Researchers may have found an 'antidepressant roadblock'

8 August 2016

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'Hope for faster treatment for depression after scientists discover why antidepressants can take months to work,' the Mail Online reports. New research suggests manipulating the brain's Gα protein may accelerate the effect of the drugs.

Currently the most widely used antidepressants belong to a class called selective serotonin reuptake inhibitors (SSRIs). These are thought to increase levels of a neurotransmitter called serotonin, which can improve mood and emotion.

However, SSRIs can be slow to act, taking from one to four weeks before any benefits start to take effect. Why they can be slow to act is poorly understood.

The research suggests a protein in the brain – called the Gα protein – acted as a kind of chemical roadblock, slowing the redistribution of SSRIs to the brain cells that will respond to it.

This was an early-stage experiment in rats. We don't know that this provides the whole answer, and findings would need to be confirmed in humans.

It is also important to stress that when it comes to antidepressants, more doesn't mean better. Taking more than your recommended dose can be extremely dangerous.

While antidepressants can be useful in helping relieve the symptoms of depression, the cause is not always addressed. 

Cognitive or talking therapies are often considered a first-line option for depression, or are combined with drug treatment to try to give the best response.

Where did the story come from?

The study was carried out by researchers from the University of Illinois and was funded by the VA Merit award.

It was published in the peer-reviewed Journal of Biological Chemistry on an open access basis, so it is free to download as a PDF.

This study has been reported accurately by the Mail Online. But while the website does point out that the study was in rats, it does not discuss the inherent limitations of animal studies.

What kind of research was this?

This animal study in rats aimed to create a better understanding of the delay in the action of antidepressants and find a way to develop faster-acting treatments.

Depression is common worldwide and a leading cause of long-term disability. Many people who are treated with antidepressants do not respond to treatment.

There is a need for a better understanding of how these drugs work, particularly why they can take several weeks to see any effect.

Many people take their own lives during the first few weeks of their drug treatment. Accelerating the effects of antidepressants could potentially save many lives.

Animal studies are often used in the early stages of research to see how biological processes may work in humans.

However, we are not identical to animals, and findings would need to be followed up in humans to confirm that the same effect is observed.

What did the research involve?

This was complex laboratory research using rat cells to observe the mechanisms of action of antidepressant medications, and the effect on cellular proteins and messenger molecules like serotonin (also known as a monoamine neurotransmitters).

Researchers used a particular type of rat brain tumour cell called C6 glioma cells, because they lack monoamine or serotonin transport proteins in their membranes. 

This, while not identical, mimics the chemical make-up of the 'depressed brain' in humans; a brain with low levels of serotonin.

Previous studies have shown antidepressant drugs relocate transport proteins called Gα to the lipid membranes.

This redistribution is in turn thought to affect levels of the signalling molecule cyclic adenosine monophosphate (cyclic AMP, or cAMP), which controls many metabolic processes.

Cells were soaked in various types of antidepressants in the laboratory. The accumulation of the medications was measured by UV absorbance and spectroscopy to identify the different substances within the cells.

The researchers aimed to look at the composition of cells to investigate their theory about the effect of antidepressants on Gα proteins and cAMP.

What were the basic results?

The researchers believe the cause for the delayed action of antidepressants is partly because of their effect on redistributing Gα proteins to the lipid cell membranes.

They demonstrated that the entry of antidepressants into the cell doesn't rely on serotonin reuptake transport protein.

Gα proteins are gradually redistributed to the cell membranes, where it then activates cAMP signalling. 

The extent of Gα protein redistribution was dependent on the dose or concentration of the antidepressant and the duration of exposure.

This gradual distribution and signalling effect may be responsible for the delayed mechanism of action of the drugs.

How did the researchers interpret the results?

The researchers concluded that, 'It appears that at least one action of antidepressants is to accumulate in lipid rafts and mediate the movement of [Gα proteins] out of lipid rafts. This may represent a novel biochemical hallmark for antidepressant action.

'Furthermore, identification of the antidepressant-sensitive molecular anchor for [Gα proteins] in lipid rafts may lead to the development of more targeted therapies for depression, including compounds that may have a much more rapid course of action.'

Conclusion

This experimental study in rat brain cells investigated the delay in the action of antidepressants. This research hopes to aid the development of faster-acting treatments in the future.

It is thought antidepressants work by increasing levels of neurotransmitters, such as serotonin, in the brain – chemicals that can improve mood and emotion.

The researchers' experiments in rats found antidepressants seem to lead to a gradual redistribution of Gα proteins to the lipid membrane of the brain cells, which in turn affects signalling processes.

However, this is a slow process that seems to depend on the dose of antidepressant and the duration of exposure.

The delay in antidepressant action is not fully understood. This research helps take us one step closer to understanding this, and hopefully from this developing faster-acting treatments.

But this was an early-stage experiment in rats. We don't know that this provides the whole answer, and findings would need to be confirmed in a human study.

While these findings may guide future drug research, it is far too early to assess how long they will take to come to fruition (or if at all).

While antidepressants can treat the symptoms of depression, the cause is not always addressed.

Cognitive or behavioural therapies are often considered to be a first-line option for depression, or combined with drug treatment to try to give the best response.

If you're concerned that your symptoms of depression are failing to respond to drug treatment, contact your GP or the doctor in charge of your care as soon as possible.

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