• The Future of Schizophrenia by Dr Jack Lewis

    Schizophrenia often involves hallucinations and delusions

    Schizophrenia often involves hallucinations and delusions

    One in a hundred adults suffer from the brain illness known as schizophrenia (for full fact sheet please click here), which means that you probably know somebody who developed this condition during the transition between adolescence and adulthood. If you happened to know them quite well, you may have noticed the very drugs that suppress the “positive symptoms”  – e.g. delusions and hallucinations – also have several unwanted side that can exacerbate the “negative symptoms” that leave them listless, unable to concentrate, unmotivated, unsociable, unemotional and, quite frankly, bored out of their brains.

    Positive symptoms are usually reliably controlled in most schizophrenic people (assuming they can tolerate the side effects) using clozapine – an anti-psychotic medication that works in mysterious ways and even in the majority of patients who gain no benefit from the wide variety of other drugs. With psychosis successfully supressed by such drug therapy, it is the negative symptoms and cognitive dysfunction that are by far the most severe impediment to a schizophrenic individual being properly integrated into society and able to live a relatively normal, independent life. The biggest hope for an effective therapy in the coming few decades stems from a combination of drugs that increase brain plasticity and cognitive training, which together might help schizophrenic people to develop a whole host of social skills and basic mental processes that have become compromised during disease progression.

    In this article I have tried to give an easily comprehensible overview of the state of play in schizophrenia treatment to date and where it might be headed in the next few decades. Please leave a comment at the very bottom of this page to let me know how successful I have (or have not!) been in achieving this aim.

     

    Cannabis strains bred to have very high levels of THC such as "skunk" are a common trigger of schizophrenia

    SCHIZOPHRENIA DEVELOPS VIA A COMBINATION OF GENES AND ENVIRONMENT

    I became interested in schizophrenia, well before I started my Neuroscience B.Sc., as a couple of childhood friends developed it in their teens; a typical scenario with this disease. The schizophrenia was almost certainly triggered in one of these boys through smoking copious amounts of an extremely powerful strain of Cannabis sativa known as skunk; selectively bred to contain excessively high levels of the neuroactive cannabinoid delta-9-tetra-hydrocannabinol (“THC”). The trigger in the other was almost undoubtedly chronic emotional distress suffered at home and at school. I thought it was a curious brain illness even then because it clearly involved both a genetic predisposition (both had a history of schizophrenia in their families) as well as an environmental trigger (psycho-active “chemical” trigger in the first and “anxiety” trigger in the second).

    Regarding possible causes of schizophrenia, genetic abnormalities typically found in families with a high incidence of schizophrenia is becoming extremely well-defined thanks to some extensive gene linkage studies. However it seems that bacterial and/or viral infections in the womb may also potentially play a role in predisposing a developing foetus to schizophrenia later in adult life.

    WHAT SCHIZOPHRENIA ISN’T

    Schizophrenia is a broadly misunderstood brain illness. This may stem from the original naming of the condition back in the days when it was first identified and poorly understood. Eugen Bleuler cut and shut together the Greek words for split (“skhizein”) and mind (“phren”), thus planting a misleading seed by suggesting that schizophrenia is defined by some degree of split personality (it is not).

    WHAT SCHIZOPHRENIA IS

    An artists portrayal of a schizophrenic auditory hallucination

    An artists portrayal of a schizophrenic auditory hallucination

    As mentioned briefly above, schizophrenia is a psychotic condition featuring a variety of “positive symptoms” – a term which collectively describes the effects of brain processes that are “in addition” to the “normal” functioning of the mind, and “negative symptoms” – describing attributes which suggest a removal or lessening of emotional responses or certain healthy thought processes.

    Positive symptoms include hallucinations – seeing and/or hearing things that are not actually there, delusions – mistaken beliefs that are not consistent with the real world, often involve an element of paranoia and the idea that thoughts are being implanted or monitored by some kind of external force to guide behaviour or snoop on private thoughts: e.g. couch potatos might believe that this external force is the television, religious individuals might attribute this perceived external influence as God, die hard X-files fans and UFO spotters may be inclined to believe it is some kind of extraterrestrial force etc. The intrusion of hallucinations and deluded thought processes makes normal interaction with the outside world much more challenging and lead to considerable confusion.

    Larger fluid filled ventricles (black holes in image) in twin with schizophrenia compared to twin without

    Larger fluid filled ventricles (black holes in image) in twin with schizophrenia compared to twin without

    Negative symptoms include low levels of motivation, social withdrawal, absence of emotional responses and depression. The negative symptoms are often overlooked in favour of the more bizarre and attention grabbing aspects of psychosis, however it is these negative symptoms that psychiatrists are almost powerless to treat effectively.

    Schizophrenia involves decreased prefrontal brain function (inducing impaired cognitive function), grey matter loss and enlarged ventricles. I distinctly remember learning during my first degree that schizophrenic brains had enlarged third ventricles and that there was something of a chicken-and-egg debate going on at the time regarding whether this was a cause or an effect of the condition. This debate has moved on over the past decade to the proposition that neuroinflammation might cause the schizophrenic brain to deviate from the normal course of neurodevelopment. The possibility of using anti-inflammatory agents to reduce disruption to normal brain development in schizophrenia and other brain illnesses is now a subject of active research.

    HOW THE DRUGS WORK (IN EVERYDAY ENGLISH) – AND WHY YOU’VE GOT TO STAY ON THEM

    Anti-psychotics like risperidone work by preventing dopamine from binding with their receptors facing into the synapse and thus reducing the effect of any released dopamine on adjacent brain cells

    Anti-psychotics like risperidone work by preventing dopamine from binding with their receptors facing into the synapse and thus reducing the effect of any released dopamine on adjacent brain cells

    Positive symptoms like hallucinations and delusions are adequately controlled in the majority schizophrenic patients using anti-psychotic drugs to suppress the excessive levels of dopamine in the mesolimbic system that actually causes the psychosis. But once a person starts feeling better, and “back to normal” they, quite understandably, can feel like they are “all fixed up” and so stop taking their drugs. Of course without the drugs to suppress the “crazy thoughts” (a term we could use to put hallucination/delusion into everyday parlance) the psychosis returns… with a vengance. This is because the medication isn’t “fixing” the brain in anyway. Anti-psychotic medication is merely plugging a leaky pipe with a cork, not soldering the hole permanently shut! The treatment only works by keeping levels of the drug swimming around in the brain at just the right concentration to “normalise” limbic dopamine levels. This can only be achieved by adding regular doses of fresh drug to replace that which has been broken down by the body and brain’s natural metabolic processes. Once the drug levels in the brain begin to diminish there is nothing there to dampen the excessive dopamine hyperexcitability in the mesolimbic systems that generates the psychosis in the first place and so the psychotic thoughts gradually returns. Take the “cork” away and the “waters of madness” start to flow again (strictly speaking a more accurate metaphor would be along the lines of laying down some plastic sheeting so that the floor doesn’t get wet – but hopefully you get the gist!).

     

    Drugs that affect dopamine levels will alter communication not just in mesolimbic tract (desired target of anti-psychotic drugs) but also nigrostriatal tract (undesired side effects)

    ANTI-PSYCHOTICS CANNOT SUPPRESS DOPAMINE LEVELS IN ONE BRAIN AREA AND NOT THE OTHERS – UNAVOIDABLE SIDE EFFECTS

    Keeping schizophrenic patients motivated to keep taking their anti-psychotics is half the struggle for psychiatrists. Unfortunately this job is made even harder because it is not possible to focus a drug effects on any one brain system. Once a psychoactive drug crosses the blood brain barrier – which acts like a passport control at immigration, only letting substances that have the correct “documents” into the brain and refusing entry to all others – it is then free to move anywhere in the brain and will spread more-or-less evenly throughout it.

    Anti-psychotic drugs are given with the intention of reducing dopamine levels in the network of brain areas involved in causing the psychosis, but unfortunately it also reduces dopamine levels everywhere else in the brain. This means that all brain systems that use dopamine to send messages across the synapse from one brain cell to the next will also be slightly suppressed. Therefore patients on dopamine-suppressing medications benefit from a reduced incidence of hallucinations and delusional thought processes (i.e. the desired dopamine-suppressing effects on mesolimbic networks), but also suffer side effects such as their movement becoming jerky and harder to initiate (i.e. the undesired, but unavoidable, dopamine-suppressing effects on nigrostriatal networks). Over the past decade our understanding of which of the many available anti-psychotic drugs cause the fewest or least severe unwanted side effects has improved dramatically and now psychiatrists are very good at tailoring treatment to individual needs.

    THE FUTURE OF SCHIZOPHRENIA TREATMENT – DRUGS FOR NEGATIVE SYMPTOMS ON THE HORIZON?

    Recent gene linkage studies have confirmed that sections of DNA involved with the dopamine system don’t seem to be quite right in schizophrenic patients, but have also indicated that genes involved in the regulation of the glutamate neurotransmitter system are also disrupted. The increasing acceptance of the glutamate hypothesis of schizophrenia has reinvigorated hope for much needed novel drugs to treat all facets of this condition. It has stimulated a flurry of research activities which are now proving to hold great promise for future drug therapies that might target not just the positive symptoms of psychosis but also the negative symptoms and cognitive dysfunctions like poor verbal memory and information processing problems that pose such difficulties for schizophrenic people.

    Negative symptoms of schizophrenia include social withdrawal

    Negative symptoms of schizophrenia include social withdrawa

    Indeed, drugs that reduce NMDA glutamate activity in the prefrontal cortex are known to induce many of the negative symptoms observed in schizophrenia. The flip side of this is that drugs that boost glutamate activity might be able to reverse both the cognitive deficits and alleviate the negative symptoms that so profoundly reduce the quality of life of schizophrenic individuals. Again even these potential future therapies will suffer the same old problems of unwanted side effects that unavoidably arise with all psychoactive drugs, particularly as glutamate communication across the synapse is very prevalent throughout the whole brain. That said if the aim is to improve neural plasticity to make cognitive training and other non-drug therapies more effective, then possibly the side effects may not prove quite as tricky as with modulating dopamine levels. We have a long way to go before these therapies are fully tested and ready to roll out in the battle against schizophrenic negative symptoms and cognitive dysfunction… but if anything is going to dramatically change the lives of the millions of schizophrenic patients across the world present and future… it is going to stem from glutamate.

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