Antipsychotics and Brain Damage: Shrinkage & Volume Loss

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Antipsychotics are drugs that alleviate symptoms of schizophrenia and psychotic episodes. These medications are considered highly effective interventions for mitigating “positive symptoms” such as hallucinations (e.g. hearing voices) and various types of delusions (e.g. assuming others are plotting against you). Approved uses for antipsychotics include treating individuals diagnosed with schizophrenia, bipolar disorder, and cases of drug-induced psychosis.

Most antipsychotics primarily function by acting as dopamine receptor (D2) antagonists. This means they bind to the dopamine receptors and prevent stimulation from misfiring or abnormally high dopamine concentrations. By inhibiting excess dopaminergic stimulation, the hallucinations and delusions that once plagued the individual begin to subside.

Despite the fact that psychotic symptoms are controlled by antipsychotics, those undergoing treatment often experience an array of damning side effects, including: severe weight gain, sexual dysfunction, hormonal imbalances, and in some cases diabetes. To make things worse, there is evidence that using antipsychotics may cause brain damage, especially when used over a long-term.

Antipsychotics and Brain Damage: Shrinkage & Volume Loss

The only people that should be taking antipsychotics are individuals diagnosed with conditions that provoke psychotic symptoms. However, drug companies have brilliantly marketed antipsychotics for a variety of off-label conditions such as: depression, anxiety, insomnia, and autism. Now, many doctors serve as mere puppets for the pharmaceutical heavyweights, unknowingly prescribing antipsychotics that cause long-term brain damage

These are the most dangerous psychiatric drugs on the market. In the past it was long assumed that schizophrenia was a neurodegenerative condition and that brain volume loss was associated with the pathophysiology of the illness. Some researchers even hypothesized that antipsychotics acted as neuroprotective agents – slowing neurodegeneration among individuals with schizophrenia.

It took awhile before researchers considered the fact that maybe the brain volume loss among those with schizophrenia may actually be a result of their antipsychotic treatment. New evidence based on neuroimaging studies confirmed the fact that antipsychotic drugs were actually causing brain damage in the form of volume loss and shrinkage. Unfortunately, many practitioners remain oblivious to this fact and continue dispensing these highly potent drugs for off-label conditions.

How Antipsychotics Cause Brain Damage

There are several ways in which antipsychotics are thought to cause brain damage. The brain damage associated with antipsychotic usage may directly influence the severity of cognitive symptoms of schizophrenia. Many users of antipsychotics experience cognitive deficits that are thought to be solely from their illness, when in reality they may be a result of the meds.

Prefrontal connectivity reductions: There is evidence derived from resting fMRI studies suggesting that connections in the prefrontal region of the brain are reduced as a result of antipsychotic treatment. A reduced number of connections may translate to reductions in complex thinking, planning, attention, emotional regulation, and memory.

Global brain volume loss: Studies have noted that antipsychotics reduce global brain volume. This means that a person’s brain with schizophrenia who has undergone years of antipsychotic treatment (especially at high doses), may display signs of neurodegeneration. Reductions in global brain volume means that nearly every aspect of brain functioning has potential to become impaired.

Grey matter volume loss: Grey matter is known to include various regions of the brain responsible for sensory perception, emotions, self-control, speech, decision making, and muscle control. Individuals taking antipsychotics experience reductions in grey matter volume, making it tougher to perform certain functions.

White matter volume loss: White matter is tissue that allows your brain to communicate with the central nervous system. It is comprised of myelin and axons, both of which facilitate chemical messages within the brain. Since those taking antipsychotics experience reductions in white matter, the communication system within their brain becomes impaired.

Source: http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2013.13030413

The Research (Timeline): Antipsychotics Impact Brain Volume

Below are studies suggesting that antipsychotics have an impact on brain volume. While some research suggests that the illness itself (schizophrenia) and symptomatic relapse may contribute to volumetric brain shrinkage, most evidence points to antipsychotics as the primary causative factor; particularly the duration of treatment and dosage.

2005: Initially, researchers analyzed the effects of antipsychotics on non-human primate models. This study involved three different groups of 6 macaque monkeys that were given Haldol, Zyprexa, or a placebo for a period of 17 to 27 months. It was determined that they had the same plasma drug levels as humans taking antipsychotics for schizophrenia.

It was noted that the monkeys taking Haldol and Zyprexa experienced an 8% to 11% reduction in brain weight and volume compared to those receiving the placebo. The brain volume loss was considered global in that it affected all regions including: frontal, parietal, temporal, occipital, and the cerebellum. The loss was most pronounced in the prefrontal and parietal lobes.

It was later noted that both grey and white matter had decreased in the treatment group. A general shrinkage in the brains of those treated with antipsychotics was an estimated 20%. This study suggested that humans may endure similar volume reductions as these monkeys.

Source: http://www.ncbi.nlm.nih.gov/pubmed/15756305

2005: In the early 2000s, researchers hypothesized that treating patients with Zyprexa (olanzapine) would experience less changes brain volume compared to those treated with Haldol (haloperidol). They designed a study that tested the effect of an atypical antipsychotic and compared it with that of a typical antipsychotic to determine differences. The study was considered longitudinal, randomized, double-blind, and controlled.

All individuals being treated for first-episode psychosis were analyzed over the course of 104 weeks and MRI assessments were conducted at baseline, week 12, week 24, week 52, and week 104. Results indicated that individuals being treated with Haldol had significantly less grey matter than those being treated with Zyprexa. It was suggested that newer generation drugs may be safer and less toxic than older ones.

Source: http://www.ncbi.nlm.nih.gov/pubmed/15809403

2009: In a report published in 2009, researchers attempted to determine whether antipsychotic medications may change regional brain volumes in humans. They also wanted to investigate whether these changes occurred more often with certain antipsychotics compared to others. They conducted a systematic review of all studies incorporating structural MRI scans among those using antipsychotics.

They compared those that had been utilizing antipsychotics for a long-term with healthy controls not taking any psychiatric medications. The researchers incorporated 33 studies that met their specific criteria of inclusion. Evidence from this study indicated that antipsychotics induced regional changes in the brain rather than widespread, global alterations.

It was noted that there were differences between atypical antipsychotics (newer) and typical antipsychotics (older) in regards to their effect on the basal ganglia. Typical antipsychotics increased basal ganglia volume, whereas atypical antipsychotics did not. Researchers hypothesize different effects on the thalamus.

Oddly enough, they didn’t suggest that brain volume decreased from antipsychotic usage. They noted differing effects based on the type of antipsychotic administered (atypical vs. typical). This research suggested that sizing of certain regions may actually increase with treatment. No evidence from this early research suggested that brain volume decreased as a result of treatment.

Source: http://www.ncbi.nlm.nih.gov/pubmed/19338710

2010: A report published in 2010 analyzed a total of 26 longitudinal studies of individuals being treated for schizophrenia. It was noted that a 14 of the 26 studies demonstrated significant reductions in global brain volume, grey matter volume, or increases in levels of cerebrospinal fluid (CSF). These changes were thought to result from being treated with an antipsychotic medication.

Authors noted that the frontal lobe of the brain endured the most changes. They highlighted the fact that one study showed varying degrees of volume loss with a variety of antipsychotics, whereas another study determined that volume changes were associated with taking any antipsychotic compared to lack of treatment (e.g. no medication). Evidence from this publication suggests that antipsychotics likely contribute to brain volume loss and increases in cerebrospinal fluid (CSF).

Source: http://www.ncbi.nlm.nih.gov/pubmed/20085668

2011: Perhaps the most evidence for brain volume loss as a result of antipsychotic treatment is derived from a study published in 2011. Researchers noted that brain volume changes associated with schizophrenia were speculated to be a result of the disease. However, they couldn’t ignore the fact that animal studies involving administration of antipsychotics demonstrated decreases in brain tissue volume.

Based on the findings from animal studies, researchers hypothesized that antipsychotics may also be contributing to brain volume loss in humans, especially when used over a long-term. For the study, researchers evaluated the influence of 4 factors on brain volume including: duration of illness, antipsychotic treatment, severity of illness, and substance abuse. The study involved a total of 211 patients with schizophrenia.

They had undergoing neuroimaging with high-resolution MRI scans upon onset of their illness. Each individual diagnosed with schizophrenia was noted as having a total of between 2 and 5 scans to determine brain volume changes over the course of approximately 7 years. Researchers discovered that the duration of treatment and dosage of the antipsychotic was associated with reductions in brain volume and increased cerebrospinal fluid volume.

Even after controlling for illness duration, severity, and substance abuse – antipsychotics appeared to decrease brain tissue volume. Specifically, the antipsychotics reduced both gray matter and white matter. Oddly enough, illicit drug abuse had no significant correlation with brain volume loss.

Results suggested that the most influential factor on brain volume among those with schizophrenia was the antipsychotic treatment. The authors of the study suggest conducting careful risk-benefit analyses when prescribing these drugs; especially for “off-label” conditions. Unfortunately, not many patients nor doctors are aware of the risks highlighted in this report.

Source: http://www.ncbi.nlm.nih.gov/pubmed/21300943

2013: More research was conducted in attempt to analyze the effect of antipsychotics treatment compared to the illness in regards to brain structural changes associated with schizophrenia. Researchers conducted a review utilizing all electronic database records up to April 2012 involving MRI scans among those being treated with antipsychotics. For the review, researchers were able to incorporate 30 longitudinal studies.

This research involved a total of 1046 individuals diagnosed with schizophrenia and 780 healthy controls. At baseline it was noted that those with schizophrenia had significant reductions in brain volume and increases in volume of the lateral ventricle (LV) region compared to controls. Initially, there were no significant decreases in grey matter, white matter, or cerebrospinal fluid.

The study revealed that over time, those with schizophrenia had significant reductions in grey matter volume. The reductions in grey matter were associated with cumulative antipsychotic treatment. Authors noted that the duration of the illness and severity were not associated with changes in brain volume.

Researchers noted that schizophrenia may alter brain volume and increase volume of the lateral ventricle (LV). However, it appears as though brain volume reductions, particularly of grey matter, are directly associated with cumulative antipsychotic treatment. This provides more evidence to suggest that antipsychotics contribute to brain volume loss.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23769814

2013: Another study analyzed the influences of antipsychotic treatment and “relapse” on brain volume among those with schizophrenia. For the study, they analyzed 202 patients who had undergone MRI scans over an average of 7 years. The researchers pointed out that the greater the intensity of antipsychotic treatment, the smaller the brain volume of those being treated.

They noted that the longer an individual had been treated and the higher the dose of the medication, the greater the volume loss associated with the medication. They also highlighted the fact that duration of symptomatic relapse was associated with decreases in total cerebral volume. The number of relapses a person had didn’t affect brain volume.

If symptomatic relapse affects brain volume, but the number of relapses don’t affect brain volume, couldn’t this be chalked completely up to the treatment. Over time, it is known that people become tolerant to their antipsychotics and their brain changes as a result of treatment. Could it not be that the antipsychotics are solely to blame for relapse and ultimately a majority of the brain volume loss?

Source: http://www.ncbi.nlm.nih.gov/pubmed/23558429

Factors that may influence brain damage from antipsychotics

Below is a list of factors to consider that may influence brain damage, shrinkage, or volume loss associated with antipsychotic treatment.

Dosage : The greater the dosage, the more likely a person is to experience brain volume loss. High doses are associated with expedited brain volume reductions compared to lower doses. For this reason, it is important to consider taking the minimal effective dose during treatment.

: The greater the dosage, the more likely a person is to experience brain volume loss. High doses are associated with expedited brain volume reductions compared to lower doses. For this reason, it is important to consider taking the minimal effective dose during treatment. Duration of treatment : It is well established that duration of treatment with antipsychotics dictates brain volume loss. The longer a person has been treated, the more severe the reductions in brain volume. An individual treated for 20 years will experience more damage than someone treated for 5 years with the same medication and dosage.

: It is well established that duration of treatment with antipsychotics dictates brain volume loss. The longer a person has been treated, the more severe the reductions in brain volume. An individual treated for 20 years will experience more damage than someone treated for 5 years with the same medication and dosage. Genetics / epigenetics : Perhaps some individuals have favorable genetics or epigentic influences that decrease their likelihood of brain damage. Certain genetics may help offset antipsychotic-induced brain damage and/or reduce the need for a high dose. Some researchers believe that genetics should be considered in regards to brain volume loss.

: Perhaps some individuals have favorable genetics or epigentic influences that decrease their likelihood of brain damage. Certain genetics may help offset antipsychotic-induced brain damage and/or reduce the need for a high dose. Some researchers believe that genetics should be considered in regards to brain volume loss. The specific antipsychotic : It is important to consider the differences in mechanisms of action associated with antipsychotics. Atypical antipsychotics are known to produce different regional changes and may be safer compared to typical antipsychotics. There may also be significant variation in regards to brain volume loss when comparing 2 different atypical agents. Since comparative studies haven’t been conducted, it is unknown whether certain formulations result in less damage than others.

: It is important to consider the differences in mechanisms of action associated with antipsychotics. Atypical antipsychotics are known to produce different regional changes and may be safer compared to typical antipsychotics. There may also be significant variation in regards to brain volume loss when comparing 2 different atypical agents. Since comparative studies haven’t been conducted, it is unknown whether certain formulations result in less damage than others. Onset of illness: Someone with late-onset schizophrenia may have less brain damage than someone with early-onset of the disease. Later onset will be associated with a shorter-term of treatment. Additionally, those with later-onset schizophrenia may have less baseline abnormalities compared to those with early-onset of the disease.

Potential synergistic factors

Illness severity : The underlying severity of the illness may dictate the degree to which someone experiences brain volume loss from medication. Those with more severe illnesses may have greater brain atrophy at a baseline, and a medication may synergistically promote decline.

: The underlying severity of the illness may dictate the degree to which someone experiences brain volume loss from medication. Those with more severe illnesses may have greater brain atrophy at a baseline, and a medication may synergistically promote decline. Relapse severity : The number of relapses doesn’t seem to have an effect on whether a person experiences additional brain damage. However, the symptomatic severity seems to play a role. Those with more severe forms of relapse are thought to experience greater brain volume loss.

: The number of relapses doesn’t seem to have an effect on whether a person experiences additional brain damage. However, the symptomatic severity seems to play a role. Those with more severe forms of relapse are thought to experience greater brain volume loss. Subtype of illness: The specific type of schizophrenia that a person has may influence whether they experience more or less brain damage as a result of antipsychotic treatment. New evidence suggests that schizophrenia is 8 different diseases characterized by specific genetic abnormalities. It should be thought that the subtype of the illness may influence the degree of cortical atrophy.

The Catch-22: Managing Symptoms of Schizophrenia vs. Antipsychotic-Induced Damage

Antipsychotics are considered a first-line, effective treatment for those diagnosed with schizophrenia. While many have tested natural remedies for schizophrenia, most of these options lack evidence to suggest efficacy. If you’re a person who has been diagnosed with schizophrenia, should you take drugs that are known to reduce brain volume?

It’s certainly difficult to knowingly expose yourself to a substance that decreases cortical volume. That said, failure to treat the schizophrenia is likely to result in significant functional impairment and reduced quality of life. Therefore it is always recommended to treat the illness, but actively acknowledge the potential risk of brain volume loss.

Fortunately, preliminary evidence suggests that volumetric decreases are more severe among rodents and non-human primates than in human populations. Still, medical professionals should work with patients to come up with harm reduction strategies.

How to Reduce Brain Volume Loss from Antipsychotics

There are some potential strategies that can be implemented to reduce brain volume loss associated with antipsychotics. Suggested strategies include: taking the smallest effective dose, only taking antipsychotics if necessary, considering the specific antipsychotic (some may contribute to greater volume loss than others), and actively work to improve your brain health.

1. Use the “Minimal Effective Dose”

Researchers are starting to recognize the importance of taking a “minimal effective dose” rather than titrating up to a specific therapeutic threshold dosage. Every person is different, and one person with less severe schizophrenia may respond well to medication prescribed at a lower dose than another individual. Despite the fact that symptoms need to be controlled, they can often be managed with a much lower dose than is suggested.

Studies indicate that there is a direct relationship between the dosage (strength) and degree of brain volume loss experienced as a result of antipsychotic treatment. Individuals with more volume loss had been on higher doses than those without as much loss. Therefore you should work with your psychiatrist to take the smallest amount that provides therapeutic benefit.

2. Only take if necessary

Antipsychotics are medications that should only be taken by individuals with conditions warranting them. In other words, you should have experienced schizophrenia and/or a psychotic break. While they are approved for bipolar disorder, there are generally safer mood stabilizers (e.g. lithium) that can be utilized over a long-term without any significant brain volume loss.

Unfortunately many people are taking antipsychotics as treatments for conditions that do not warrant their usage. As an example, some individuals are prescribed Seroquel for insomnia. Do you think it’s worth risking brain volume to help you fall asleep? Probably not.

Antipsychotics are also commonly utilized as antidepressant augmentation strategies. They are thought to “enhance the effect” of a person’s antidepressant. Unfortunately most users are unaware of the fact that they are putting their brain at risk for potential damage over the long-term.

3. Consider the specific antipsychotic

Each antipsychotic will have unique effects in terms of how your body interacts with it. You may want to consider GeneSight – genetic testing to determine which medication is best suited for your body. In addition, you may want to consider whether the drug you’re taking is considered a “typical” (older) or “atypical” (newer) antipsychotic.

The older typical antipsychotics produce different regional changes compared to the newer atypical ones. Also keep in mind that certain atypical antipsychotics may be safer and more targeted than others, allowing you to take a lower dose. It may take some experimentation to determine the optimal antipsychotic for long-term brain health.

4. Attempt to improve brain health

Since you know you’ll be taking an antipsychotic, you may want to take extra steps to potentially mitigate volumetric loss associated with treatment. This may mean exercising on a daily basis, particularly cardio which is known to increase BDNF levels and ultimately contribute to neurogenesis or synaptogenesis. There is also evidence that dietary intake can influence brain functioning and ultimately brain health – so make sure you’re eating an optimal diet for mental health.

There are also many supplements that you could consider to help offset antipsychotic-induced brain damage. Obviously you’ll want to talk to your doctor before supplementing anything along with an antipsychotic medication due to potentially unwanted contraindications. There are many neuroprotective agents and nootropics, some of which may combat volume loss stemming from your medication.

Another activity that has been documented as increasing brain volume, particularly activation of the prefrontal cortex and grey matter is meditation. Those that become adept at meditation may find that the increased grey matter derived from consistent practice may improve brain health and ultimately mitigate some of the volume reduction.

Can you determine brain volume loss from antipsychotic treatment?

Yes. In an article I wrote called “How to Improve Psychiatric Treatment Outcomes,” I recommended getting brain scans to determine how you are responding to treatment. Certain scans such as an fMRI should help you determine brain volume changes throughout treatment. Other brain scans may show blood flow (e.g. SPECT) and tools like a QEEG can determine how brain waves may be changing over time.

Assuming you wanted to track brain volume changes to yourself over time, you could get a baseline “pre-treatment” brain scan followed by another every 6 months, every year, or even every couple years. This will help you gauge the medication-induced changes that occur over an extended duration. Additionally, a neurologist will be able to compare your baseline brain scans with those that you get during treatment to determine specific areas that may be experiencing decline.

Should the fact that antipsychotics cause brain damage scare you?

Those that need to take antipsychotics may be alarmed by evidence suggesting that they cause brain damage over time. Unfortunately, antipsychotics are generally considered the only effective treatment option for individuals with schizophrenia and psychosis. Long-term prognoses for those who adhere to treatment are considerably better than those who stop taking their medications.

The benefits associated with taking antipsychotics for those with schizophrenia are thought to considerably outweigh drawbacks – including volumetric reductions. These medications allow people to function in society and ultimately improve quality of life. The upside is that brain volume reductions as a result of treatment aren’t generally regarded as severe.

Furthermore, they can be minimized by taking the minimal effective amount. In the coming years, it is hoped that a newer generation of more targeted medications help reduce symptoms of schizophrenia with fewer side effects and no brain volume loss. Doctors should responsibly inform patients taking antipsychotics for “off-label” conditions that brain damage may stem from their usage.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23172002

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