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Why do antidepressants have a delayed onset of action?

Why do antidepressants have a delayed onset of action?


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Why do antidepressants take so long to reach efficacy? I've read of theories about it perhaps being due to the strength of negative feedback via serotonergic and adrenergic autoreceptors during the first few weeks of treatment. What I'm looking for in an answer is the following:

  • The current theories regarding why currently-in-practise antidepressant regimens have a delayed onset of action.
  • The evidence for these theories.
  • How these theories fit in with the monoamine hypothesis or whether it is inconsistent with the monoamine hypothesis and how.
  • Possible solutions to this problem of delayed responses to antidepressant therapy.

All of this is strictly theoretical, there are no actual people involved here, this is simply a scientific inquiry.


Short answer
The mechanism of action of serotonin-specific reuptake inhibitors, a commonly-prescribed class of antidepressants, is a downregulation of 5HT1A receptors through negative feedback. This downregulation of receptors takes time.

Background
Serotonin-specific reuptake inhibitors (SSRIs) are a class of antidepressants commonly prescribed to treat depression. Their therapeuric effects may need weeks of treatment (Celada, 2004), which can be explained by their action on 5HT1A receptors in the dendritic region of the serotoninergic neurons in the raphe nucleus. By blocking serotonin (5HT) reuptake, negative feedback mechanisms cause the 5HT1A receptors to downregulate. This downregulation of the presynaptic modulatory 5HT1A receptors changes the firing pattern of the serotonergic neuron into a more fluttering mode, so that it releases more 5HT (Duman, 2007). More 5HT makes you feel better. That is how it fits into the monoaminergic hypothesis. To have the 5HT1A receptors respond this way takes time, as it is an adaptive response that downregulates of 5HT1A receptors, i.e., less receptors are present on the cell's membrane.

This is only an expanation of delayed action of SSRIs, a specific subclass of antidepressants. For example, there are newer classes of antidepressants that seem to work faster (5HT4 action) (Duman, 2007).

References
- Celada et al., J Psychiatry Neurosci (2004); 29(4): 252-65
- Duman, Neuron (2007); 55(5): 712-25


Do some antidepressants work faster than others?

The clinical utility of antidepressant drugs is impaired by the delay in onset of their therapeutic action. It is becoming increasingly clear that differences exist between antidepressants with respect to this property, both within and between pharmacologic classes. Post hoc analyses of comparisons between selective serotonin reuptake inhibitors and dual-action antidepressants such as mirtazapine and venlafaxine indicate that the dual-action drugs may have a faster onset of action. At least in the case of mirtazapine, the earlier onset appears to be via a specific antidepressant effect and not an effect on sleep or other accessory symptoms. Studies that compare mirtazapine and venlafaxine are relatively rare and lack sufficient statistical power to determine a difference in the onset of action. Although these differences have been shown in clinical efficacy studies not specifically designed to detect differences in onset of action, a definitive demonstration of early onset of action awaits the results of appropriately designed and powered clinical studies currently planned or in progress.


S-adenosyl-methionine (SAMe) for Depressed Mood

THE BASICS

As I write I am thinking of many of my own patients who find themselves struggling more as the days grow shorter. This post is about S-adenosyl-methionine (SAMe), a widely used natural supplement with an established track record for treating depressed mood.

How SAMe works to improve depressed mood

SAMe is a naturally occurring molecule in bacteria, plants, and animals and plays many important roles at the level of genes, immune function, and amino acid metabolism. In humans, SAMe is an important methyl donor, an essential step in the synthesis of several neurotransmitters from amino acids in the diet. The antidepressant effects of SAMe are probably related to multiple mechanisms of action including increased brain levels of serotonin, dopamine, and norepinephrine. The synthesis of these neurotransmitters by SAMe requires vitamin B12 and folate. Many depressed individuals are deficient in B vitamins, thus individuals taking SAMe for depressed mood will benefit from taking vitamin B12 and folate (especially in the form of l-methyl-folate) concurrently. In addition to the effects of SAMe on the above neurotransmitters, it has been suggested that antidepressant effects of SAMe are mediated by anti-inflammatory effects, changes in neuronal membrane fluidity, increased rate of serotonin turnover, inhibition of norepinephrine reuptake, and beneficial synergistic effects of SAMe on dopamine activity. Antidepressant effects of SAMe may also be mediated by anti-inflammatory effects and changes in neuronal cell membrane fluidity.

Research findings show efficacy comparable to antidepressants

SAMe has been widely used for decades to treat depressed mood and osteoarthritis in many European countries where it is available on a prescription basis in oral form, as an intramuscular injection, or for intravenous use. SAMe degrades rapidly when exposed to air and stable oral preparations posed manufacturing challenges for many years. Thus, many early studies investigated the antidepressant efficacy of SAMe administered intramuscularly or intravenously. Early studies reported that effective antidepressant doses of SAMe are significantly smaller when administered intravenously, and showed that few patients receiving SAMe intravenously had adverse effects.

In the U.S., SAMe is available in oral form only and can be purchased as an over-the-counter tablet in pharmacies and health food stores. Shelf-life can be prolonged by refrigeration and protecting SAMe from degradation in blister packs. e-counter supplement in pharmacies and health food stores. Oral SAMe is available in two different forms. Oral forms of SAMe are combined with other molecules to reduce the rate of oxidative degradation and extend shelf life. The butane-disulfonate is available as an enteric-coated tablet and may have significantly greater bioavailability and longer shelf life than the tosylate form.

The standard maintenance regimen of oral SAMe for depressed mood is between 800 and 1600 mg/day in two-to-four divided doses. A common strategy is to start SAMe at a dose of 200mg twice daily, and gradually increase to 400mg twice daily, monitoring for side effects and therapeutic response. Absorption is improved when SAMe is taken on an empty stomach (i.e., before meals).

Advantages of SAMe compared to prescription antidepressants

Most currently available antidepressants have a delayed onset of action, thus consistent improvement in mood may be noticeable only after four to six weeks of daily use. In contrast, SAMe has a relatively rapid onset of action, usually within one week of starting treatment. Another important advantage of SAMe is the absence of clinically significant interactions with prescription medications and relatively few side effects compared to antidepressants.

In addition to its mood enhancing effects, there is evidence that augmentation with SAMe (400mg) twice daily, in individuals who are not responding to antidepressant therapy, may improve memory and other cognitive problems that often accompany depressed mood (Levkovitz 2012)

SAMe enhances response to antidepressants

Meta-analyses of placebo-controlled studies support that SAMe when used as a monotherapy is as effective as many widely prescribed antidepressants (Hardy et al 2003 Sharma et al 2017). Studies published in peer-reviewed medical journals support that combining SAMe with an SSRI antidepressant or venlafaxine (a serotonin-norepinephrine reuptake inhibitor) improves overall response and may accelerate response rate equivalent to results achieved when augmenting an SSRI antidepressant with bupropion or venlafaxine. The mechanism of action by which SAMe augments the effects of widely used prescription antidepressants in cases in which a patient has become non-responsive, may involve re-externalizing neurotransmitter receptors that have been internalized by the nerve cell membrane during prolonged exposure to an antidepressant.

THE BASICS

Findings of a landmark study published in the American Journal of Psychiatry provided "preliminary evidence that SAMe can be an effective, relatively well-tolerated, and safe adjunctive treatment strategy for SSRI non-responders diagnosed with major depressive disorder"(Papakostas 2010). Individuals included in the study continued on recommended doses of commonly prescribed antidepressants including paroxetine, citalopram, duloxetine and others, while also taking SAMe. The authors noted that significantly more patients treated with adjunctive SAMe experienced clinical improvement and remission compared to matched patients receiving a placebo. The significance of findings was limited by small study size (73 total patients), the short duration of the study (6 weeks), and failure to include a comparison group taking an antidepressant only.

Combining SAMe with an SSRI or other antidepressant is an integrative approach that improves outcomes while permitting a reduction in the dose of the conventional antidepressant by as much as 30%. The advantages of reducing the dose of a conventional antidepressant include fewer side effects and improved adherence to treatment. In addition to improving the efficacy of antidepressants, there is evidence that the adjunctive use of SAMe may reduce sexual side effects frequently caused by SSRIs and other antidepressants.


SIDE EFFECTS OF SSRIs

The improved tolerability of the SSRIs is attributable to their selectivity and to their absence of interaction with other receptors, such as histaminic, cholinergic, dopaminergic, and noradrenergic. Serotonin receptors comprise at least 7 classes, which are further divided at the subreceptor level. These receptors mediate a variety of functions unrelated to mood, including sleep, appetite, and sexual function, as well as symptoms such as pain, nausea, depression, and anxiety. 11 By increasing the inhibition of serotonin reuptake, more of the neurotransmitter is available to interact with any of these receptors or subtype receptors. Therefore, most SSRI side effects are dose related and can be attributed to serotonergic effects. For example, nausea, a common side effect of SSRI therapy, most likely results from stimulation of 5-HT3 receptors and can usually be alleviated by reducing the dose of the SSRI. 10 In contrast, fluoxetine-induced skin reactions are not dose related and apparently are idiosyncratic.

There are some differences in the adverse effect profiles of the available SSRIs ( Table 2 ). Gastrointestinal (GI) disturbances are the most frequently reported side effects. 10 Individually, postmarketing surveillance studies suggest that fluvoxamine is associated with the highest frequency of GI disturbances, while anxiety, agitation, and insomnia are most often reported with sertraline and fluoxetine. 10, 12 Overall, citalopram appears to be the best-tolerated SSRI, followed by fluoxetine, sertraline, paroxetine, and fluvoxamine. The latter 2 drugs are associated with the most side effects and the highest discontinuation rates because of side effects in clinical trials. 13 During long-term SSRI therapy, the most troubling adverse effects are sexual dysfunction, weight gain, and sleep disturbance.

Table 2.

Comparison of Frequent Side Effects Associated With Currently Available Selective Serotonin Reuptake Inhibitors a

Sexual Dysfunction

The interference in sexual functioning caused by SSRIs is quite complicated, possibly involving nitric oxide. The effect appears to be attributable to stimulation of postsynaptic 5-HT2 receptors, possibly in the spinal cord. Clinically, the effect can manifest as decreased libido, male impotence, delayed ejaculation, or anorgasmia. These are common characteristics of depression itself, as well as adverse effects of antidepressant therapy. 5 Therefore, effects attributable to antidepressant therapy should be cautiously interpreted and normalized against baseline. According to clinical trials specifically designed to assess sexual function in patients receiving SSRIs, the type and severity of sexual dysfunction vary by gender. Depressed women tend to have greater reduction of sexual desire and increased difficulties with orgasm at baseline compared with men. Women experience some remission of these symptoms with continued SSRI treatment. In contrast, men tend to experience continuing orgasmic inhibition and overall sexual dysfunction as a side effect of SSRI therapy. 5 Increased sexual desire and priapism are also possible with SSRI therapy. For both sexes, SSRI-induced orgasmic delay and anorgasmia are more common than decreased libido. 5

The method used to obtain information about sexual function directly affects the reporting of sexual side effects with SSRI therapy ( Table 3 ). Only 2% to 7% of patients spontaneously report sexual side effects with SSRI therapy, but when a sexual dysfunction questionnaire is used, the incidence of sexual dysfunction rose to 55% for SSRIs, 14 and is as high as 92% for the TCA clomipramine. 15 Based on these observations, physicians should obtain thorough sexual function histories before initiating SSRI therapy and, through detailed, frank discussions, compare reported changes during treatment with self-evaluated pretreatment levels of sexual functioning. Ideally, a validated sexual dysfunction questionnaire, such as the Arizona Sexual Experience Scale (ASEX), 16 would be used to capture and standardize sexual side effect information during SSRI therapy.

Table 3.

Incidence (%) of Patients Reporting Sexual Dysfunction With the Selective Serotonin Reuptake Inhibitors in Some Studies, Depending on Methods for Determining Adverse Events a

For patients who find sexual dysfunction intolerable as a side effect of SSRI therapy, substituting another SSRI may attenuate these side effects. Citalopram did not seem to cause sexual impairment in patients who had experienced such events with another SSRI. 17 Within the class of SSRIs, erectile dysfunction, vaginal lubrication difficulties, and decreased libido in both sexes are most common with paroxetine, particularly in the first month of therapy. 5, 10 Anorgasmia appears to be the most common dose-dependent side effect of citalopram therapy. 18

Table 3 illustrates the differences in published incidence rates for SSRI-induced interference with sexual function, depending on the method used to collect information. Few studies have compared the frequency of sexual dysfunction reported by patients treated with citalopram with that of patients taking other SSRIs. Although the exact mechanism for SSRI-induced sexual dysfunction is unknown, the influence of other receptor systems, including dopaminergic, cholinergic, and serotonergic, and agents such as prolactin and nitric oxide have been proposed. 5

Weight Gain

Like sexual dysfunction, weight gain was infrequently reported during premarketing clinical trials of the SSRIs. Because of the weight loss that occurred during the early, short-term clinical trials with fluoxetine, it was investigated as a potential weight loss agent. 19 However, weight gain subsequently emerged as a common side effect of long-term SSRI therapy. Although some SSRIs are typically associated with weight loss during initial therapy, weight is often regained after 6 months and can be followed by additional weight gain with long-term use. Uncontrolled studies have reported mean weight gains of 15 lb (6.75 kg) for sertraline, 21 lb (9.45 kg) for fluoxetine, and 24 lb (10.80 kg) for paroxetine after 6 to 12 months of therapy. 20, 21 Although studies to date suggest that citalopram is less likely to cause weight gain, 22 one clinical series of 18 patients reported 8 patients with mixed anxiety and mood disorders who had an average weight gain of 15.7 lb (7.1 kg) after receiving citalopram for 5 weeks. 23

Effects on Sleep

In depressed patients, normal sleep patterns are altered, with an increased duration and earlier onset of rapid eye movement (REM) sleep, reduced slow-wave sleep, and more awakenings. 10 Additionally, the SSRIs interfere with sleep architecture, potentially complicating the sleep of depressed patients. Fluoxetine, paroxetine, and sertraline delay the onset of REM sleep, and fluoxetine and paroxetine increase awakenings and reduce REM sleep, slow-wave sleep, total sleep time, and sleep efficiency. In contrast, sertraline minimally increases sleep efficiency and reduces nocturnal wakefulness time, which may benefit depressed patients whose sleep disturbance is troubling. 24

Other Side Effects

Discontinuation reactions have been reported after withdrawal of prolonged SSRI treatment and constitute a syndrome that is not well characterized. Clinical trials designed to examine this syndrome in terms of receptor physiology have been inconclusive. Presumably, the discontinuation syndrome results from neurophysiologic readjustment in the central nervous system to compensate for the pharmacologic activity of the SSRI. The symptoms include dizziness, nausea, lethargy, headache, anxiety, and agitation. They are generally mild, begin within a week of discontinuing SSRI therapy, and resolve within 3 weeks. 25 Some reported problems are more disabling, for example, falls and absence from work. Reinstatement of the SSRI resolves symptoms. The discontinuation syndrome is best avoided by slowly tapering SSRI therapy. As expected, withdrawal side effects are more common with SSRIs that have the shortest half-lives (i.e., paroxetine, fluvoxamine). 25

An additional advantage of SSRIs over TCAs is a reduced risk of drug-drug interactions. However, the administration of 2 or more serotonergic drugs or an overdose of 1 agent can cause the serotonin syndrome, a potentially life-threatening disorder characterized by myoclonus, hyperreflexia, sweating, shivering, incoordination, and mental status changes. 11 The serotonin syndrome can be distinguished from other SSRI-induced side effects by the clustering of clinical features, their severity, and duration. 10 The coadministration of serotonergic drugs (e.g., 2 SSRIs or an SSRI plus an MAOI) should be avoided. Additionally, when substituting one SSRI for another in a given patient, a suitable washout period should be ensured that reflects the half-life of the drug being replaced. 9


‘It's the way that you look at it’𠅊 cognitive neuropsychological account of SSRI action in depression

The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients.

1. Introduction

(a) Serotonergic drugs and depression

One of the cornerstones of the serotonin hypothesis of depression is the claim that drugs that potentiate serotonin neurotransmission are effective antidepressants. This was observed with older, pharmacologically non-selective agents such as the tricyclic antidepressants and the monoamine oxidase inhibitors. However, the advent of selective serotonin reuptake inhibitors (SSRIs) indicated that agents whose acute pharmacological action is essentially confined to potentiation of serotonin activity can be useful as antidepressant drugs. Of course, other drugs which lack acute actions at serotonin neurons, for example, bupropion, are also effective antidepressants. Taken together the data suggest that serotonin potentiation may be sufficient to produce a clinical antidepressant action but it is not necessary [1,2]. Similar observations have been made concerning the role of catecholamines but the focus in this presentation will be on serotonin.

(b) Serotonin dependence of SSRIs

It has become part of clinical lore that antidepressant drugs, including SSRIs, take a number of weeks to act, that is, to produce a therapeutically beneficial effect in depressed patients. We will be examining this assumption in more detail later, but at this point, it is helpful to note that the proposed delay in onset of antidepressant drug action has given rise to an enormous volume of research investigating the neuroadaptive effects of repeated antidepressant administration in both humans and animals [1,2].

This research is based on the notion that because antidepressants take several weeks to work, their antidepressant effects cannot be because of their acute pharmacological actions which are manifest within hours of ingestion of the first dose of treatment. Hence, the acute pharmacological actions of antidepressants must trigger a cascade of other ‘adaptive’ neurobiological events which evolve over time, and which are responsible for the clinical therapeutic effect [1,2].

When considering the action of antidepressants, therefore, it is important to bear in mind that acute pharmacological actions such as serotonin potentiation will be complemented by other neuroadaptive changes as the course of treatment proceeds. This gives rise to the possibility that the ability of SSRIs to potentiate serotonin neurotransmission could become less important as treatment develops and by the time the patient experiences clinical benefit, acute serotonin potentiation might be playing a relatively unimportant role in this effect.

Studies using the technique of acute tryptophan depletion (ATD) have shown clearly that this view is mistaken. ATD uses a dietary manipulation to produce an acute reduction in serotonin neurotransmission by restricting availability of tryptophan for serotonin synthesis. In patients who have responded to SSRIs and remained on treatment successfully for a number of weeks, ATD produces acute depressive relapse within a couple of hours [3]. This finding suggests that continued potentiation of serotonin function is needed for the expression of the antidepressant effect of SSRIs in depressed patients. Interestingly, patients on SSRIs do not relapse when brain catecholamine function is lowered by alpha-methyl-para-tyrosine, showing specificity of this effect to serotonin [4].

Of course, other explanations can be put forward to explain the ability of ATD to cause depressive relapse in patients taking SSRIs. For example, abrupt cessation of SSRIs produces unpleasant withdrawal symptoms [5]. If ATD produces the same effect in patients taking SSRIs, SSRI withdrawal symptomatology could be mistaken for depressive relapse. On the contrary, SSRI withdrawal produces a characteristic syndrome with anxiety, emotional lability and insomnia, and a variety of physical symptoms including dizziness, light-headedness, nausea and paraesthesia [5]. Such symptoms are not reported following ATD in patients taking SSRIs [3].

It is also conceivable that administration of SSRIs produces a form of ‘serotonin dependence’ such that when serotonin levels are lowered in anyone taking SSRIs, the person concerned will become depressed. This proposal is hard to test experimentally. However, a small study in healthy volunteers who were given short-term treatment with SSRIs did not find that any subjects treated in this way showed abnormal mood lowering following ATD [6].

(c) Neuroadaptive effects of SSRIs

As noted previously, numerous studies have examined the neuroadaptive effects of repeated antidepressant treatment with the aim of identifying what particular neurobiological changes coincide with the time course of the clinical antidepressant effect. Over the years, several different changes have been identified and suggested to be important in the therapeutic effect of treatment. In the case of SSRIs, a popular theory posits that desensitization of serotonin autoreceptors on serotonin cell bodies and terminals is necessary before the full effects of the SSRI to increase serotonin neurotransmission can be expressed [7]. This interesting hypothesis suggests that combination of SSRIs with autoreceptor antagonists might facilitate speed of onset of therapeutic action and perhaps also produce a better overall clinical effect [8].

More recently, attention has been directed to the effects of repeated administration of SSRIs and other antidepressants on the elaboration of neurotrophins and other cellular processes such as synaptogenesis and neurogenesis [9,10]. A key role has been posited for the neurotrophin, brain-derived neurotrophic factor (BDNF) in terms of increasing synaptic plasticity and facilitating neurogenesis. Animal models of depression are associated with decreased BDNF production, diminished neurogenesis and impaired synaptic plasticity. These effects are reversed by repeated SSRI treatment. This finding provides a cellular basis for understanding the action of antidepressants and their delayed onset of action [11].

In fact, BDNF has rather complex roles in brain function and SSRIs do not increase BDNF in all brain regions. There are also some doubts as to whether the extent of neurogenesis, which in fact appears fairly limited and restricted to a few brain areas such as the hippocampus, can really explain the effects of antidepressants to improve mood in depressed patients [12]. However, it is interesting that antidepressants might produce effects on synaptic plasticity because this mechanism has been implicated in learning and memory, and neuropsychological process of this nature is presumably important to the action of psychotherapies in depression. It is therefore intriguing that antidepressants and psychotherapies might in some ways share a common neurobiological substrate.

(d) How long do antidepressants take to work?

As noted above, it is generally believed that antidepressants take several weeks to produce an antidepressant effect. This may give rise to the impression that no clinically discernible change in mental state occurs until a number of weeks of treatment have elapsed. However, this is not the case. A meta-analysis by Taylor et al. [13] examined the rate of improvement on the Hamilton Depression Rating Scale for Depression (HAM-D) week by week in depressed patients randomized blindly to treatment with either SSRIs or placebo. The HAM-D is a standard clinician-rated depression scale often used in trials of drug treatment.

The meta-analysis showed that in fact, relative to placebo, improvements in depression scores in the SSRI-treated patients were clearly apparent by the end of the first week of therapy. Indeed, the improvement seen over this time was greater than in any subsequent week though the overall difference between placebo and active drug accumulated as time went by [13]. The picture therefore is of a steady linear improvement in depressive symptoms from the very start of treatment which increased over time. This suggests that, in fact, psychological improvement starts very early in the course of antidepressant drug treatment and the apparent delay in onset of action is because of its incremental nature. That is, although the improvement starts early, it takes a number of weeks before the effect is obvious to patient and clinician. There is no evidence from this analysis of a ‘step change’ in antidepressant effect over a number of weeks of treatment, which suggests that similar mechanisms are likely to be involved in antidepressant action from the start of treatment up until the point at which improvement becomes clinically detectable.

2. A cognitive neuropsychological account of antidepressant action

(a) Negative emotional biases in depression and anxiety

While there has been much research on the pharmacological and cellular actions of SSRIs, there has been less attention directed to how such effects act to improve the symptoms of low mood, anxiety and social dysfunction which characterize the disorders they treat. Such a translational account may benefit from considering the actions of antidepressant drugs at a systems level, specifically on the emotion-related functions of neural systems believed to play a role in anxiety and depression.

Psychological approaches to depression have emphasized the role of negative biases in information processing in the maintenance of this disorder [14]. Mood congruent biases in the recall of emotionally valenced information in incidental memory tasks and in the monitoring and classification of emotional information have been reported to occur in depression [15,16]. Depressed patients are also more likely to classify ambiguous facial expressions as negative and this tendency persists into clinical remission [17,18]. Similarly, anxiety has been associated with attentional and interpretational biases towards threat including increased initial orienting to and recognition of fearful facial expressions [19].

The translation of these negative or threat-relevant biases of perception, attention and memory into conscious thoughts, memories and actions is believed to play a key role in precipitating and maintaining depressive states [14]. Such negative cognitions are an important target for treatment in cognitive behaviour therapy for depression and anxiety. Thus, cognitive therapists are fond of quoting the Greek stoic philosopher, Epictetus, who said, ‘Men are disturbed not by things, but by the view which they take of them’. Thus, cognitive therapy aims to resolve depression by helping patients consciously reframe their negative views of themselves and the world in a more balanced way [14].

(b) Antidepressants and emotional processing

There is increasing interest in the effects of antidepressants on the way the brain processes emotional information. Such effects have been assessed in healthy volunteers, participants at risk of depression or anxiety and currently depressed patients. Here, we review this literature focusing on the effects of SSRIs on emotional processing in humans and attempt to synthesize this into a coherent account of how SSRIs may act to relieve depressive disorders. Such an account can be used to supplement neuroadaptive theories of antidepressant action by showing how psychological mechanisms recruited at the start of treatment may over time produce clinical antidepressant effects.

(c) Acute effects of SSRIs on emotional processing in healthy volunteers

(i) Behavioural effects

Although the full effects of SSRI administration on serotonin function may develop over repeated treatment through autoreceptor desensitization, there is evidence that even acute treatment increases serotonin levels to some extent. This is true both in preclinical studies measuring serotonin release with microdialysis [20] and in indirect measures in human volunteers employing, for example, the increase in salivary cortisol as an indirect index of enhanced serotonin activity [21].

In a task of emotional processing, we found that a single dose of the SSRI, citalopram (20 mg), increased the recognition of happy facial expressions [22]. In addition, citalopram increased attention to positive socially relevant stimuli in a visual probe task after a single administration [23]. These results suggest that even acute administration of SSRIs may be sufficient to increase positive emotional processing, and thereby reverse the negative biases seen in depressed patients.

Interestingly, acute SSRI administration also appears to increase threat processing in healthy volunteers. In particular, fearful face recognition and startle responses are enhanced following acute SSRI administration [22,23]. This early increase in threat processing is consistent with clinical descriptions of increased anxiety and agitation in a subgroup of patients early in SSRI treatment before anxiolytic actions are seen [24] and a similar sequence of effects with increases in anxiety followed by anxiolytic effects has been described in animal models of anxiety [25]. This is consistent with neuroadaptive changes in serotonin and other mechanisms over the course of continued SSRI treatment.

Performance in these human models of emotional processing may therefore tap into similar underlying processes as those seen clinically and could be useful in our attempts to understand the mechanisms which mediate unwanted as well as desired effects of SSRI treatment. It is noteworthy that some antidepressants apparently decrease anxiety on acute administration in this model. For example, a single dose of mirtazapine, which acts as an antagonist at both α2-adrenoceptors and postsynaptic serotonin2A/2C receptors, decreased fear recognition and startle responses, similar to the profile seen with repeated SSRI administration [26]. These effects are consistent with the hypothesis that the anxiolytic actions of SSRIs may relate to downregulation of postsynaptic, possibly serotonin2C receptors [27].

(ii) Neuroimaging effects

A number of studies have examined the effects of acute SSRI administration on emotional processing in healthy volunteers using functional magnetic resonance imaging (fMRI). The usual model of emotional processing employed has been the presentation of emotional faces based on the well-described ability of fearful faces to increase amygdala activity as judged by the blood oxygen level-dependent (BOLD) signal. Most studies have found that acute administration of SSRIs decreases the amygdala response to fear and other aversive stimuli [28–30] (figure 1). However, one study, which used a large intravenous dose of citalopram (20 mg) found the opposite, that is, an increased amygdala response to aversive emotional stimuli [31]. Interestingly, a single oral dose of the antidepressant mirtazapine (15 mg), also decreased the amygdala response to fear [32] (figure 2). It will be of interest to explore the effect of acute treatment with antidepressants on amygdala responsivity as a common mechanism of antidepressant drug action.

Figure 1. Effect of acute citalopram (20 mg orally) on amygdala response to emotional faces. Increased right amygdala activation in the placebo group associated with the contrast between unmasked fear and unmasked neutral faces and plot of mean percentage blood oxygen level-dependent (BOLD) signal change in this right amygdala cluster after acute oral treatment with citalopram and placebo. Image is thresholded at Z = 2.3, p = 0.05, corrected. Bars show the mean error bars show the s.e.m. Asterisks represent significant level of difference from placebo ( ** p < 0.01). Adapted from Murphy et al. [30] with permission.

Figure 2. Effect of acute mirtazapine administration (15 mg orally) on amygdala response to emotional faces. (a) Axial, coronal and sagittal images depicting significantly increased activation in placebos for the contrast fear versus happy facial expressions (images thresholded at Z = 2.0, p = 0.05, corrected) in the right temporal cortex, extending to hippocampus and amygdala (peak voxel 28, −18, −18). (b) BOLD percent signal change extracted from the significant cluster in the right temporal cortex to fear and happy faces. Error bars show s.e.m. **p < 0.01. Adapted from Rawlings et al. [32] with permission.

Apart from the study with high-dose intravenous citalopram, these neuroimaging observations of decreased amygdala responses after acute SSRI treatment support a role for serotonin in processing threat, but do not sit easily with the observed behavioural observations of increased recognition of fearful facial expressions with acute SSRI administration. It is therefore possible that the acute anxiogenic-like effects of SSRI treatment in healthy volunteers in behavioural studies do not involve the amygdala. It is also possible that if the SSRI were to increase baseline amygdala activity, there may be an apparent decrease in the response to a fearful face because a ‘ceiling’ level in amygdala response may be more easily reached. This possibility could be excluded using better characterization of baseline cerebral blood flow, with arterial spin labelling techniques in MRI.

(d) Subchronic effects of SSRI administration in healthy volunteers

(i) Behavioural effects

We have examined the effects of 7 days of treatment with SSRIs in healthy volunteers, because at this time point the effect of SSRIs to reduce ratings on clinical ratings scales of depression in depressed patients is apparent. We found further evidence of positive biasing in a number of tasks of emotional processing consistent with the effects seen after a single dose. For example, volunteers receiving 7 days' citalopram treatment (20 mg daily) were more likely to see ambiguous facial expressions as happy and to recall positive personality adjectives in a memory task. Repeated administration of citalopram also reduced threat-relevant processing—that is, opposite to the effects of acute administration. In particular, 7 days of citalopram reduced the perception of fearful, angry and disgusted facial expressions and reduced modulation of startle responses by threat-relevant pictorial stimuli [33]. These results support the argument developed above that early increases in fear processing with acute administration may reflect initial anxiogenic actions of SSRIs which reverse with repeated treatment.

Other studies have shown that repeated SSRI administration increases affiliative problem-solving behaviour and decreases submissive behaviour in healthy volunteers [34,35], showing a striking parallel to the increased co-operation and social dominance seen with SSRI administration in male vervet monkeys [36]. Such results suggest that antidepressants not only increase the processing of positive affective stimuli but also that these effects get translated into improved social interactions and behaviour. This suggests a mechanism by which antidepressants could produce an early remediation of aspects of the social dysfunction seen in depression.

(ii) Neuroimaging

Imaging studies with fMRI show neural effects that are congruent with the behavioural changes produced by repeated SSRI administration on emotional processing. For example, our group found that 7 days of treatment of healthy volunteers with citalopram (20 mg daily) attenuated the amygdala and fusiform responses to fearful facial expressions, again a pattern opposite to the neural biases reported in depression [37] (figure 3). This finding was confirmed in healthy volunteers with either citalopram (20 mg) or escitalopram (10 mg) [38] administered in a treatment for 10 days. The apparent persistence of this effect was shown in a further study where a lowered amygdala response to fear was apparent in volunteers who received escitalopram for a period of 21 days [39].

Figure 3. (a) Effect of 7 days of treatment with citalopram (20 mg daily) on the medial temporal lobe response to fearful facial expressions. Mixed effects whole-brain analysis, FMRIB Software Library (Oxford) clusters determined by Z > 2.3 and (corrected) cluster significance threshold of p < 0.01. (b) Extracted signal change from amygdala regions of interest showing decreased response to fear in both right and left sides in participants taking citalopram. Adapted from Harmer et al. [37] with permission.

In summary, the early effects of SSRI administration on the processing of positive emotional stimuli are maintained after one week of treatment, but the effects on threat processing are reversed. This pattern of effect—increased positive bias and decreased threat-relevant bias—seems relevant to the actions of SSRI treatment in both anxiety and depression. Neuroimaging data show that the amygdala and associated visual processing circuitry (the fusiform gyrus) are modulated by SSRI drug administration suggesting a mechanism by which these drugs may affect automatic emotional evaluation of these stimuli and associated changes in attentional processing.

(e) Studies in depressed patients

Functional MRI studies of SSRI drug administration in depressed patients have yielded results largely consistent with the effects of SSRI treatment in healthy volunteer models. However, the majority of studies to date in depression have examined long-term SSRI treatment and effects of drug treatment per se are therefore usually confounded by resolution of depressive symptomatology.

Thus, the increased neural responses to negative facial expressions seen in the amygdala, ventral striatum and fronto-parietal cortex in depression were normalized following eight weeks of SSRI treatment, accompanied by significant improvement in mood [40,41]. This treatment also increased coupling between the amygdala and prefrontal cortex, striatum and thalamus, suggesting dynamic changes within emotional circuits important in depression [42]. Treatment with venlafaxine for eight weeks also normalized decreased anterior cingulate responses seen to negative versus neutral affective stimuli in depressed patients as well as affecting insular responses as early as two weeks after treatment [43].

Recent evidence also suggests that SSRI treatment can normalize diminished responses to positive affective stimuli in depression, with increased extra-striate responses to happy facial expressions being seen after eight weeks of treatment and wide-spread normalization of hypoactive responses to positive affective stimuli after 22 weeks of treatment [44,45]. These findings in depressed patients suggest modulation of the same critical emotional and visual processing circuitry by SSRI treatment which is abnormal in depression.

Rather than reflecting relatively global actions of antidepressants on blood flow and related processes, these effects appear to be exquisitely modulated by stimulus valence. In particular, antidepressants appear to reduce visual and emotional processing of negative and threat-relevant emotional information while increasing the processing of positive and socially reinforcing emotional cues. While this is seen almost immediately in healthy volunteer studies, it has not been clear whether such effects are seen in neural response before mood change in depressed patients since assessments have always been carried out after at least two weeks of treatment.

In a recent study, we addressed this problem by randomizing depressed patients to either escitalopram or placebo for 7 days and examining the amygdala response to fearful faces after this period of treatment. Both placebo- and escitalopram-treated participants had very similar scores on the HAM-D at 7 days however, the patients taking escitalopram had significant lower amygdala responses. As expected, the amygdala responses of the placebo-treated patients were significantly greater than those of healthy controls. These findings suggest that in depressed patients short-term treatment with SSRIs can indeed remediate exaggerated negative emotional biases prior to clinically significant improvement in mood.

(f) Implications for antidepressant action and the ‘delayed’ clinical response

The findings which we have reviewed indicate that antidepressants can produce rapid changes in the processing of emotional information. Both acute and short-term SSRI treatment lead to positive biases in emotional perception and memory, that is, the opposite effects to those seen in the depressed state.

Although the effects of antidepressants on emotional processing appear to be present from the initiation of treatment, it is clear that time is needed before subjective improvement is substantial, although probably rather less than has traditionally been assumed. Our data suggest that antidepressants act on early and relatively automatic stages of information processing, prior to subjective improvement in clinical state. Indeed, both behavioural data from the dot-probe task and the neural loci of SSRI are consistent with a modulation of attentional processing of emotional stimuli even at very fast presentation times [23,33]. This is consistent with effects on initial orienting to these stimuli.

However, the subjective experience of depression is very much associated with conscious negative appraisal and evaluation of emotional life. How could this be altered by changes in automatic emotional processing? We suggest that the positive re-biasing of automatic processing produced by acute SSRI might, in an appropriate interpersonal environment, lead to changes in the strategic processing associated with conscious emotional experience. Such a psychological process might well involve ‘re-learning’ a range of emotional associations which would inevitably take time and exposure to a real-world environment. On this view, antidepressant drugs have ‘bottom-up’ effects on emotional processing which become translated into improved mood and conscious appraisal only over time and with experience of life in the context of new processing biases.

The notion that re-learning might be involved in subjective improvement in depression sits intriguingly with the observation that antidepressants promote synaptic plasticity in animal experimental studies [11]. It is possible that antidepressants can produce effects on synaptic plasticity independent of their actions on emotional processing and that the increased synaptic plasticity facilitates the emotional re-learning process which we have hypothesized above. But, equally, increased synaptic plasticity may be facilitated by the alterations in emotional experience produced by the antidepressant, perhaps analogous to the way in which manipulations of the external environment can also promote synaptic plasticity in animal studies [46].

Depression is a complex clinical syndrome characterized not only by lowered mood but also by vegetative and cognitive symptoms. How far can changes in emotional processing account for the resolution of this multiple symptomatology during the course of successful antidepressant treatment? We suggest that the changes in emotional processing we have described can indeed explain this kind of global improvement because attention and appraisal are of fundamental importance in how the brain decides what matters to it. Thus, the ability of antidepressant drugs to interfere with a preferential focus on negative stimuli means that the brain is once again open to emotionally positive information and positive interpretation of experience.

We have argued above that this effect, over time, could lead to greater reactivity and improvement in mood and a decrease in social and occupational withdrawal. In the same way, the lessening of preoccupation with negative themes could free up processing resources for tasks such as episodic memory which are typically impaired in the depressive state [47]. Equally, vegetative symptoms can be strongly influenced by attention and appraisal. For example, fluvoxamine treatment in depressed patients was associated with improvement in reported subjective sleep quality even though objectively measured sleep parameters showed a trend to worsen [48]. Of course, negative biases in information processing have long been a target of cognitive behavioural therapy for depression, and it is therefore of interest that antidepressant drugs may also act on similar emotional mechanisms but presumably at an implicit rather than explicit level.

If this hypothesis is correct one might expect that the early changes in emotional bias produced by antidepressant treatment would predict eventual therapeutic outcome and this proposal is supported by some preliminary evidence, which requires replication and extension [49]. It is also of great interest that negative biases in emotional processing may be persistent in recovered unmedicated patients who demonstrate abnormalities in behavioural and neural responses similar to those apparent in acute depression [50,51]. It would be predicted that such biases should be attenuated by continued antidepressant treatment. This may provide a mechanism for the established efficacy of antidepressant treatment in long-term maintenance therapy and a possible means of identifying patients who require it.


Is delayed onset of action of antidepressants just another myth ?

There's a lot of material on Google Scholar about delayed onset or early onset of action of antidepressants.
I chose this article to sum up what I'm wondering about : Two-week delay in onset of action of antidepressants: new evidence (2006)

Many sources purport that antidepressants have a delayed onset of action, measured in weeks rather than days. Recent data using weekly or daily mood ratings demonstrate that maximum improvement occurs during the first 2 weeks, with some improvement within the first 3 days. Methodological issues may underlie the delayed-onset hypothesis.

I read on every forum about depression that you have to wait for the medication to kick in, that it may take weeks. Some users even deny one can feel anything during the first days, even if other users feel something.

Finally, people get so used at being patient that they seem able to wait indefinitely for some illusory improvement.
To me, it looks like that kind of advice just teach patients to be. patient. And I don't think waiting passively for a medication-related improvement is a healthy thing to teach.

I even read in a book written for patients that you can wait "up to 12 weeks" for your depression to improve. It's an extreme example, but gives an idea of the kind of advice patients can be given. If an antidepressant doesn't work for you, waiting 12 weeks before switching to another medication seems excessive, to say the least.

Another lines from the article linked above :

Given these findings, it is pertinent to ask why the view that antidepressants have a delayed onset of action is so commonly held. There are two possibilites.

The first is imprecision concerning the use of the term "onset of action" when we really mean "time to substantial remission". This is understandable if we assume that patients want to know when they will feel much improved rather than when they will begin to feel a little better. The second is a failure to distinguish initial therapeutic benefit, which occurs within days of starting an antidepressant, from the concept of drug v. placebo separation, which accrues more slowly.

It has been clear this is false for a long time. The reason this became popular is also obvious, in my opinion. Patients are told this to convince them to stay on the drugs during the first two weeks, when side effects are strong. If you can get patients through the initial side effects and they develop tolerance, they will be unlikely to stop the drug at that point.

I'm not sure it's a myth, I experience it several times with amitriptyline. To be of note, I do have some autoimmune condition which usually makes me feel bad or very bad after eating, and amitriptyline improves that, but it takes several days to do so. Maybe it's antihistamine action which takes time for my body to heal, or another method of immune system suppression, but it does make sense to me that it some cases antidepressant action might be delayed. Maybe I also misinterpret what's happening, but I'm biased against antidepressants and this still happens with me. Other drugs like SSRIs don't work on me either. So YMMV, but I think there are plausible modes of action which can take time for drugs to kick in.

Patients are told this to convince them to stay on the drugs during the first two weeks, when side effects are strong. If you can get patients through the initial side effects and they develop tolerance, they will be unlikely to stop the drug at that point.

It sounds obvious to me now that you said it. I'm trying so hard to keep an open mind towards antidepressants that I tend to refrain from thinking that kind of things, but I have to admit the reason you give was approximately why I was interested in the subject of delayed onset in the first place.

And even if I try hard to keep an open mind, I often get a bit exasperated of reading on forums the same old things about antidepressants which keep people from judging by themselves.Denying that people can feel better after a few days or a few hours is close to denying what people feel when they think the medication get them more tired or whatever symptom that looks like a depression symptom.

When some people say on forums they feel something improving after a short time, other people tell them it must be some placebo effect because antidepressants need time to kick in.

Denying what patients feel only make them confused, until they don't know what they feel anymore.If you no longer know how you feel with a medication anymore, the only way left to judge if you need the medication is to trust your doctor. You become passive and surrender to medical advice alone.

Doctors can't predict what kind of psychoactive effects antidepressants will bring to each patient, so it's important not to contest too much what patients feel. Even if sometimes it may be some placebo effect or some nocebo effect, it's worth listening to what they feel.

lOL that is a silly reason.

Give proof for your absolutely horrible preposterous opinion.

One thing about depression is that it’s a phenomenon that’s completely enmeshed with a person’s life. I think the improvement is an interaction between the medication and other things in a persons life that change more slowly. If you sleep a little better, are more motivated, feel less anxious, etc. things in your life start to go a bit better and slowly your mood and perception of how you’re doing improves. That part takes time, regardless of how the medication works.

I sort of think that sustained changes in complex brain phenomena like mood require time. Notably there are some other treatments that also seem to accrue benefit slowly or after crossing some threshold (ECT, rTMS), but others that occur quickly (ketamine). So it seems like it can go either way.

There is one related thing I’ve been thinking about lately, which is the observation that when depressed patients get better they are often the last to realize what’s happening. What I mean is that if you ask friends and family, they often notice a difference (brighter affect, better appetite, more talkative, etc.) well before the patient reports subjective improvement. Sometimes this takes the form of improved scores on clinical rating scales, but if you ask the person they say they aren’t better. But, critically, in my experience this phenomenon often predicts subjective improvement, but it’s just delayed relative to these other indicators.

I don’t know if there is data on this, so it may only be another bit of common clinical wisdom subject to similar biases. For what it’s worth though, I see this all the time. It wasn’t something I was taught, but I have found that other psychiatrists have noticed the same thing.

I personally think there is something very important in this observation and it could in part be responsible for the delayed response topic of the OP. Depressed people are often extremely pessimistic and I think there is a fear of writing off treatments that might help too early. Antidepressants could start to work quite quickly, but if the those benefits don’t reach conscious experience right away then there is a perception that nothing is improving.

This brings up a lot of ancillary topics about how to quantify improvement that might be interesting to discuss. Anyway, it’s not an evidence-based observation - that I know of - but, at least sometimes, clinical wisdom must have a basis in reality. At least in my opinion.


Summary

Most currently available antidepressants target monoamine neurotransmitter function. However, a purely neurotransmitter-based explanation for antidepressant drug action is challenged by the delayed clinical onset of most agents and the need to explain how neurochemical changes reverse the many different symptoms of depression. Novel approaches to understanding of antidepressant drug action include a focus on early changes in emotional and social processing and the role of neural plasticity. In this Review, we discuss the ways in which these two different theories reflect different or complementary approaches, and how they might be integrated to offer novel solutions for people with depression. We consider the predictions made by these mechanistic approaches for the stratification and development of new therapeutics for depression, and the next steps that need to be made to facilitate this translation of science to the clinic.


Why do antidepressants take so long to work?

Antidepressants move G proteins out of lipid rafts in the cell membrane. Credit: Molly Huttner.

An episode of major depression can be crippling, impairing the ability to sleep, work, or eat. In severe cases, the mood disorder can lead to suicide. But the drugs available to treat depression, which can affect one in six Americans in their lifetime, can take weeks or even months to start working.

Researchers at the University of Illinois at Chicago have discovered one reason the drugs take so long to work, and their finding could help scientists develop faster-acting drugs in the future. The research was published in the Journal of Biological Chemistry.

Neuroscientist Mark Rasenick of the UIC College of Medicine and colleagues identified a previously unknown mechanism of action for selective serotonin reuptake inhibitors, or SSRIs, the most commonly prescribed type of antidepressant. Long thought to work by preventing the reabsorption of serotonin back into nerve cells, SSRIs also accumulate in patches of the cell membrane called lipid rafts, Rasenick observed, and the buildup was associated with diminished levels of an important signal molecule in the rafts.

"It's been a puzzle for quite a long time why SSRI antidepressants can take up to two months to start reducing symptoms, especially because we know that they bind to their targets within minutes," said Rasenick, distinguished professor of physiology and biophysics and psychiatry at UIC. "We thought that maybe these drugs have an alternate binding site that is important in the action of the drugs to reduce depressive symptoms."

Serotonin is thought to be in short supply in people with depression. SSRIs bind to serotonin transporters - structures embedded within nerve-cell membranes that allow serotonin to pass in and out of the nerve cells as they communicate with one another. SSRIs block the transporter from ferrying serotonin that has been released into the space between neurons - the synapse - back into the neurons, keeping more of the neurotransmitter available in the synapse, amplifying its effects and reducing symptoms of depression.

Rasenick long suspected that the delayed drug response involved certain signaling molecules in nerve-cell membranes called G proteins.

Previous research by him and colleagues showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic AMP, which they need in order to function. The dampened signaling could be why people with depression are "numb" to their environment, Rasenick reasoned.

In the lab, Rasenick bathed rat glial cells, a type of brain cell, with different SSRIs and located the G proteins within the cell membrane. He found that they accumulated in the lipid rafts over time—and as they did so, G proteins in the rafts decreased.

"The process showed a time-lag consistent with other cellular actions of antidepressants," Rasenick said. "It's likely that this effect on the movement of G proteins out of the lipid rafts towards regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work."

The finding, he said, suggests how these drugs could be improved.

"Determining the exact binding site could contribute to the design of novel antidepressants that speed the migration of G proteins out of the lipid rafts, so that the antidepressant effects might start to be felt sooner."

Rasenick already knows a little about the lipid raft binding site. When he doused rat neurons with an SSRI called escitalopram and a molecule that was its mirror image, only the right-handed form bound to the lipid raft.

"This very minor change in the molecule prevents it from binding, so that helps narrow down some of the characteristics of the binding site," Rasenick said.


Older Antidepressants: Tricyclics and MAOIs

These drugs were among the first to be used for depression. Although they're effective, they can have serious side effects and can be especially dangerous in overdose. Nowadays, many doctors only turn to these drugs when newer -- and better tolerated -- medicines haven't helped. Tricyclics and MAOIs might not be the best approach for someone who was just diagnosed. But they can sometimes be very helpful for people with treatment-resistant depression, or certain forms of depression (such as depression with anxiety).

  • Tricyclic antidepressants (TCAs) include amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), and nortriptyline (Pamelor). Like reuptake inhibitors, tricyclics seem to block the reabsorption of serotonin and epinephrine back into nerve cells after these chemicals are released into a synapse. Because of the potential side effects, your doctor might periodically check your blood pressure, request an EKG, or recommend occasional blood tests to monitor the level of tricyclics in your system. These medicines might not be safe for people with certain heart rhythm problems.
  • Monoamine oxidase inhibitors (MAOIs) include selegiline (Emsam), isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). These drugs seem to work a little differently. Monoamine oxidase is a natural enzyme that breaks down serotonin, epinephrine, and dopamine. MAOIs block the effects of this enzyme. As a result, the levels of those neurotransmitters might get a boost.
    The downside is that MAOIs also prevent the body's ability to break down other medicines metabolized by this enzyme (such as Sudafed, or stimulants) -- raising the risk for high blood pressure -- as well as an amino acid called tyrosine, which is found in certain foods like aged meats and cheeses. MAOIs also shouldn't be combined with other medicines that can raise serotonin (such as certain migraine medicines, or other antidepressants), because that can cause a buildup of excessive serotonin (called "serotonin syndrome"), which could be life threatening.
  • Nutraceuticals or “medical food” which includes l-methylfolate (Deplin). This is a prescription strength form of folate, also known as one of the essential B vitamins, B9. Depression is often related to low levels of folate which affect the neurotransmitters that control moods and l-methylfolate has proven to be effective in stimulating the production of neurotransmitters.

ELI5: Why does it take so long for mood stabilizing drugs such as antidepressants to work?

A few reasons. Medicines for mood generally (all that I know of, but I'm not licensed, just mentally ill, so) work by increasing some of the chemicals your brain uses to talk to itself. This starts right away, but it can take a while for the levels to get to normal numbers. Also, when you have the wrong levels of chemicals, you start thinking thoughts that aren't true, and they hurt you. The more you think these thoughts, the easier it becomes to think them, and the faster you can do it. It becomes a habit, like brushing your teeth. Because you do not have the normal chemicals for your brain, it is really hard to break that habit - you usually feel bad, and the thoughts make you feel worse, but because you felt bad already it can be really hard to think good thoughts. So even though the chemicals are usually at normal levels before you feel all of the effects for them, it takes a while for you to learn to think good thoughts. The good news is that any kind of thought can be a habit - so if you notice yourself starting to think bad thoughts again, you can redirect yourself to the good thoughts instead, and the more you think them, the easier and faster they will be. The thoughts and medicine work together so you can be healthy.

(Scishow actually has a great video on this on YouTube btw, and they do a great job of breaking things down to a layperson level, fact checking, and correcting themselves, historically, so I definitely recommend them! They talk a bit fast, so you might have to slow the video down slightly, but YouTube actually has that built in, and I would be more than happy to explain how if anyone needs it.)