I was sad to have completed my very last assignment in my favorite course, but the subject matter of this last discussion post was near and dear to my heart. The discussion revolved around the pathology of addiction and mood disorders. Luckily I will have Dr. Ettinger again next term for Psychopharmacology!
After repeated use of an addictive drug, what changes are observed in the nucleus accumbens and frontal cortex?
Addiction can occur to many different substances, even when they have no similarities in structure. The common denominator in addiction is sudden increase of the neurotransmitter dopamine and how it affects the mesolimbic pathway (often referred to as the reward pathway). This reward system is evolutionarily vital, giving us the drive to seek out behaviors that keep us alive or encourage us to procreate. Repeated stimulation of this system can cause enduring structural changes. After repeated use, these addictive substances begin to alter the structure of neurons that receive dopamine; They upregulate the proteins CREB and c-FOS. Route of administration (ROA), quick delivery, and high bioavailability enhances CREB and c-FOS upregulation; However, it is not essential for addiction to become present. These proteins contribute to downregulation of dopamine receptors in the nucleus accumbens, and changes to mesocortical structures lead to hypofrontality—or decreased frontal lobe activity–which enhances drug-associated cues and promotes drug-seeking behaviors, while simultaneously decreasing the executive function needed to regulate actions. This explains why addicts are known to be lacking in impulse control, while they exhibit poor judgment, high-risk behavior and sometimes anti-social behavior. Addiction is complex, drug use does not always lead to addiction (even for those with predisposition) but when an addictive substance is used too much it often leads to tolerance, dependence, and the subsequent life-damaging and life-threatening pattern of events. There have been many unfortunate situations where a person with no prior addictive tendencies, has been in a car crash or other event that created a need for pain medication, and an addiction was born of necessity rather than choice. Furthermore, some substances or even activities become addictive to some and not others (Ettinger, 2017; Kalat, 2018).
Dopamine pathways (the axons—often myelinated—that these projections travel through) originate in the brainstem in the ventral tegmental area (vta). The ventral tegmental area and a part of the limbic system, the nucleus accumbens (which is below the lateral ventricles) are important to appetitive and addictive, internally motivated, behaviors. While many of the projections from the VTA end at the nucleus accumbens, some also go on to the frontal cortex. One noteworthy bit of information is that these changes in availability of receptors can be viewed in the nucleus accumbens and frontal cortex with PET scans.
Why would drugs that block dopamine be unsuccessful in treating addictions?
One reason that simply blocking dopamine wouldn’t work is that addiction is complex, and while dopamine is an important aspect, it is not the only factor. From an evolutionary standpoint, this is good. Stability in reward-driven behavior is good—until we consider hyper-hedonic, maladaptive, reward-driven behavior that can be life-altering and often life-threatening. Researchers once thought that blocking dopamine synapses was key to eliminating opiate-related dependence. A growing body of research indicates an over emphasis of the influence of dopamine in addiction. It is clear that dopamine is a component, but maybe not the key component; the amount of dopamine released does not correlate to probability of becoming dependent upon a drug, or euphoria associated with a drug. Further, pharmaceutical companies have tried for many years to use drugs that block dopamine synapses to reduce the reward properties of opiate drugs, failing to lessen dependence (Kalat, 2019).
What drugs are used to treat opiate addictions and how do they work?
Ironically heroin (one of the most worrisome of the opioids) was synthesized in the 1800’s as a “safer” alternative to morphine. At times, heroin was even suggested as an alternative to alcohol. Now we know that heroin is one of the most addictive, deadly, and destructive drugs of abuse. Nonetheless, it is still considered optimal to switch to an alternative medication, despite potential addiction to the alternative. Opiates are considered “natural” form as they are directly derived from opium, where as opioids are synthesized, therefore they are the synthetic form of opiates. Methadone, while addictive, is considered a safer alternative to heroin and is offered to heroin users through methadone clinics. Heroin is sometimes smoked, but more often it is taken intravenously and that can be dangerous—especially considering the environment of those self-administering the drug. Beyond environmental and hygiene concerns and risk of infection, users often share needles, risking potential transfer of blood-born diseases. Methadone can be taken orally, which in itself is a safter alterative. Route of administration (ROA) is an important factor in addictiveness of a drug—when a drug is injected directly into the blood stream it causes a rush and increases probability of disruptive behavior and heightened addictive potential and usually significantly increased bioavailability of the drug. Interestingly, many drug users prefer the ROA used when they first became addicted to a drug—as though they are “chasing the high” that originally got them hooked. Buprenorphine and Levomethadyl Acetate are comparable to methadone. Levomethadyl Acetate has the added benefit of lengthened half-life, so users visit the clinic than three times per week rather than daily. These drugs do not end addiction, they simply combat the most undesirable, risky, adverse effects of the drugs they are replacing (Ettinger, 2017; Kalat, 2019). Methadone is an analgesic that inhibits pain impulse transmission at the spinal cord by interacting with the opioid receptors and it can produce CNS depression, as do opiates/opioids. Buprenorphine and Levomethadyl Acetate are also opioid analgesics and partial agonists but they activate the opiate receptors to a lesser degree. Naltrexone is an opioid antagonist and antidote; as an antagonist it competes with opioids at opioid-receptor sites and disrupt neurotransmitter activity.
Describe brain differences between normal and depressed patients. How do these differences contribute to symptoms?
A notable difference in brain activity of normal and depressed patience is level of activity in the left prefrontal cortex. In “normal” non-depressed patients, you’ll see increased activity in the area when they are in a happy mood. Inversely, depression is associated with increased activity in the right PFC. It is posited that this represents predisposition rather than reaction. When asked to solve a verbal problem, depressed individuals often gaze to the left while solving the problem, signifying right hemisphere dominance. It is worth mentioning that MDD (major depressive disorder) is not simply a deficiency in serotonin; but apparently it is related to an increase in the expression of autoreceptors on presynaptic terminals of serotonin neurons. Autoreceptors regulate the synthesis and release of neurotransmitter through these neurons (Remember how marijuana works with autoreceptors?). Autoreceptors basically send a message saying stop sending that neurotransmitter, I already got it. They halt or impede activity of these neurons. Autoreceptors become over expressed and downregulate serotonin release in a few potential ways according to research. Chronic stress can cause downregulation through the release of stress hormones; Furthermore, it can occur dependent upon genes that determine autoreceptors, suggesting a genetic component (Kalat, 2019).
How do antidepressant drugs appear to work in alleviating depression?
Main classes of antidepressants include: MAOIs, SSRIs, and SNRIs, tricyclics, and atypical antidepressants. MAOIs, or monoamine oxidase inhibitors, such as phenelzine, block monoamine oxidase, a presynaptic enzyme that metabolized catecholamines and serotonin into inactive forms. When MAOIs block the enzyme, the presynaptic terminal has increased transmitter availability for release. The MAOIs were the earliest antidepressants, but they are no longer first-line solutions as they have undesirable side effects. People taking MAOIs must avoid food containing tyramine because MAOIs cause vulnerability to blood pressure increase. SSRIs, or selective serotonin reuptake inhibitors, are often first-line treatment for depression. They are similar in mechanism to tricyclics, but they select the serotonin neurotransmitter. They bind to the center of the serotonin transporter protein and lock it into a shape that prevents serotonin from binding to it—you could say reuptake is inhibited. SSRIs produce milder side effects than tricyclics, but effectiveness is comparable. Common SSRIs include Prozac, Sertraline, Luvox, Citalopram and Paxil. Interestingly, Tramadol (Ultram) is a medication that is now used for mild and/or chronic pain but was not intended to be marketed as such. Tramadol is a combination of an SSRI, SNRI, and has analgesic properties. Tramadol has not been shown to improve mood, but it is a common pain medication that has shown little potential for abuse and far milder CNS depressant properties; therefore, it is less dangerous. SNRIs, or serotonin norepinephrine reuptake inhibitors, block reuptake of serotonin and norepinephrine. Unlike other antidepressants, SNRIs have be reported to improve certain aspects of memory. Tricyclics, block the transporter proteins that reabsorb serotonin, dopamine and norepinephrine into the presynaptic neuron, causing prolonged presence of the neurotransmitter in the presynaptic cleft. Unfortunately, tricyclics cause many undesirable side effects, such as dry mouth, drowsiness, and difficulty urinating. They block histamine receptors causing the drowsiness, acetylcholine receptors causing dry mouth and difficulty urinating, and they also block some sodium channels which can cause heart irregularities. Finally, atypical antidepressants, include any other antidepressants not previously mentioned. One atypical antidepressant, bupropion, inhibits reuptake of dopamine and to a lesser extent, norepinephrine. As you can see, antidepressants vary regarding which neurotransmitters they work on—whether it be dopamine, norepinephrine, serotonin, or a combination. While they all work relatively equally, in many cases SSRIs are preferable because of relatively milder side effects. Ketamine is the most recent addition to the antidepressant front. Ketamine antagonized NMDA glutamate receptors and increases formation of new synapses simultaneously, producing rapid antidepressant effects in patients who have been unresponsive to first-line treatments (Kalat, 2019). Psilocybin is also a newly approved and promising treatment option.
How is bipolar disorder different from major depression?
In individuals with MDD, or simply major depression, the nucleus accumbens becomes less responsive to reward causing a flat affect. They are often hopeless and plagued with low self-esteem and combined effects often lead to suicidality. Absence of happiness is more accurate when describing these patients, rather than sudden sadness. People with this type of depression or generally unable to find joy, causing them to lose hope. Major depressive disorder affects nearly every household in the U.S. at one point or another. While anxiety disorders are most prevalent, MDD is a close second among psychological disorders. A common problem among those who suffer from MDD, depression, and bipolar is sleep disturbances which exacerbate mood problems. Depression is said to be related to having circadian rhythm out of phase with one’s environment. Seasonal Affective Disorder is a cause of depression that is dependent on seasonal change, associated with sadness and sleep disturbances in the fall and/or winter months. Using a “SAD light” is known to help with seasonal affective disorder, using a bright light to reset the circadian rhythm (I use a SAD light myself and I can attest to their effectiveness).
Bipolar disorder has two components, depression, and mania (though euthymia could, in a way, be considered a third phase, being the state of remission between the two extremes). Many people think of bipolar of mood disturbances that happen often (even daily) but with the exception of rapid-cycling, the periods of depression and mania usually last for months at a time (often 6 months at a time). Bipolar individuals often become depressed during the late Fall and Winter months. How is this different for seasonal affective disorder? Bipolar disorder has the component of extreme changes in energy level, with mania being above normal and depression being below normal. Bipolar I disorder is considered more extreme, while Bipolar II is considered milder. During a manic episode in bipolar I, individuals often go days without need for sleep and cycle between experiences of euphoria, restlessness, and agitation. Hallucinations can occur as well. Hypomania is a common component of bipolar II, though with both types of mania, increased self-confidence is common and sometimes delusions of grandeur. It is much less common for a bipolar individual to seek help during a manic episode, as they are considered enjoyable to a certain extent. Depression, on the other hand, is far less tolerable and often causes bipolar sufferers to seek help. The severity and length of the manic episode compounds the severity and length of the depressive episode. Mood stabilizers often create a floor and a ceiling, per se, and help alleviate symptoms. I personally was diagnosed as bipolar in my 20’s. I stopped taking mood stabilizers at one point shortly after diagnosis because I missed mania so much that I was willing to tolerate the depression; this is common among bipolar sufferers.
What are some of the most effective drug treatments for bipolar disorders?
Lithium (lithium salts) is one of the most time-tested and effective treatments for bipolar disorder. When taking lithium, an individual has to have levels monitored often, as high dose is toxic and low dose is ineffective; in other words, the optimal dose is just under the toxic dose. The need to monitor levels to keep the right balance is an unattractive quality and sways doctors and patients toward milder treatments when applicable. Lithium is also less preferable for women during childbearing years because of the potentially harmful side-effects. Lithium’s mechanism of effect is associated with hippocampal cells. Bipolar individuals are known for forming hyperexcitable hippocampal cells and when lithium lessens the hyperexcitability, positive effects are seen. More tolerable medications, particularly during childbearing years, are often anticonvulsants which regulate sodium channels. Depakene, Depakote, and Lamotrigine are common anticonvulsants prescribed. It is also common to supplement with antidepressants. Bipolar patients are likely to have a comorbid (co-existing) diagnosis of impulsive behaviors such as compulsive buying, post-traumatic stress disorder (PTSD), panic disorder, or substance use disorder. Suicidality is also common among bipolar individuals. Impulsivity is also a hallmark trait of bipolar individuals, which makes the suicidality that much more dangerous. As many of my readers know, I personally have been treated—at different times—with many different medications for comorbid disorders. Psychiatrists and doctors are often unaware of how a patient will react to a medication until they try it (Ettinger, 2017; Kalat, 2019).