However, further studies with a larger sample size and extended follow-up is warranted to determine full reliability. Despite having apparent limited success in very early clinical studies [ 91 ], recent preclinical studies indicate that it may be more efficacious with regards to the modulating the affective aspects of nicotine intake. A study in rodents identified a decrease in conditioned responding to the nicotine CS and thus reducing incentive value of drug administered [ 92 ].
An analogue of imipramine, has also shown recent success preclinically [ 93 ]. This analogue was utilised due to the shared norepinephrine reuptake inhibition properties of bupropion and nortriptyline, but not their dopaminergic bupropion or serotonergic nortriptyline effects [ 94 - 96 ].
Previous studies assessed the effects of noradrenergic manipulations on alternative measures of nicotine dependence-related behaviours [ 97 ], with focus on nicotine self-administration, but not on the affective aspects of nicotine withdrawal. This study by Paterson et al. Due to the previous success of antidepressants in smoking cessation, and the common prescription of fluoxetine as main drug used to treat depression, it has been the focus of several trials for smoking cessation aids.
One multi-centre clinical trial tested fluoxetine hydrochloride, in addition to cognitive behaviour therapy sessions, in patients. Their study revealed enhanced quit rates associated with both 60mg and 30mg doses of fluoxetine.
These results suggest a modest, short-term effect of fluoxetine on smoking cessation but abstinence rates were not sustained in the long-term [ 98 ]. This may, however, not be due to lack of efficacy, but in the structure of the trial, and how the drug is administered and a real-world alternative for providing smoking cessation. A recent randomised, open-label clinical trial investigated the efficacy of sequential use of fluoxetine for smokers with increased depressive symptoms. The findings reveal that the best outcome for smoking cessation is when fluoxetine is prescribed before the target quit date [ 99 ].
In addition, a double-blind placebo-controlled trial, that investigated fluoxetine alongside nicotine patches and cognitive-behavioural group therapy, suggests that fluoxetine may also moderate withdrawal symptoms, despite not being manifested in improved smoking cessation rates. Additionally, it also showed that fluoxetine may also be considered if weight gain hinders smoking cessation and has been shown to improve both positive and negative mood states after quitting smoking [ , ].
A double-blind randomised experiment of smokers looked at the effects of the nicotine patch with or without paroxetine [ ].
Patients taking the drug reported a greater reduction in cravings and depressive symptoms. Evidence from rodent studies suggests that nicotine can exert anxiolytic effects via a serotonergic mechanism and this ability to diminish stress is a leading factor correlated with high relapse rates upon abstinence [ ].
Therefore, another study looked at the effects of paroxetine on physiological response to stress and smoking. The findings show that the drug reduced stress-induced increases in systolic and diastolic blood pressure in smokers.
However, the study stated that further examination is needed to determine the long term cardiovascular impact of taking such a drug [ ]. Sertraline is another SSRI antidepressant that has been investigated for smoking cessation characteristics. One trial tested sertraline in smokers with a history of depression [ ]. Sertraline reportedly lowered withdrawal symptoms like irritability, anxiety, cravings and restlessness.
However, abstinence rates after treatment were not statistically significant at 6-month follow-up. Another study verifies these findings by indicating that there was a significant effect of sertraline on post-quit Hamilton Depression Rating Scale scores but not on abstinence [ ]. This shows sertraline when given alone was ineffective as a cessation aid and would suggest that the drug only has antidepressant properties.
The combination of sertraline, buspirone and cognitive behavioural therapy has, however, shown optimal promotion of smoking cessation [ ]. It has been hypothesised that nicotine stimulates the release of neuronal serotonin.
Unusual reports of nausea with smoking suggested that nicotine may also increase serotonin release in the small intestinal nerve plexus. Enhanced levels of 5-HT by sertraline may cause nausea. An investigation of two case studies reporting a link between nausea and smoking showed that sertraline produced nausea in Sertraline may not actually stop people smoking but studies such as this implicate it as a negative reinforcement therapy in smoking cessation programs, much like disulfiram for alcohol dependence.
At low doses venlafaxine acts as a selective serotonin reuptake inhibitor SSRI , at medium doses the drug acts as a noradrenaline reuptake inhibitor NRI and at very high doses it has been seen to inhibit dopamine reuptake. A study concluded that there was no difference between abstinence rates for venlafaxine and a placebo after 8 weeks and that the drug induced more side-effects than the placebo [ ].
Another clinical trial tested venlafaxine against a placebo in smokers [ ]. At a twelve-month follow-up, there was reportedly no significant increase in abstinence amongst the venlafaxine group. These findings of not being able to aid long term abstinence of tobacco smoking has been verified by other trials, however, this drug has shown potential in reducing the total number of cigarette packs consumed in conjunction with nicotine replacement and behavioural counselling [ ].
Furthermore, two groups of animals, one exposed to tobacco smoke and the other not exposed to tobacco smoke, were subjected to Porsolt's test for testing antidepressant activity and Morris Water Maze Test for spatial memory function. In the group exposed to tobacco smoke, joint administration of venlafaxine and nicotine induced a significant reduction of immobility as compared to the control and nicotine groups.
In the Morris Water Maze Test, single and chronic administration of venlafaxine, alone and with nicotine, showed reduced of escape latencies and lower numbers of crossed quadrants in both exposed and non-exposed rats, which indicates improved performance.
This indicates an alternative approach to smoking cessation by antidepressant use that targets cognitive dysfunction associated with nicotine withdrawal as well as mood alteration [ ]. In terms of interpersonal variation on treatment response, a genetic mutation in the dopamine D2 receptor gene has been correlated with altered efficacy of venlafaxine. Results like these suggest a role of genetic variation in determining how individuals will react to certain drug therapies. Although no clinical trials have been performed with reboxetine, a noradrenaline reuptake inhibitor, one pre-clinical study investigated whether reboxetine could modify noradrenaline, dopamine, serotonin or acetylcholine transporters in rat brain.
They concluded that reboxetine potently and selectively inhibits noradrenaline uptake in the hippocampus of rats, four times more than dopamine and serotonin uptake transporters are inhibited. The drug did not appear to alter the function of the three neurotransmitters but it may modify the neurotransmitter transporters and this could explain the delay of its effects. Furthermore, the results indicated that noradrenaline may be more important in nicotine reward than first thought, as previously seen with imipramine.
The study concluded that considering the concordance of smoking behaviour and mood disorders, reboxetine could potentially be an alternative cessation aid [ 74 ]. Subsequently, it has been shown that reboxetine blocked responses induced by nicotine conditional stimuli and nicotine-induced hyperactivity [ 92 ]. Since the discovery of monoamine oxidase MAO inhibition and nAChR both increase synaptic monoamines and that tobacco smoke contains non-nicotinic compounds that inhibit MAO, it has been suggested that MAO inhibitors may be another drug class used for treatment of tobacco smoking [ , ].
As a proof-of-concept, moclobemide MAO A inhibitor was investigated in a long-term placebo-controlled trial as a smoking cessation aid [ ]. Subjects were given mg of the drug every day for one week prior to quit and for two months after.
This was then decreased to mg per day for another month. They reported a significant decrease in smoking with the drug at 6 months but not at 12 months. This study did not show the drug to have any effect on withdrawal from nicotine either. With regards to MAO-B inhibitors, selegiline was investigated against placebo in a randomised controlled trial, of smokers, for effects on smoking cessation [ ].
Patients were given 2. Selegiline also appeared to reduce nicotine cravings at 4 weeks. These findings have been verified by other studies, showing that inhibition of MAO-B successfully increases abstinence and that this enzyme places a significant role in smoking behaviour and cessation. A preliminary placebo-controlled trial of selegiline hydrochloride in 40 smokers also showed some positive results in smoking cessation [ ].
Overall, trials of selegiline as a smoking cessation agent have produced some promising results. Selegiline appears to reduce cravings and decrease the number of cigarettes smoked by reducing threshold levels of smoking satisfaction [ ]. From these findings, it may be suggested that by pharmacologically reducing MAO-B activity during early stages of abstinence, it may help long-term cessation rates.
Tryptophan is a precursor for the neurotransmitter serotonin. It is regarded as to having antidepressant properties and is thought to elicit its effects due to its ability to increase brain serotonin levels [ ]. This is also inferred when reducing levels of serotonin by inducing acute tryptophan depletion ATD in nicotine-dependent schizophrenic patients and controls.
This showed that ATD increased the desire to smoke in both groups by intensifying psychopathological symptoms [ ]. This suggests an important role of serotonin in both smoking and mood. It also implicates the tryptophan supplementation as a potential smoking cessation method. However, there has been contradicting evidence from a randomised double-blind placebo-controlled trial on tryptophan depletion and the modulation of smoking withdrawal and nicotine action [ ].
This study shows that although tryptophan depletion resulted in reduced levels of serotonin in the brain, it did not appear to affect nicotine withdrawal symptoms such as mood or electroencephalographic EEG readings. A short-term study using tryptophan as a cessation aid revealed that the serotonin enhancing actions of tryptophan and a high carbohydrate diet could relieve nicotine withdrawal symptoms [ ].
After 2 weeks, subjects treated with tryptophan smoked less cigarettes per day as well as reports of reduced reports of anxiety and withdrawal symptoms. In addition to this, a preclinical study showed tryptophan rich food supplementation had reduced nicotine withdrawal-induced depression and anxiety in rats, using the Elevated Plus Maze, Open Field Test and Forced Swim Test [ ]. This further underlines the potential of tryptophan or tryptophan based substances as a possible adjunct therapy for nicotine cessation.
There is an intricate and diverse link between depression and smoking dependence. It includes neurobiological, genetic and environmental aspects which overlap one another to produce a complex condition which is difficult to treat. The variations in individuals potentially determine how effective different antidepressant agents are for smoking cessation. An extensive range of antidepressant drugs have been evaluated in smoking cessation trials, compounds that exhibit diverse pharmacological targets.
These trials were largely compared against nicotine replacement therapy for reference purposes. Despite the clinical success of antidepressants such as bupropion and nortriptyline, the development and subsequent success of varenicline has diminished interest in further developing antidepressants as potential smoking cessation aids.
Consequently, varenicline is stated to be the most efficacious smoking cessation aid available clinically, with the mechanism of action not fully understood. However, it has been postulated that the drug works by attenuating the reinforcing properties of nicotine and thus, reduces tobacco intake.
In addition, withdrawal from nicotine administered via osmotic minipumps has shown to impair attentional processes measured within the 5-choice serial reaction time task that was time-dependent which are similar in nature to the disturbances in attention reported by smokers during withdrawal [ , ].
Furthermore, nicotine and other subtype nAChR agonists have been demonstrated to improve sustained and divided aspects of attention using the five-choice serial reaction time task [ ]. Nicotine administered both acutely and sub-chronically in normal non-compromised rats improves performance in the attentional set shifting test [ ]. Corroboratively, there is clinical and preclinical evidence that shows that varenicline also can have a positive effect on cognitive performance upon nicotine withdrawal , ].
These neurocognitive models propose that targeting the impaired upper cortical functions by pharmacological means may be more effective than simply attenuating the reinforcing properties of nicotine in the VTA and N. Thus, several researchers are repositioning the use of commonly available cognitive enhancers as potential treatment for tobacco withdrawal. Due to the antidepressant and cognitive restorative properties of varenicline, there may be a requirement for a new generation of antidepressants that can provide multiple actions; manage the underlying depression and facilitate smoking cessation.
Effective strategies for smoking cessation include targeting the impaired cognitive function and emotional states during the process of withdrawal with nicotinic compounds along with antidepressants as adjuncts.
These forms of treatment will require optimisation as smokers with depression are more nicotine dependent and are more likely to have lower quit rates, and thus an ever-increasing strain on health services globally. There is strong need for systematic approaches to smoking cessation, and psychiatric treatment.
Researchers have found, these conditions are more complex than targeting one pathway and expecting substantial drug efficacy.
The suggested approach of targeting multiple pathways to address specific symptoms may allow for higher efficacy and, if successful, better translation to numerous other psychiatric and neurological conditions. The authors declare no conflict of interest, financial or otherwise. National Center for Biotechnology Information , U. Journal List Curr Neuropharmacol v. Curr Neuropharmacol.
Published online May. Author information Article notes Copyright and License information Disclaimer. This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.
This article has been cited by other articles in PMC. Abstract Background Before the advent of varenicline, antidepressant drugs were reported to exhibit better clinical efficacy than nicotine replacement therapy as smoking cessation aids. Objectives This review article will evaluate the various theories relating to the use of antidepressant drugs as smoking cessation aids and the underlying mechanisms link tobacco smoking and depression to explain the action of antidepressants in smoking cessation.
Keywords: Antidepressant, smoking cessation, nicotine, withdrawal, dependence, bupropion. Introduction 1. Health Impact Addiction to tobacco smoking is the most prevalent preventable cause of disease, morbidity and mortality across the world. Mechanism of disorder: Acute exposure It is well accepted that the DA-releasing properties of nicotine in the nucleus accumbens has been shown to underlie its primary reinforcing effects that are qualitatively similar to other strongly reinforcing drugs such as cocaine, amphetamine and morphine [ 7 , 8 ].
Mechanism of disorder: Chronic exposure Upon long exposure of nicotine to the brain, neuronal adaptations develop which is believed to be associated with learning of environmental cues linked with receiving the drug.
Brain regions associated with nicotine addiction With specific regards to nicotine addiction, the dopamine reward pathway is coupled with activity from numerous brain regions which are believed to contribute to nicotine dependence [ 15 ]. Comorbidity of psychiatric disorders and addiction Epidemiological studies have indicated that the occurrence of nicotine dependence is significantly higher in those with certain psychiatric illnesses [ 35 ]. Brain regions changed in psychiatric disorders Confluently, the brain regions that are related to substance abuse behaviour with nicotine are also implicated in numerous psychiatric disorders.
Drug trials with antidepressants for smoking cessation The atypical antidepressant, bupropion hydrochloride, in by Hurt and colleagues, was reported to have successful efficacy by way of smoking cessation in a randomised, double-blinded, placebo-controlled trial. Tricyclic antidepressants 8. Nortriptyline After the success of bupropion, further investigations have been carried out on other types of antidepressants.
Doxepin This serotonergic tricyclic antidepressant has only briefly been described as a smoking cessation aid. Imipramine Despite having apparent limited success in very early clinical studies [ 91 ], recent preclinical studies indicate that it may be more efficacious with regards to the modulating the affective aspects of nicotine intake. Selective serotonin reuptake inhibitors SSRI 9. Fluoxetine Due to the previous success of antidepressants in smoking cessation, and the common prescription of fluoxetine as main drug used to treat depression, it has been the focus of several trials for smoking cessation aids.
Paroxetine A double-blind randomised experiment of smokers looked at the effects of the nicotine patch with or without paroxetine [ ]. Sertraline Sertraline is another SSRI antidepressant that has been investigated for smoking cessation characteristics.
Venlafaxine At low doses venlafaxine acts as a selective serotonin reuptake inhibitor SSRI , at medium doses the drug acts as a noradrenaline reuptake inhibitor NRI and at very high doses it has been seen to inhibit dopamine reuptake.
Noradrenaline reuptake inhibitors Reboxetine Although no clinical trials have been performed with reboxetine, a noradrenaline reuptake inhibitor, one pre-clinical study investigated whether reboxetine could modify noradrenaline, dopamine, serotonin or acetylcholine transporters in rat brain. Monoamine oxidase inhibitors Moclobemide Since the discovery of monoamine oxidase MAO inhibition and nAChR both increase synaptic monoamines and that tobacco smoke contains non-nicotinic compounds that inhibit MAO, it has been suggested that MAO inhibitors may be another drug class used for treatment of tobacco smoking [ , ].
Selegiline With regards to MAO-B inhibitors, selegiline was investigated against placebo in a randomised controlled trial, of smokers, for effects on smoking cessation [ ]. Tryptophan Tryptophan is a precursor for the neurotransmitter serotonin. Discussion There is an intricate and diverse link between depression and smoking dependence. Conclusion There is strong need for systematic approaches to smoking cessation, and psychiatric treatment.
Consent for Publication Not applicable. Acknowledgements Declared none. My withdrawal symptoms mimic those of when I forget to take the effexor. Help or advice would be appreciated.
Guest over a year ago You think you have problems quitting smoking? Wait until you try quitting the Effexor. Better smoke now and get a prescription to wean you off that drug as this is one bad drug to be hooked on. No one told us this, please read all that you can in the www. I am also on Topamax all for pain management for back injury. Here is my layman's partial interpretation of what might have caused my foul mood: As I understand it, nicotine affects the level of norepinephine in the brain perhaps the main reason people continue to smoke.
As changes in nicotine blood levels occur due to smoking cessation activities, norepinephine levels are also affected at least temporarily. As an aside, even if nicotine blood levels are held constant, the particular type of nicotine delivery system i. I might be wrong on this one but it sure seemed like it to me? As I had fully anticipated, based on my prior experiences with other SSRI's Prozac and Paxil , my rage mood disappeared on the first day of the low dose Zoloft trial.
However, even at this extremely low dose, Zoloft rendered me totally unmotivated, void of enthusiasm, and emotionless after just one week of the trial. This also did not surprise me since Paxil and Prozac had the same effect. SSRI's turn me into what my wife affectionately refers to as her "do nothing boy". So I took myself off the Zoloft and within a day was experiencing SSRI withdrawal which, for me, includes what I call a "one-quart-low serotonin depression" lasting about a week this time.
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The nicotine patch and bupropion, a medication used to reduce nicotine cravings, are two commonly used smoking cessation aids. Both have been shown to reduce smoking rates, however, the effectiveness of combining the two treatments has not been widely examined. This study will evaluate the effectiveness of the nicotine patch combined with bupropion at reducing smoking rates among younger, low-income, and minority individuals.
Detailed Description:. Drug Information available for: Nicotine tartrate Bupropion hydrochloride Bupropion Nicotine polacrilex.
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