Traditional Treatment vs. Our Programme

Conventional treatment for bipolar disorder type I:

Manic phases respond to Lithium, which can help stabilise moods. Patients may be prescribed antipsychotics, particularly for the symptoms of mania or psychosis which can occur, as can symptoms of severe depression.

For depressive phases, the view is to treat with Quetiapine and Lamotrigine, as well as a combination of Olanzapine and Fluoxetine (NICE guidelines), and in the USA Lurasidone, another antipsychotic:

• Lamotrigine: Despite Lamotrigine having been hailed as a treatment for bipolar disorder, most studies have shown that it is of little to no value in any of the acute phases of bipolar disorder. Please refer to table 2 in this paper. Lamotrigine may be helpful in the maintenance phase, but this needs to be weighed against the pros and cons versus Lithium. We personally do not recommend it because, as a recent metastudy concluded: ‘There is little or no strong evidence in support of (Lamotrigine’s) efficacy in acute mania, unipolar depression, or rapid-cycling (bipolar disorder).’

• Quetiapine: Is generally used in the depressive phases. Sometimes Lurasidone or Latuda is also used. The biggest problem clinicians face with bipolar disorder type I  and II is subthreshold bipolar disorders occurring within the condition between episodes of mania, depression, and hypomania. This means that patients may suffer manic phases shorter than 7 days, hypomanic phases shorter than 4 days, and mixed and depressive phases shorter than 14 days. It does not mean that the condition is milder, in fact, it is equally severe – particularly in the depressive phases.

Longitudinal studies have shown that subthreshold bipolar disorders are themselves a predictor of bipolar disorder type I further down the line, particularly in children and adolescents.  The presence of subthreshold bipolar symptoms in both bipolar disorder type I and type II when the manic/mixed/hypomanic/depressive episodes settle is very difficult to treat. It also predicts severe psychosocial dysfunction and disability, as well as marked treatment resistance.There isn’t anything published on the effectiveness of any treatment given in an attempt to control subthreshold symptoms of bipolar disorder type I and II, except this study on Quetiapine added to mood stabilisers which showed subthreshold symptoms were resistant to it when it came to full remission.

• Olanzapine and Fluoxetine combination: This combination has a remission rate of 48.8% and a striking side effect profile. Weight gain and diabetes are long-term risks with this treatment.

Treatment for bipolar type II

In their World Mental Health Survey Initiative, the World Health Organisation found that 0.4% of the global population is estimated to suffer from bipolar type II. This makes up 16.6% of all bipolar disorders.

Typically the condition is plagued with failure of diagnosis. This is often because firstly clinicians fail to ask about periods of hypomania (similar to mania but not as severe). Secondly, patients do not feel that they are impaired during these phases (because they are still functioning) and so forget to mention them.

Traditional treatment for bipolar type II:

For hypomanic phases, there is no distinction between bipolar I and II in the treatment of any phase of either condition.

For depressive phases, the view is to treat with Quetiapine and Lamotrigine, Lurasidone or a combination of Olanzapine and Fluoxetine:

• Lamotrigine: NICE advocates Lamotrigine to treat bipolar disorder type II, despite research studies showing that Lamotrigine is of no value in the treatment of bipolar disorder type II.
• Quetiapine: The use of Quetiapine is also recommended but many patients complain of side effects, in particular: tiredness, lethargy, lack of energy and lack of creativity. It is effective in inducing remission in depressive phases but ineffective for subthreshold symptoms in this condition, which predicts poor functioning and a high relapse probability, as per this paper.

Treatment for subthreshold bipolar disorder

Subthreshold bipolar disorder is a rapid cycling condition. There is an overall agreement across guidelines regarding the treatment of bipolar disorder type I and II, but there is far less scientific evidence and certainty regarding the treatment of subthreshold presentations. To date we can find no effective treatments published for subthreshold bipolar disorder, despite it making up the greatest majority of bipolar disorders.

The National Institute for Health and Care Excellence (NICE) provides guidance, advice, quality standards and information services for health, public health and social care. Unfortunately current (NICE) guidelines on bipolar only make recommendations for assessment and treatment of bipolar disorder type I and II, excluding subthreshold bipolar disorder. The NICE draft for consultation agrees that there is a concept known as bipolar spectrum, yet makes clear that the guidelines only refer to bipolar type I and II. And in spite of the fact that subthreshold bipolar sufferers are actually the majority.

What plagues this condition is what is known as rapid cycling, whereby people can experience 4 or more mood changes in a year. Sometimes the presentation is of several moods in a day or multiple mood changes over a week or so. We call this ‘change of polarity’. The problem for clinicians has been that there are no distinct episodes of 7 days of mania, 4 days of hypomania and 2 weeks of depression, as described in bipolar I and II. This means, if clinicians follow the NICE guidelines, subthreshold bipolar disorder falls off their radar and gets diagnosed as depression or Treatment-Resistant Depression (TRD).

In the NICE guidelines bipolar disorder is described as 7 days of mania or 4 days of hypomania. It fails to include people who may experience (for example) 3 days of mania or 2 days of hypomania. Do they not count as bipolar patients?

Those who don’t fall into the 7 days of mania (of bipolar I) or 4 days of hypomania (in bipolar II), i.e. those with subthreshold bipolar disorder, actually make up around 55-60% of all people with bipolar disorders. That is a very large number of people.

Given the impact on quality of life that subthreshold bipolar disorder has, and the fact that it fails to respond to the standard treatment, this condition needs much more awareness, training and recognition in the UK.

Indeed, in the United Kingdom, sadly, clinicians are not trained to look for signs of subthreshold bipolar disorder or treat it. The result is that these patients are usually misdiagnosed with depression and are treated with a combination of Cognitive Behavioural Therapy (CBT) and antidepressants.

In fact, 40% and 70% of people with “major depression” have subthreshold bipolar disorder and can be directly harmed by treatment with antidepressants. They tend to be diagnosed with treatment-resistant depression (TRD) and prescribed many antidepressants which can make the condition worse in the long run.

Treatment for rapid cycling

How does rapid cycling come into play? Rapid cycling is a pattern of bipolar activity. It can occur in all forms of bipolar disorder and makes the condition treatment-resistant.

Bipolar disorder is considered to be rapid cycling when it involves four or more changes in mood or ‘episodes’ in a 12 month period. It can be precipitated by stress, alcohol, drug use, caffeine (even decaffeinated drinks) and/or head injuries.

The NICE guidelines state that there is no strong evidence for treating rapid cycling any differently to non-rapid cycling bipolar disorders.

However, grade 1 evidence (the highest grade class of evidence) from Calabrese et al, and Kemp et al shows that this is incorrect, as treatments for non-rapid cycling have been shown to be ineffective in rapid cycling. Specifically, that rapid cycling is resistant to Lithium, and Valproate, even when Lamotrigine is added. In addition, subthreshold bipolar disorder (a rapid cycling condition) is resistant to Quetiapine.

In short, the recommendation to treat rapid cycling bipolar disorder (RCPD) no differently to non-rapid cycling bipolar disorder leaves RCBP disorder patients without treatments tailored to their specific condition, exposing them to risks of the illness and side effects of ineffective treatment without any benefits.

The Maudsley Prescribing Guidelines in Psychiatry is the essential evidence-based handbook on safe and effective prescribing of psychotropic agents for medical professionals. When it comes to rapid cycling, the Maudsley guidelines outline a number of medications to consider, with the preferred options in bold. This is due to the presence of evidence that is backed by randomised placebo-controlled trials.

There are three drugs (see below) backed up with randomised controlled trials, and these are marked as “preferred agents” in the Maudsley guidelines. However, all is not as it seems, as these randomised controlled trials were flawed. We explain:

• Aripiprazole: In the randomised controlled trial, there were dropout rates of 50%. If you were to apply what is known as ‘intention to treat analyses’, which takes into account the dropout rates, the drug will be considered ineffective.
• Quetiapine: The randomised controlled trial lasted only 8 weeks. To treat rapid cycling you need a period of stability of at least 16 weeks. In addition, the trial also looked at an endpoint, which is not good enough in rapid cycling. This is because the current cycle may have an endpoint at 8 weeks, meaning patients appeared well, however it may just mark the end of their current cycle. The reality is that at the 8 week endpoint the patient may go into another cycle. We were unable to obtain drop out rates on Quetiapine.
• Olanzapine: The randomised controlled trial looked at rapid cycling patients but only studied the mania phase of bipolar type I. In addition, the study was only for a very short period of 3 weeks with a high drop out rate of over 50%. This is not long enough to judge whether the condition responds to treatment or not.

In our opinion, the Maudsley guidelines should have included Levothyroxine as a treatment option. Why? A successful randomised controlled trial by Walshaw et al, looked at the use of Levothyroxine in high doses. The trial showed it to be effective at reducing cycle frequency and severity, increasing time in normal mood and decreasing depressive, manic and mixed symptoms in rapid cycling. Side effects were mild and largely not very different from placebo. This trial ran for 16 weeks (longer than all randomised controlled trials above). Due to the low numbers in the trial, a specific statistical analysis had to be conducted to compensate for this. Of the studies mentioned above, the Washaw et al. study is probably the best as it took account of weekly changes of mood rather than end points, had only a 8.6% dropout rate, and ran for an extended period of 16 weeks. However, like other treatments, it failed to induce remission in RCT.

Here at The London Psychiatry Centre, we know how much subthreshold bipolar patients suffer, and we deployed our bipolar treatment protocol for years accordingly. Unlike other treatments for bipolar disorder that are ineffective for subthreshold bipolar disorder and subthreshold symptoms within bipolar I and II, The London Psychiatry Centre’s groundbreaking bipolar treatment programme offers evidence-backed, truly effective treatment for subthreshold bipolar disorder. The protocol induces long, stable remissions with a substantial reduction in disability and few reversible side effects upon Levothryoxine dose reduction.

Treatment For All Types Of Bipolar Disorder With Our Programme

The London Psychiatry Centre’s groundbreaking programme uses precision medicine to treat bipolar disorder with a combination of mitochondrial treatment, rTMS and high-dose Levothyroxine. This paper in Frontiers in Psychiatry explains more on how our protocol works.

Our programme is backed by two evidence-based, peer-reviewed papers published by The London Psychiatry Centre in the International Journal of Psychiatry Research, and the Journal of Clinical Medicine.

Our published cohort studies are recommendation Grade B, the highest grade of recommendation published for subthreshold symptoms in bipolar type I and II as well as subthreshold bipolar disorders. It is also the only one which shows total remission of subthreshold and severe rapid cycling mixed/depressive symptoms across the whole spectrum of bipolar disorder (type I, type II, and subthreshold) as of 2022.

Below you will find a brief overview of the differences between traditional treatment for bipolar and our treatment programme.