Current antidepressants can take weeks to improve symptoms of depression.
New research explores reasons for this delay and provides clues to develop more rapid-acting drugs.
Key Facts:
- Most antidepressants increase brain serotonin and norepinephrine, but their mood benefits are delayed for weeks. Researchers are investigating other mechanisms that could explain this lag.
- Two leading theories focus on neural plasticity changes and effects on emotional processing biases. These may work together to produce clinical improvement over time.
- Studies of rapid-acting ketamine reveal it quickly increases growth of new brain cell connections. This contrasts with slower actions of standard drugs on connectivity.
- Some evidence suggests conventional antidepressants rapidly reduce negative emotional biases, but environment interactions are likely needed to translate this into mood improvements.
Source: Lancet Psychiatry
For 60 years doctors have prescribed antidepressant medications that increase brain serotonin and norepinephrine.
While these drugs provide relief for many battling depression, they typically take 2-4 weeks to substantially improve mood and other symptoms like low energy, poor concentration, altered sleep and appetite.
Scientists have long pondered why there is such a lengthy delay: the neurotransmitter changes occur within hours, so what explains the prolonged wait for clinical benefits?
Uncovering alternative mechanisms underlying the lag in antidepressant response is key to developing faster-acting options for this devastating and debilitating mental illness.
How Current Antidepressants Work in the Brain
Selective serotonin reuptake inhibitors (SSRIs) like Prozac and Zoloft prevent serotonin signaling molecules from being reabsorbed, leaving more available in brain synapses.
This rapidly blocks the serotonin transporter (SERT) protein that clears away serotonin after release, amplifying the signal between neurons.
Similar classes of medications have analogous immediate effects on the signaling chemical norepinephrine or both.
So why don’t mood improvements happen quicker if these critical mood regulating neurotransmitters are elevated so fast?
The Delayed Clinical Onset of Antidepressants Remains a Puzzle
The disjunction between immediate neurotransmitter changes but lagged symptoms relief led scientists to probe what downstream neuroadaptive effects evolve in the days and weeks after starting antidepressants.
By uncovering mechanisms that parallel the timeline of clinical efficacy, researchers hope to find alternative drug targets more directly linked to improving mood.
This could pave the way for faster medications.
Two leading theories suggest antidepressants may exert delayed mood benefits by:
- Stimulating Neural Plasticity
- Shifting Biases in Emotional Processing
The Neuroplasticity Hypothesis of Antidepressants
Brain imaging reveals patients with depression exhibit reduced gray matter volume in key areas like the hippocampus and prefrontal cortex important for memory, mood and cognition.
Chronic stress can diminish neural connectivity in these regions.
Animal research shows long-term traditional antidepressant treatment progressively strengthens structural and functional connections between neurons in these zones – enhancing overall neural plasticity.
For instance, the drugs boost brain-derived neurotrophic factor (BDNF), a pivotal protein facilitating neural growth and signaling.
Human studies corroborate this. Autopsies show lower BDNF levels in the hippocampus and prefrontal cortex of depressed patients compared to controls.
Chronic SSRI treatment gradually increases BDNF, likely enabling neural rewiring that supports symptom relief.
This time course mirrors when people generally note mood improvements around 6-8 weeks.
So one theory posits that by reversing deficits in neural plasticity and connectivity in areas like the hippocampus, standard antidepressants elicit their functional effects on mood down the road.
Ketamine Triggers Rapid Changes in Synapses to Treat Depression
In recent years, intravenous ketamine has generated excitement by producing quick antidepressant actions – often within hours – even for treatment resistant patients.
What explains its exceptionally fast effects?
Researchers are finding ketamine promptly activates remodeling of neural connections and reverses losses associated with depression, but on an accelerated timeline compared to traditional drugs.
Studies in rats show it rapidly stimulates BDNF release and growth of new dendritic spines – tiny postsynaptic compartments receiving signals from other neurons.
This ability to swiftly renew plasticity and connections may enable fast turnaround in mood for some people.
The synaptic effects stem from ketamine blocking NMDA receptors for glutamate – the chief excitatory neurotransmitter in the brain.
This unexpected NMDA receptor inhibition causes a burst of glutamate release, jumpstarting rebuilding of mood-regulating circuits disrupted in depression.
So by acutely restoring neuroplasticity through glutamate pathways, ketamine may bypass the delayed sequence induced by standard antidepressants like SSRIs.
Cognitive Effects: Early Emotional Processing Shifts with Antidepressants
Separate research reveals another dimension in play – antidepressants rapidly alter emotional processing biases within first doses, prior to mood changes.
Patients viewing images during brain scans show reduced amygdala reactivity to negative stimuli after just 7 days on SSRIs.
At a behavioral level, single doses of conventional antidepressants make healthy volunteers more attuned to positive facial expressions and social cues compared to negative ones – a relatively fast central nervous system shift detectable before mood improvements manifest.
For patients, those exhibiting early adjustments in reaction to positive emotional triggers are more likely to respond to continued standard antidepressant treatment.
Decreasing excessive negative bias may be vital first step underpinning efficacy.
However, weeks of environmental interactions are likely needed for patients to experience subjective mood gains from the emotional processing changes.
Perhaps rewiring maladaptive neural associations through life encounters enables translation to clinical improvements.
But what about rapid improvements with ketamine?
Ketamine’s Effects on Emotional Biases in Depression
There has been less focus on ketamine’s short-term impact on emotional and cognitive processing.
But intriguing animal research suggests that unlike standard drugs that mainly amplify positive acquisition, ketamine may rapidly reduce negative affective biases – diminishing already encoded aversive emotional memories in areas like the prefrontal cortex.
This combination of swiftly rebooting mood-regulating circuits together with potential acute reduction in reactivity to negatives could explain the exceptionally rapid effects for some people.
The psychological and cellular processes may synergize, linking reactive low mood with underlying biology.
Role of BDNF in Antidepressant Mechanism of Action
The protein BDNF figures centrally across these frameworks as a pivotal mediator of neuroplasticity no matter whether stimulated rapidly with ketamine or more slowly via standard antidepressants.
BDNF facilitates neural signaling, connectivity rewiring and overall resilience.
Studies show deleting the BDNF gene blocks behavioral benefits of both drug classes.
And special depressed individuals genetically vulnerable to low BDNF are less responsive to ketamine compared to counterparts, highlighting it’s integral for treatment success.
So enhancing release and signaling cascade effects of this pivotal neurotrophic protein could be a path to faster, robust mood improvements by targeting interconnected systems vulnerable in depression.
Integrating Cellular, Cognitive and Environmental Factors of Antidepressants
Putting all this together: conventional antidepressants may improve mood by progressively restoring neuroplasticity in emotion circuits, while lessening excessive negative emotional reactions to life encounters – with both effects accumulating over weeks of treatment.
Ketamine likely acts more rapidly on each domain via similar BDNF and glutamate pathways.
A key research goal now is exploring precisely how neuroplasticity processes relate to emotional and cognitive processing changes over varying timescales.
This can help understand combination therapies that most effectively produce rapid, reliable real-world improvements by harmonizing molecular, psychological and environmental dimensions.
Future Treatment: Multifaceted Antidepressant Actions
Elucidating multifaceted antidepressant mechanisms spanning neural connectivity, emotional biases and BDNF signaling pathways sets the stage for discovering faster-acting pharmacological options.
Patients ask year after year when something better will come along.
We now have leads to follow in terms of molecular targets and temporal sequences that may accelerate benefits.
Future studies building on the foundations covered here offer hope of transforming a longstanding medical dilemma that has left many without timely relief.
References
- Study: How to antidepressants work? New perspectives for refining future treatment approaches
- Authors: Harmer et al. (2017)
