Dr. Henry Nasrallah
Scientific Director, the CURESZ Foundation

The Seven Catastrophic Consequences of Psychotic Recurrences

It is very unfortunate when individuals with schizophrenia relapse repeatedly.  The #1 cause for the recurrence of psychosis is either inconsistent adherence to antipsychotic (AP) medications or total non-adherence (1).  The reasons for poor adherence in schizophrenia are related to the illness itself, and patients should not be blamed.

The symptoms of schizophrenia that lead to adherence (2) include: 1) Anosognosia, or the lack of insight that one is very sick with delusions and hallucinations, leading to patient rejection of medication 2) Cognitive difficulties including serious memory impairment, which lead to forgetting to take the AP, 3) Negative symptoms, including apathy, lack of motivation (avolition) and loss of the ability to do many things, including taking medications every day, 4) Suspiciousness that he common side effects of AP medication is evidence of being poisoned, 5) Alcohol and drug use which are very common in persons with schizophrenia living in the community, and being intoxicated or stoned precludes taking prescription medication.  The combination of all those factors inevitably leads to a high rate of medication nonadherence after discharge from the first hospitalization.

Just like type 1 diabetes or hypertension, where medications must be taken every day or risk relapse, persons with schizophrenia must take their oral pills every day without interruption.  A published study showed that a drop of only 25% in The AP blood level (which means missing a dose once every 4 days) is enough to cause a relapse in schizophrenia (3).

Long-acting injectable (LAI) APs were developed in the 1970’s, precisely to solve the problem of non-adherence with oral medication.  However, due to the delay in scientific advances about the brain-damaging effects of psychosis (which appeared 3 decades later), clinicians back then were completely unaware that psychosis is associated with the dangers of recurring psychosis and resultant brain damage. They also believed that patients should “make their own decisions,” despite the well-known fact that the decision-making region of the brain (frontal lobe) is impaired in schizophrenia. Patients were even led to regard LAI treatment as “stigmatizing” and as a “punishment” for multiple relapses, so they resisted the LAIs. Now LAIs are regarded as a most compassionate and effective therapeutic approach to save patients with schizophrenia from psychosis-induced brain damage.

Around the year 2000, psychiatric neuroscience research revealed that psychosis destroys brain tissue and causes brain atrophy (4) due to neuroinflammation and free radicals (5) both of which damage gray and white matter. Brain structure and function deteriorate with every psychotic relapse.  This prevents persons who develop schizophrenia from ever returning to their baseline preceding the first-episode psychosis (FEP), which is very tragic for young individuals in late adolescence or early 20’s.

The following are 7 catastrophic consequences of recurrent psychotic episodes (6) which are due to poor adherence:

  • Brain tissue loss and brain atrophy and disintegration of the extensive network of myelinated fibers (about 137,000 miles) which connects all brain regions and create a unity of self.
  • Treatment-resistance patients respond to low doses of AP in the first-episode of psychosis (FEP) but need higher and higher dose with each psychotic relapse until eventually they become completely treatment-resistant (and will need Clozapine, which most patients never have access to). The brain structure deteriorates successively with each episode and that’s why APs that previously worked no longer do so.
  • Functional disability, and inability to return to school or college or to work, whatever patients were doing before the FEP. Thus, with repeated relapses, those young people become totally disabled instead of being productive members of society.
  • When individuals with schizophrenia become psychotic and behave erratically, sometimes they are killed by police, and many more are arrested and jailed, and often sentenced to prison. They no longer get admitted to state hospitals (because they have all been shuttered), and so are surrounded by armed guards instead of doctors, nurses and social workers who compassionately provide them with medical care instead of being thrown into a prison with murderers and rapists.
  • Many people are not aware with the incredibly high rate of suicide among young people with schizophrenia when they relapse.  Some studies report over 10,000% higher (7) death rates from suicide compared to young persons of the same age in the general population.
  • Non-adherence can lead to drug abuse, a chaotic lifestyle and living on the sidewalks of large cities, with risk of becoming victims of crime.
  • Psychosis can cause unusual behavior, and poor dress and grooming, which intensify the public’s negative bias against serious mental illness.

Yet against this dismal outcome, there is hope and good news for persons with schizophrenia.  The use of LAI very early, i.e. immediately after the first hospitalization, can make a huge difference in preventing deterioration.  There are published studies that relapses in the first year after the FEP if LAIs are started is 650% lower than the rate of relapses in patients receiving oral AP (8).  I have personally had patients who did not relapse for 5 continuous years after switching them to injectable AP.  Preventing relapses is vital because recent research demonstrates that disability actually begins after the second, not the first episode of psychosis (9).  Thus, preventing the second episode is the key to remission and recovery in schizophrenia.  Thus, the deterioration and downhill course of schizophrenia can be prevented in most patients by using LAI AP right after the first hospitalization for schizophrenia (10).

There are other important advantages to using second-generation LAI formulations. 24 published studies report that they are neuroprotective (i.e. help preserve the brain tissue integrity) (11).  Also, a 7-year follow-up study in Sweden reported that a second-generation LAI antipsychotic was associated with the lowest mortality rate from all causes (12).  This is very important given the high premature mortality in schizophrenia.

In summary, until a cure for schizophrenia is discovered, the best way to give patients a chance to return to their baseline and avoid the tragic, life-altering consequences, is to use second-generation LAIs immediately after discharge from the first hospitalization. Yet, inexplicably, this is rarely done, and 99% of clinicians in the country prescribe pills and do not use LAI APs for several years until patients have already relapsed several times.  By that time, the patients have already lost substantial amounts of brain tissue and have become disabled and criminalized and incarcerated.  Imagine how much different the landscape of schizophrenia would be if clinicians prevented any further episode of psychosis after the first one.  Many young people with a diagnosis of schizophrenia may be able to return to their baseline, further their education, get a job, get married, raise a family and exercise their constitutional right to pursue happiness (13).

Henry A Nasrallah,

Scientific Director

References:

  1. Valligan DI et al: Patients Prefer Adherence 11:449-468, 2018
  2. Nasrallah HA: Current Psychiatry 16:4-7, 2017
  3. Subotnik KL et al: Am J Psychiatry 168:286-292, 2011
  4. Cahn W et al: Arch Gen Psychiatry 59:1002-1010, 2002
  5. Kohler-Torsberg O et al: Frontiers in Psychiatry 11:1-3, 2020
  6. Nasrallah HA: Current Psychiatry 20:9-12, 2021
  7. Zaheer J et al: Schizophrenia Research 222:282-38, 2020
  8. Subotnik KL et al: JAMA Psychiatry 72:822-829, 2015
  9. Taipale H et al: Lancet Psychiatry 9:271-279, 2022
  10. Nasrallah HA: Current Psychiatry 21:6-9, 2022
  11. Chen AT et al: Schizophrenia Research 208:1-7, 2019
  12. Taipale H et al: Schizophrenia Research 197:274-280, 2018
  13. Nasrallah HA et al: Current Psychiatry 20:14-16, 202