By the time psychosis appears in someone with schizophrenia, biological changes associated with the illness may have already been present for years. A 2015 article by R.S. Kahn and I.E. Sommer in the journal Molecular Psychiatry describes some of these abnormalities and how treatments might better target them.
One such change is in brain volume. At the time of diagnosis, schizophrenia patients have a lower intracranial volume on average than healthy people. Brain growth stops around age 13, suggesting that reduced brain growth in people with schizophrenia occurs before that age.
At diagnosis, patients with schizophrenia show decrements in both white and grey matter in the brain. Grey matter volume tends to decrease further in these patients over time, while white matter volume remains stable or can even increase.
Overproduction of dopamine in the striatum is another abnormality seen in the brains of schizophrenia patients at the time of diagnosis.
Possibly years before the dopamine abnormalities are observed, underfunctioning of the NMDA receptor and low-grade brain inflammation occur. These may be linked to cognitive impairment and negative symptoms of schizophrenia such as social withdrawal or apathy, suggesting that there is an at-risk period before psychosis appears when these symptoms can be identified and addressed. Psychosocial treatments such as individual, group, or family psychotherapy and omega-3 fatty acid supplementation have both been shown to decrease the rate of conversion from early symptoms to full-blown psychosis.
Using antipsychotic drugs to treat the dopamine abnormalities is generally successful in patients in their first episode of schizophrenia. Use of atypical antipsychotics is associated with less brain volume loss than use of the older typical antipsychotics. Treatments to correct the NMDA receptor abnormalities and brain inflammation, however, are only modestly effective. (Though there are data to support the effectiveness of the antioxidant n-acetylcysteine (NAC) on negative symptoms compared to placebo.) Kahn and Sommer suggest that applying treatments when cognitive and social function begin to be impaired (rather than waiting until psychosis appears) could make them more effective.
The authors also suggest that more postmortem brain analyses, neuroimaging studies, animal studies, and studies of treatments’ effects on brain abnormalities are all needed to clarify the causes of the early brain changes that occur in schizophrenia and identify ways of treating and preventing them.
Cariprazine is a new atypical antipsychotic that has positive results in the treatment of schizophrenia, bipolar mania and depression, and as an add-on treatment to antidepressants in unipolar depression. In a recent study by Frank Tarazi and colleagues, cariprazine shared some actions with aripiprazole (trade name Abilify), which is approved by the Federal Drug Administration as an adjunctive treatment for unipolar depression in addition to treating mania in bipolar disorder and schizophrenia.
Both cariprazine and aripiprazole partially block dopamine receptors. They allow a little stimulation of the receptors (activating or agonist effects) while preventing dopamine from binding there. With ongoing treatment, this blocking action prompts an increase in the number of dopamine receptors to compensate for the blocking.
In rats, both drugs led to increases in several types of dopamine receptors, but cariprazine did so at lower doses. Following 28 days of treatment with aripiprazole at doses of 5–15 mg/kg, rats had higher levels of D2 and D4 receptors in several brain regions than other rats that received no drug. Higher doses of aripiprazole also increased D3 receptors in some regions, indicating that the drug works less well at those receptors. Lower doses of cariprazine (0.06–0.6 mg/kg) increased D2 and D4 receptors significantly, and increased D3 receptors more than aripiprazole did, and in a greater number of forebrain regions.
Among antipsychotic drugs, both aripiprazole and cariprazine are unique in providing a little stimulation (partial agonist effects) at dopamine receptors, while all others drugs in the class are pure blockers (antagonists) of dopamine receptors.
The researchers concluded that cariprazine was more potent than aripiprazole at dopamine receptors, especially D3 receptors.
Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striatum.
Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striata.
Finding an Appropriate Control
Comparing ketamine to placebo has challenges because ketamine produces mild dissociative effects (such as a feeling of distance from reality) that are noticeable to patients. At the 2013 meeting of the Society of Biological Psychiatry, James W. Murrough and collaborators at the Mount Sinai School of Medicine reported their findings from the first controlled trial of intravenous ketamine in depression that uses an active control, the short-acting benzodiazepine midazolam, which has sedative effects and decreases anxiety, but is not known as an antidepressant. On virtually all measures intravenous ketamine was a more effective antidepressant following 2 infusions per week.
These data help dispel one of the criticisms of intravenous ketamine, that studies of the drug have not been sufficiently blinded (when patients and medical staff are kept from knowing which patients receive an active treatment and which are in the placebo control group) and that the lack of an appropriate active placebo contributed to the dramatic findings about ketamine’s antidepressant effects. It now appears that these criticisms have been appropriately answered and that intravenous ketamine is highly effective not only in comparison to placebo but also to an active comparator.
This research was presented as a poster at the meeting and published as abstract #442 in the meeting supplement to the journal Biological Psychiatry, Volume 73, Number 9S, and was also published in the Archives of General Psychiatry in 2013.
Slowing Down Ketamine Infusions to Reduce Side Effects
Ketamine is commonly given in 40-minute intravenous infusions. Timothy Lineberry from the Mayo Clinic reported in Abstract #313 from the meeting that slower infusions of ketamine over 100 minutes were also effective in producing antidepressant effects in patients with treatment-resistant depression. Lineberry’s research group used the slower infusion in order to increase safety and decrease side effects, such as the dissociative effects discussed above. In the 10 patients the group studied, they observed a response rate of 80% and a remission rate of 50% (similar to ketamine’s effects with 40-minute infusions).
Family or Personal History of Alcohol Dependence Predicts Positive Response to Ketamine in Depression
Mark J. Niciu and collaborators at the NIMH reported in Abstract #326 that a personal or family history of alcohol dependence predicted a positive response to IV ketamine in patients with unipolar depression.
Ketamine Acts on Monoamines in Addition to Glutamate
Ketamine’s primary action in the nervous system is to block glutamate NMDA receptors in the brain. In addition to its effects on glutamate, it may also affect the monoamines norepinephrine and dopamine. Kareem S. El Iskandarani et al. reported in Abstract #333 that in a study of rats, ketamine increased the firing rate of norepinephrine neurons in a part of the brain called the locus coeruleus and also increased the number of spontaneous firing dopamine cells in the ventral tegmental area of the brain.
Editor’s Note: These data showing that ketamine increased the activity of two monoamines could help explain ketamine’s ability to induce rapid onset of antidepressant effects, in addition to its ability to immediately increase brain-derived neurotrophic factor (BDNF, important for long-term memory and the creation of new synapses) and to restore healthy mushroom-shaped spines on the dendrites of neurons in the prefrontal cortex.
Monoamine oxidase inhibitors (MAO-Is) are a type of antidepressant that is often effective for people with anxious depression or comorbid panic attacks, especially when other antidepressants don’t work. This may be because MAO-Is work on all three neurotransmitter systems implicated in depression: dopamine, norepinephrine, and serotonin.
In a recent study presented at the 65th Annual Scientific Convention of the Society of Biological Psychiatry, Julia Sacher et al. found that six weeks of therapeutic doses of the MAO-I moclobemide (at doses of 300 mg twice a day) significantly decreased monoamine oxidase A, as measured by PET scans in brain regions implicated in mood disorders. In a comparison of moclobemide, placebo, and the herbal preparation St. John’s Wort, only moclobemide had a significant effect. Read more
Robin Murray gave a plenary presentation at the 65th Annual Scientific Convention of the Society of Biological Psychiatry this year, in which he indicated that the genetic risk for schizophrenia and other major mental disorders may be overestimated. He suggested that even in identical twins there are considerable differences in incidence of major psychiatric illnesses, and sharing an environment could further inflate the appearance of genetic risk.
Evidence of some genetic vulnerability factors, such as neuregulin, disbindin, DISC-1, zinc finger transcription factors, and neurexin, has been replicated. However, these genes appear to contribute only about 1% of the vulnerability to schizophrenia or bipolar illness. Copy number variations (CNVs, extra or missing copies of a gene, which may alter its activity) and gene micro-deletions (in which small bits of DNA are missing) have been found in about 5% of patients with schizophrenia, in some patients with autism and mental disabilities, but not in those with bipolar illness.
Murray emphasized the importance of psychosocial and neuromotor markers of neural development in determining risk of subsequent major psychiatric illness, rather than the relatively weak genetic effects. He cited the work of MacCabe (2009), who collected information from 907,000 individuals in Sweden. Their scholastic achievement at age 15?16 was rated, and hospitalizations for psychosis were recorded from age 17?31. Of the 315,000 followed for the long term, 493 developed schizophrenia and 208 developed bipolar disorder.
Predictors of cognitive and motor development in these two major psychiatric illnesses appeared to differ. In those who went on to develop schizophrenia, there was a slower rate of motor development, receptive language, and overall IQ in adolescence, while in those who went on to develop bipolar disorder, there was a faster rate of motor development, more language facility, and higher IQ in adolescence.
In a study of rodents exposed to stress (by being forced to enter another rodent’s territory) and given the opportunity to self-administer cocaine, those exposed to a few brief episodes of stress increased their cocaine use and engaged in binge-like episodes, while those exposed to stress chronically showed suppressed cocaine use.
At the American College of Neuropsychopharmacology meeting in December 2009, Klaus Miczek and colleagues from Tufts University in Boston presented a fascinating study indicating that the temporal aspects of the experience of social stress may have dramatic impact not only on defeat stress behaviors and the associated biochemistry, but also on the likelihood that an animal adopts cocaine self-administration. These investigators compared episodic versus chronic defeat stress in rodents.
Episodic social defeat stress consisted of four brief confrontations between an intruding animal and an aggressive resident rat over the course of a period of ten days. In contrast, chronic subordination stress involved the continuous exposure of the intruder rat to an aggressive resident over five weeks, during which time the intruder lived in a protective cage within the resident’s home cage.
The episodically defeated intruder rats showed increases in intravenous cocaine self-administration and prolonged binge-like episodes, along with increases in brain-derived neurotropic factor (BDNF), which is necessary for long-term learning and memory, in the midbrain ventral-tegmental area (VTA) and increased dopamine release in the nucleus accumbens, the reward area of the brain. In contrast, the continuously subordinate rats showed the opposite pattern of suppressed cocaine intake, suppression of dopamine release in the n. accumbens, and reduced BDNF in the VTA.
The atypical antipsychotic quetiapine (Seroquel or Seroquel XR) has a range of efficacy in a number of illnesses, depending on the size of the dose given. Read about some of its uses below, including as an adjunct to antidepressants in unipolar depression; as a treatment for generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD); and, at higher doses, as a treatment for mania and depression. Some of its potential mechanisms of action are described as well.
Quetiapine as an adjunct to antidepressants in unipolar depression
Posters at the American Psychiatric Association meeting in San Francisco in May 2009 showed new data from a series of studies of quetiapine in unipolar depression that showed the drug in monotherapy (at 150mg & 300mg) was significantly more effective than placebo. Studies were also positive when quetiapine was used as an adjunct compared with placebo for patients showing inadequate or incomplete responses to antidepressants such as selective serotonin reuptake inhibitors (SSRIs).