Pharmacological Treatment of Psychiatric Disorders: State of the Art

Pharmacological Treatment of Psychiatric Disorders: State of the Art

Treatment of mental disorders is complicated, and while there are drugs approved to treat psychiatric disorders, many of them are lacking in various ways, such as poor efficacy, side effects, dependence and abuse potential, lack of long term efficacy, etc. Treatments that are especially effective often have pharmacological targets that make them a risk for abuse and severe dependence, such as tramadol, an opioid agonist for depression (Bumpus 2020)(Barber 2011) and benzodiazepines for anxiety (Shader & Greenblatt 1993). In this post I look at drugs which have pharmacological effects making them promising treatments for psychiatric disorders with higher efficacy, lower side effects, and low/no dependence.

The Problem of Downregulation

A major obstacle in treating psychiatric disorders long term is that treatments which are effective in the short term lead to compensatory downregulation of the pharmacological targets that provide the beneficial effects, making drugs lose their efficacy over time, and leading to a withdrawal syndrome of amplified symptoms if one discontinues taking the drug. For this reason, essentially all psychiatric drugs currently used in America and Canada have a withdrawal syndrome upon discontinuation, and the development of new drugs such as kappa-opioid antagonists for depression (Jelen et al. 2022) are burdened by this problem as well, having lower abuse potential but still producing withdrawal and a decline in efficacy over time. Selective serotonin reuptake inhibitors, while described as being effective only after a period of chronic administration, actually have an immediate effect on psychiatric symptoms (Griebel et al. 1999) as serotonin is anxiolytic, whereas the long term benefits come from upregulation of BDNF from chronic SSRI administration (Björkholm & Monteggia 2016), and SSRIs decrease serotonin over time, causing a withdrawal syndrome upon discontinuation (Bosker et al. 2010). For this reason, drugs which do not work by direct agonism or antagonism of a target to produce beneficial effects, and instead work through long term up/down regulation of targets are highly needed. 

NRF2 & Opioid Upregulation - Sulforaphane

The opioid system is strongly linked to mood related disorders, including borderline personality disorder, depression, social anxiety, and post traumatic stress disorder (Jelen et al. 2022)(Bandelow et al. 2010)(Lanius et al. 2019). Opioids are highly effective for treating depression (Bumpus 2020) and social anxiety & rejection sensitivity (Bershad et al. 2016), however the reduction in efficacy over time combined with severe withdrawal and addiction potential complicates their ability to be used as psychiatric medications (Jelen et al. 2022). Opioid upregulation is a topic which is under researched compared to upregulation of neurotransmitters like dopamine, however there is evidence of opioid upregulating mechanisms that do not require exposure to pain (e.g., opioid antagonism upregulates opioid signaling but acutely causes dysphoria) - one of these is through activation of NRF2, and sulforaphane - a compound occurring in broccoli and some other vegetables and sold as a dietary supplement with pharmacological activity as an NRF2 activator has been studied in relation to this. Sulforaphane has been demonstrated to have acute opioid-like effects on pain and anxiety, and to strongly potentiate the effects of opioid agonists like morphine (Redondo et al. 2017)(Wang & Wang 2017)(Ferreira-Chamorro et al. 2018)(Fu et al. 2021)(Ghazizadeh-Hashemi et al. 2021). Sulforaphane is demonstrated to upregulate mu-opioid receptors (Wang & Wang 2017)(Ferreira-Chamorro et al. 2018)(Fu et al. 2021), and activity of sulforaphane as a long term opioid upregulator in humans is supported by one study which showed an antidepressant effect which increased over time with repeated administration (Ghazizadeh-Hashemi et al. 2021). Upregulation of opioid receptors has been demonstrated as an effect of NRF2 agonists (Pol 2022). Overall, sulforaphane appears to be a promising treatment for opioid-related psychiatric disorders lacking many of the downsides of using an opioid agonist.

CREB & Dopamine Upregulation - Bromantane

Dopamine has been linked to psychiatric disorders such as social anxiety (Robinson et al. 2006), ADHD (Cortese et al. 2018), depression, and anhedonia (Cao et al. 2019). Current psychiatric drugs that target dopamine to increase its activity all act as agonists of dopamine receptors through increasing concentrations of dopamine or directly activating dopamine receptors, which leads to reduced efficacy over time, a “crash” from dopaminergic medications as they wear off, and a withdrawal syndrome from discontinuation, and furthermore have high abuse and addiction potential. Most dopaminergic psychiatric drugs also increase activity of norepinephrine significantly, which leads to side effects like anxiety, irritability, insomnia, increased heart rate, sweating, which dopamine does not produce itself (DeYoung 2013) etc - the effect on norepinephrine particularly making them poor for treating social anxiety as norepinephrine increases anxiety (DeYoung 2013). Bromantane is a drug that has been demonstrated to upregulate the expression of tyrosine hydroxylase and aromatic L-amino acid decarboxylase which are the enzymes responsible for synthesis of dopamine in the body, resulting in heightened dopamine levels acutely and long term without a dopamine “crash” and no withdrawal or dependence (Mikhaylova et al. 2007)(Iëzhitsa et al. 2010). As would be expected, bromantane actually reduces anxiety in humans unlike typical dopaminergic stimulants that increase anxiety (Voznesenskaia et al. 2010), and while has not been studied for ADHD, demonstrates cognitive enhancing effects (Morozov et al. 2000)(Viatleva et al. 2000) and it is sold as a dietary supplement, leading many to experiment with bromantane for treating various conditions, and is reported by users to improve ADHD symptoms (Bromantane - PsychonautWiki). The upregulation of the dopamine synthesizing enzymes is due to bromantane activating CREB (Mikhaylova et al. 2007).

Serotonin Upregulation & Dopamine Regulation - Bacopa

Serotonin and dopamine have opposing as well as shared effects on affect and behavior (Cloudfindings 2024a,b). Serotonin deficits and excessive or dysregulated dopamine are associated with mania (Andrade 2004)(Kassm & Naja 2018)(Berk et al. 2007), psychosis (Kapur & Remington 1996), antisocial behavior (Yildirim 2016)(Moore et al. 2002), hypersexuality & paraphilia (Cloudfindings 2024b), likely narcissism (Kastner-Bosek et al. 2021)(Rogoza et al. 2016), and likely eating disorders (Cloudfindings 2022). Bacopa monnieri is a herb that possesses pharmacological effects as an upregulator of serotonin synthesis via increasing expression of tryptophan hydroxylase (Rajathei et al. 2014), and also blunts dopamine release (Jash & Chowdary 2014). While suppressing dopamine often has many unwanted side effects, for individuals who have particular maladaptive expression of low serotonin/high dopamine symptoms, shifting the balance toward serotonin may have a normalizing effect that would not render an individual sexually dysfunctional or unmotivated. Bacopa has shown efficacy in treating anxiety & depression (Calabrese et al. 2008), antipsychotic effects in mice (Chatterjee et al. 2015), and efficacy in treating ADHD (Dave et al. 2014). Bacopa has an advantage over typical serotonergics in that it acts via upregulation of serotonin synthesis, however it is unclear if bacopa does produce a withdrawal syndrome, and it may have direct agonistic effects on serotonin in addition to upregulation of tryptophan hydroxylase. 

Glutamate Regulation - N-acetyl cysteine 

N-acetyl-cysteine is a compound sold as a dietary supplement and also used to treat overdose of acetaminophen, which acts as a regulator of glutamate and dopamine activity, having a balancing effect where glutamate is increased in parts of the brain where it's low, and decreased when its high (Berk et al. 2013). This effect of NAC makes it effective for treating a vast range of psychiatric disorders, especially disorders involving compulsive behavior, showing efficacy for treating OCD (Afshar et al. 2012), dermatillomania in which symptoms resolve completely with NAC treatment (Silva-Netto et al. 2014), addictions (Asevedo et al. 2014), positive, negative and cognitive symptoms of schizophrenia (Berk et al. 2008)(Yolland et al. 2020), social symptoms of autism (Lee et al. 2021), depression (Fernandes et al. 2016), and anxiety & anhedonia (Chakraborty et al. 2020). It is unclear if NAC can produce a withdrawal syndrome, however some users do report a withdrawal-like syndrome, though it is speculated that these symptoms may indicate NAC induced deficiency in vitamin B12, some users reporting recovery from the syndrome with supplementing B12. NAC may also produce emotional blunting as a side effect, which may be undesirable for some people. 

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