Bipolar UK asks Professor Stephen Bazire, Honorary Professor at the School of Pharmacy, University of East Anglia, and Director of Mistura Enterprise and Mistura Informatics, to help clear up the confusion about bipolar and sodium valproate.

What is sodium valproate? 

Firstly, we need to get name(s) clarified, as it can be confusing. The active molecule is actually called valproate but, to be soluble in water, needs to be made into a salt. These are mainly sodium valproate, valproic acid and semisodium valproate. The therapeutic effect is the same regardless of the salt. 

Sodium valproate was first launched in the UK in 1977 as Epilim®. Sodium valproate and valproic acid are now available in the UK under many brand names including Epilim®, Convulex®, Episenta®, Epival®, Epilim Chrono®, Epilim Chronosphere®, Dyzantil®, and many others. Just to add to the complexity, valproate semisodium (called divalproex in America and Canada) is marketed as Depakote® and Syonell®. You may even see mention of another derivative called valpromide (e.g. in the USA). 

Valproate has two main uses. Firstly as a treatment for epilepsy, to help control or prevent fits (seizures or blackouts). Secondly, to help in mood disorders, especially if the person is experiencing mania or hypomania, and as a longer-term mood stabiliser.

What bipolar symptoms does sodium valproate treat? 

Valproate has been used for many years to help manage manic and hypomanic symptoms, often with other medicines, but is much less useful for bipolar depression. Higher doses (e.g. 1000-2000mg a day) can be helpful for getting on top of the acute symptoms of mania early to help stop them getting worse. 
 
Valproate seems to be effective in both bipolar type 1 and bipolar type 2 in treating manic and hypomanic symptoms. It is not usually much help for bipolar depression, but it does work differently for different people.

How does sodium valproate work? 

It is not clear exactly how valproate works – there are several explanations but no definitive answer.
 
One theory is that there is a neurotransmitter (a chemical messenger) in the brain called GABA, which works to calm the brain down. Once GABA has done its job, enzymes in the brain break GABA down so that it can no longer work. 
 
In people with normal levels of GABA this prevents there being too much GABA; however, it is thought that there may not be enough GABA in the brain for some people. This lack of GABA may ‘trigger’ fits in people with epilepsy or over-activity/mania in people with bipolar. Valproate helps to stop the breakdown of GABA, leaving enough of this chemical in the brain to help prevent the fits, blackouts and over-activity.
 
Another theory is that valproate may stop what is called the ‘repetitive firing of neurones’. When a message is passed in the brain, there is a short gap (called a refractory period) before the next message can be passed, during which time the nerve ending re-sets itself (in about one thousandth of a second). 
 
Valproate may increase this ‘refractory’ period or time by a small amount. Normally, this would make no difference at all. But if the brain is overactive and lots of messages are being passed in quick succession (e.g. when you are feeling driven or high), the effect of the valproate will be to slow the number of messages back to the normal level.

Who can be prescribed sodium valproate? 

At the moment, in the UK, anyone with epilepsy or bipolar can, at least theoretically, be prescribed valproate but there are significant restrictions for prescribing and what the person must agree to do, outlined below.

Why are the regulations changing for sodium valproate?

It has been known since the 1990s that valproate has a risk of harming unborn babies. When I was a member of the first NICE bipolar guidelines panel in 2004, we included a caution about valproate in pregnancy but the severity of this effect has only been fully identified over the last decade or so. 
 
As more data has become available, the UK has continued to update its regulations.

What are the new regulations? 

In 2019, the UK imposed a ban on prescribing valproate for any female of childbearing potential unless:

  • There is no effective alternative AND
  • The prescription is approved by two specialists, independently AND
  • The female agrees to be on the UK “Pregnancy Prevention Programme” (PPP) and follow the conditions.

Sadly, this message hasn’t gotten through to everyone and in June 2021, NHS England released a letter to be sent to every female taking ‘sodium valproate’, with reminders about contraception, pregnancy and regular reviews. 
 
On 31 January 2024, even stricter guidelines were released:
 
If you are under 55 and already taking valproate (male and female):

  • Females must be on the Pregnancy Prevention Programme (see below) 
  • Males must talk to their prescriber about the safety and risks for their fertility

If you are under 55 and may start taking valproate (male and female):

Valproate can only be started in someone aged under 55 (male or female) if: 

  • Two independent specialist consultants agree that there is no alternative treatment (either because the others have too many side effects or do not work for you) AND
  • It is clear that there are no reproductive risks

The UK Valproate Pregnancy Prevention Programme:

If you could get pregnant (‘a woman of child-bearing potential’), however unlikely, you must:

  • Be on the UK “Valproate Pregnancy Prevention Programme” and follow their rules AND
  • Use ‘highly effective contraception’ the whole time you are taking valproate (see definition below) AND
  • Have an annual review with your doctor, the first with a second specialist, and complete the ‘Annual Risk Acknowledgement Form’ AND
  • If you find you are pregnant you must seek expert medical help within the next 24 hours. Healthcare professionals will help you to stop valproate as quickly and as safely as possible.

What is the definition of ‘highly effective contraception’? 

Even the Pill plus an extra form of contraception such as a barrier method (e.g. condom, cap etc) is not considered effective enough. Women must have a ‘user independent’ form of contraception, such as an intrauterine device or implant. 
 
User independent means that it does not need the person themselves to remember to do anything.iIt could include a long-acting reversible contraceptive (LARC), a copper intrauterine device (Cu-IUD), levonorgestrel intrauterine system (LNG-IUS), progestogen only implant (IMP), or female sterilisation, all of which have a failure rate of less than 1%. 
 
If you are switching from valproate to another medicine, these rules apply until the switch is complete.

What is the risk for males?

For males, the situation is less clear than in females. In January 2024, the European Medicines Agency warned about men taking valproate in the 3 months before conception, as this has been linked to neurodevelopment disorders (problems with brain development) in the child, as well as an effect on fertility. These neurodevelopment disorders include autism, learning disability, ADHD, communication disorders, and movement disorders. 
 
The research showed (but did not prove, as there were some errors in the study) that around 5 out of 100 children had a neurodevelopmental disorder when born to fathers who had taken valproate, compared with around 3 out of 100 when born to fathers who took lamotrigine or levetiracetam. The UK regulators are reviewing all the data as of 2024. 
 
Any male patients who start taking valproate will need to fill in a new ‘Risk Acknowledgement Form for male patients starting valproate’. 

What is the risk to an unborn baby?

There is a risk of major congenital problems for children exposed to valproate in pregnancy. This can occur in about 1 in 10 (11%) babies (e.g. a 1 or 2 in 100 (1-2%) chance of spine problems, such as spina bifida).
 
Once born to a mum who took valproate in pregnancy, there are further possible problems for the child:
 
Neurodevelopment (brain development)

  • Up to about 30-40% (1 in 3) of these children may have a permanent disability due to neurodevelopment brain disorders
  • Autistic spectrum disorders are about 3-5 times more common in these children than in the general population
  • ADHD (attention deficit hyperactivity disorder) may be more likely in these children
  • Delayed development, such as talking and walking, low intellectual abilities, poor language skills, and memory problems are also more common in these children

IQ 

  • There is a higher chance of a child having higher educational needs, and having their IQ lower by about 7-10 points (although breastfed children do much better)
  • In one study, at 6 years of age, the average child IQ of a child born to a mother who took valproate in pregnancy was 97, which is on average 10 points lower than if the mother took other anticonvulsants such as carbamazepine, lamotrigine or phenytoin during pregnancy
  • Average IQs for the children were higher if the mother also took folic acid throughout pregnancy (get this prescribed for you to get the right dose)

Physical 

  • Hearing impairment or deafness in the child is also more likely, due to ear and/or nose malformations and/or to a direct effect on hearing itself. If this occurs, it seems to be a permanent effect in most children

What’s the best way to come off sodium valproate?

Unless you become pregnant, you should make any changes gently. A sudden or abrupt change isn’t treating your brain with respect and can leave you vulnerable to relapse. So, you will need to plan in advance. 
 
Get advice from your doctor who will closely support you to make a slight reduction in your dose every few weeks and introduce any new medications in the safest way possible. This will give your brain time to adapt to the change. 


Last updated: 18 June 2024