works with the other three pathways to give a coordinated control of movement, including delicate manipulations. The four pathways can be grouped into two main system pathways – a medial system and a lateral system. The medial system includes the reticulospinal pathway and the vestibulospinal pathway, and this system provides control of posture. The corticospinal and the rubrospinal tract pathways belong to the lateral system which provides fine control of movement.

Components of the reticulospinal tracts

The tract is divided into two parts, the medial (or pontine) and lateral (or medullary) reticulospinal tracts (MRST and LRST).
  • The MRST is responsible for exciting anti-gravity, extensor muscles. The fibers of this tract arise from the caudal pontine reticular nucleus and the oral pontine reticular nucleus and project to the lamina VII and lamina VIII of the spinal cord (BrainInfo)
  • The LRST is responsible for inhibiting excitatory axial extensor muscles of movement. It is also responsible for automatic breathing. The fibers of this tract arise from the medullary reticular formation, mostly from the gigantocellular nucleus, and descend the length of the spinal cord in the anterior part of the lateral column. The tract terminates in lamina VII mostly with some fibers terminating in lamina IX of the spinal cord.
The ascending sensory tract conveying information in the opposite direction is known as the spinoreticular tract.

Functions of the reticulospinal tracts

  • Integrates information from the motor systems to coordinate automatic movements of locomotion and posture
  • Facilitates and inhibits voluntary movement; influences muscle tone
  • Mediates autonomic functions
  • Modulates pain impulses
  • Influences blood flow to lateral geniculate nucleus of the thalamus.

Clinical significance of the reticulospinal tracts

The reticulospinal tracts are mostly inhibited by the corticospinal tract; if damage occurs at the level of or below the red nucleus (e.g. to the superior colliculus), it is called decerebration, and causes decerebrate rigidity: an unopposed extension of the head and limbs. The reticulospinal tracts also provide a pathway by which the hypothalamus can control sympathetic thoracolumbar outflow and parasympathetic sacral outflow.[citation needed]

History

The term "reticular formation" was coined in the late 19th century by Otto Deiters, coinciding with Ramon y Cajal’s neuron doctrine. Allan Hobson states in his book The Reticular Formation Revisited that the name is an etymological vestige from the fallen era of the aggregate field theory in the neural sciences. The term "reticulum" means "netlike structure", which is what the reticular formation resembles at first glance. It has been described as being either too complex to study or an undifferentiated part of the brain with no organization at all. Eric Kandel describes the reticular formation as being organized in a similar manner to the intermediate gray matter of the spinal cord. This chaotic, loose, and intricate form of organization is what has turned off many researchers from looking farther into this particular area of the brain. The cells lack clear ganglionic boundaries, but do have clear functional organizations and distinct cell types. The term "reticular formation" is seldom used anymore except to speak in generalities. Modern scientists usually refer to the individual nuclei that compose the reticular formation.

Moruzzi and Magoun first investigated the neural components regulating the brain's sleep-wake mechanisms in 1949. Physiologists had proposed that some structure deep within the brain controlled mental wakefulness and alertness. It had been thought that wakefulness depended only on the direct reception of afferent (sensory) stimuli at the cerebral cortex

The direct electrical stimulation of the brain could simulate electrocortical relays. Magoun used this principle to demonstrate, on two separate areas of the brainstem of a cat, how to produce wakefulness from sleep. First the ascending somatic and auditory paths; second, a series of "ascending relays from the reticular formation of the lower brain stem through the midbrain tegmentum, subthalamus and hypothalamus to the internal capsule." The latter was of particular interest, as this series of relays did not correspond to any known anatomical pathways for the wakefulness signal transduction and was coined the ascending reticular activating system (ARAS). 

Next, the significance of this newly identified relay system was evaluated by placing lesions in the medial and lateral portions of the front of the midbrain. Cats with mesancephalic interruptions to the ARAS entered into a deep sleep and displayed corresponding brain waves. In alternative fashion, cats with similarly placed interruptions to ascending auditory and somatic pathways exhibited normal sleeping and wakefulness, and could be awakened with somatic stimuli. Because these external stimuli would be blocked by the interruptions, this indicated that the ascending transmission must travel through the newly discovered ARAS.

Finally, Magoun recorded potentials within the medial portion of the brain stem and discovered that auditory stimuli directly fired portions of the reticular activating system. Furthermore, single-shock stimulation of the sciatic nerve also activated the medial reticular formation, hypothalamus, and thalamus. Excitation of the ARAS did not depend on further signal propagation through the cerebellar circuits, as the same results were obtained following decerebellation and decortication. The researchers proposed that a column of cells surrounding the midbrain reticular formation received input from all the ascending tracts of the brain stem and relayed these afferents to the cortex and therefore regulated wakefulness.

Rejuvenation

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